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HPN November 2016

Issue 32

HOSPITAL PROFESSIONAL NEWS IRELAND Ireland’s Dedicated Hospital Professional Publication

IN THIS ISSUE: NEWS: Junior Doctors threaten strike action Page 4

As an adjunct to diet and exercise for appropriate patients with type 2 diabetes



CONFERENCE: Hospital Consultant's Association Page 12 CLINICAL: 21st Congress European Haematology Association Page 16 REPORT: Getting it right says HMI Page 22



CPD: Parkinson's Disease Page 23

Legal Category: POM. Marketing Authorisation Holder: Merck Sharp & Dohme Limited, Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, UK. Date of revision: January 2016. © Merck Sharp & Dohme Ireland (Human Health) Limited, 2016. All rights reserved. Further information is available on request from: MSD, Red Oak North, South County Business Park, Leopardstown, Dublin D18 X5K7 or from Date of preparation: October 2016.

Red Oak North, South County Business Park, Leopardstown, Dublin 18, D18 X5K7 Ireland

4412_JMT_JAN_A5_ReminderAd_v.indd 1


Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to MSD (Tel: 01-299 8700)

19/10/2016 09:46

FEATURE: Management of Type 2 Diabetes Page 28

That Enstilar moment ®

Discover what the NEW foam spray Enstilar can do for your plaque psoriasis patients

Extraordinary Delivery

Visit Abbreviated Prescribing Information for Enstilar® 50 micrograms/g + 0.5 mg/g cutaneous foam Please refer to the full Summary of Product Characteristics (SmPC) ( before prescribing. Indication: Topical treatment of psoriasis vulgaris in adults. Active ingredients: 50 µg/g calcipotriol (as monohydrate) and 0.5 mg/g betamethasone (as dipropionate). Dosage and administration: Apply by spraying onto affected area once daily. Recommended treatment period is 4 weeks. The daily maximum dose of Enstilar should not exceed 15 g, i.e. one 60 g can should last for at least 4 days. 15 g corresponds to the amount administered from the can if the actuator is fully depressed for approximately one minute. A twosecond application delivers approximately 0.5 g. As a guide, 0.5 g of foam should cover an area of skin roughly corresponding to the surface area of an adult hand. If using other calcipotriol-containing medical products in addition to Enstilar, the total dose of all calcipotriol-containing products should not exceed 15 g per day. Total body surface area treated should not exceed 30%. Safety and efficacy in patients with severe renal insufficiency or severe hepatic disorders have not been evaluated. Safety and efficacy in children below 18 years have not been established. Shake the can for a few seconds before use. Apply by spraying, holding the can at least 3 cm from the skin, in any orientation except horizontally. Spray directly onto each affected skin area and rub in gently. Wash hands after use (unless Enstilar is used to treat the hands) to avoid accidentally spreading to other parts of the body. Avoid application under occlusive dressings since systemic absorption of corticosteroids increases. It is recommended not to take a shower or bath immediately after application. Contraindications: Hypersensitivity to the active substances or any of the excipients. Erythrodermic and pustular psoriasis. Patients with known disorders of calcium metabolism. Viral (e.g. herpes or varicella) skin lesions, fungal or bacterial skin infections, parasitic infections, skin manifestations in relation to tuberculosis, perioral dermatitis, atrophic skin, striae atrophicae, fragility of skin veins, ichthyosis, acne vulgaris, acne rosacea, rosacea, ulcers and wounds. Precautions and warnings: Adverse reactions found in connection with systemic corticosteroid treatment, e.g. adrenocortical suppression or impaired glycaemic control of diabetes mellitus, may occur also during

topical corticosteroid treatment due to systemic absorption. Application under occlusive dressings should be avoided since it increases the systemic absorption of corticosteroids. Application on large areas of damaged skin, or on mucous membranes or in skin folds should be avoided since it increases the systemic absorption of corticosteroids. Due to the content of calcipotriol, hypercalcaemia may occur. Serum calcium is normalised when treatment is discontinued. The risk of hypercalcaemia is minimal when the maximum daily dose of Enstilar (15 g) is not exceeded. Enstilar contains a potent group III-steroid and concurrent treatment with other steroids on the same treatment area must be avoided. Skin on the face and genitals are very sensitive to corticosteroids. Enstilar should not be used in these areas. Instruct the patient in the correct use of the product to avoid application and accidental transfer to the face, mouth and eyes. Wash hands after each application to avoid accidental transfer to these areas. When lesions become secondarily infected, they should be treated with antimicrobiological therapy. However, if infection worsens, treatment with corticosteroids should be discontinued. When treating psoriasis with topical corticosteroids, there may be a risk of rebound effects when discontinuing treatment. Medical supervision should therefore continue in the posttreatment period. Long-term use of corticosteroids may increase the risk of local and systemic adverse reactions. Treatment should be discontinued in case of adverse reactions related to long-term use of corticosteroid. There is no experience with the use of Enstilar in guttate psoriasis. During Enstilar treatment, physicians are recommended to advise patients to limit or avoid excessive exposure to either natural or artificial sunlight. Topical calcipotriol should be used with UVR only if the physician and patient consider that the potential benefits outweigh the potential risks. Enstilar contains butylhydroxytoluene (E321), which may cause local skin reactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes. Pregnancy and lactation: There are no adequate data from the use of Enstilar in pregnant women. Enstilar should only be used during pregnancy when the potential benefit justifies the potential risk. Caution should be exercised when prescribing Enstilar to women who breast-feed. The patient should be instructed not to use Enstilar on the breast when breast-feeding. Side effects: There are no common adverse reactions based on the clinical studies. The most frequently reported adverse reactions are application site

reactions. Uncommon (≥1/1,000 to <1/100): Folliculitis, hypersensitivity, hypercalcaemia, skin hypopigmentation, rebound effect, application site pruritus, application site irritation. Not known frequency: Hair colour changes. Calcipotriol: Adverse reactions include application site reactions, pruritus, skin irritation, burning and stinging sensation, dry skin, erythema, rash, dermatitis, psoriasis aggravated, photosensitivity and hypersensitivity reactions, including very rare cases of angioedema and facial oedema. Systemic effects after topical use may appear very rarely causing hypercalcaemia or hypercalciuria. Betamethasone (as dipropionate): Local reactions can occur after topical use, especially during prolonged application, including skin atrophy, telangiectasia, striae, folliculitis, hypertrichosis, perioral dermatitis, allergic contact dermatitis, depigmentation and colloid milia. When treating psoriasis with topical corticosteroids, there may be a risk of generalised pustular psoriasis. Systemic reactions due to topical use of corticosteroids are rare in adults; however, they can be severe. Adrenocortical suppression, cataract, infections, impaired glycaemic control of diabetes mellitus, and increase of intra-ocular pressure can occur, especially after long-term treatment. Systemic reactions occur more frequently when applied under occlusion (plastic, skin folds), when applied on large areas, and during long-term treatment. Precautions for storage: Do not store above 30°C. Extremely flammable aerosol. Pressurised container. May burst if heated. Protect from sunlight. Do not expose to temperatures exceeding 50°C. Do not pierce or burn, even after use. Do not spray on an open flame or other ignition source. Keep away from sparks/open flames. No smoking. Legal category: POM. Marketing authorisation number and holder: PA 1025/5/1. LEO Pharma A/S, Ballerup, Denmark. Last revised: May 2016 Further information can be found in the Summary of Product Characteristics or from: LEO Pharma, Cashel Road, Dublin 12, Ireland. e-mail: ® Registered trademark MAT-04854 Date of preparation: September 2016

Reporting of Suspected Adverse Reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, Website:, e-mail: Adverse events should also be reported to Drug Safety at LEO Pharma by calling +353 1 4908924 or e-mail




HPN November 2016 Issue 32



Professor Patrick Plunkett receives 6th William Stokes Award P5


Kelly Jo Eastwood There has been much response to the Government’s announced budget. Not much of it positive when it comes to health expenditure.

Breakdown of the 2016 Budget Announcement P8


Huge numbers needed to meet hospital bed crisis says IHCA P12 Lack of adequate facilities for Stroke patients P38

Dr Tom Ryan, IHCA President, said that the cumulative cuts of ¤1.7 billion in health sector capital expenditure since 2008 have resulted in an acute health infrastructure that is crumbling, with many hospitals attempting to treat patients with inadequate capacity and equipment that is increasingly obsolete. He said that it is disappointing that the 2017 Budget has not allocated significantly increased capital funding to address the critical acute hospital and mental health capacity deficits which are preventing consultants and frontline staff from treating patients without delays.


Issues with HIV adherence P47 Regulars CPD: Parkinson's Disease P23 12

Feature: Rheumatoid Arthritis P43

Clinical Profiles: P50 38

Hospital Professional News is Circulated to all independent, multiple and hospital pharmacist, pre reg pharmacists, students pharmacy student’s offi cial bodies, government officials and departments, Pharmacy Managers, Manufactures, Wholesalers. Buyers of pharmacy groups and healthcare outlets. Circulation is free to all pharmacists Subscription rate for Hospital Pharmacy News ¤60 plus vat per year All rights reserved by Hospital Professional News. All material published in Hospital Professional News is copyright and no part of this magazine may be reproduced, stored in a retrieval system of transmitted in any form without written permission. Pharmacy Communication Ireland have taken every care in compiling the magazine to ensure that it is correct at the time of going to press, however the publishers assume no responsibility for any effects from omissions or errors.

MANAGING DIRECTOR Natalie Maginnis EDITOR Kelly Jo Eastwood 00447876548989 ACCOUNTS Rachel Wilson

Meanwhile, the Private Hospitals Association has said they believe the announcement of a ‘fresh approach’ to waiting lists is to be welcomed. The Minister has secured at least ¤70m over the next two years to treat patients who have been on waiting lists for unacceptably long periods. The funding will be administered by the National Treatment Purchase Fund (NTPF) which has a track record in procuring patient care efficiently.

Event Gallery: P48

PUBLISHER IPN Communications Ireland Ltd Clifton House, Lower Fitzwilliam Street, Dublin 2 (01) 669 0562

The Irish Hospital Consultants Association (IHCA), while welcoming the increase in next year’s health budget, has expressed its serious concern that this will not be sufficient to address the growing waiting lists and increased patients demand for healthcare due to demographic and other reasons. In particular, the 2017 Health Budget fails to address the critical capacity constraints that have arisen from years of cuts in acute hospital and health sector capital expenditure.


PHA Chief Executive, Simon Nugent, says that by securing and announcing funding for 2018 as well as 2017 the Minister has sent a clear signal – to both patients and private hospitals – that he has a long term strategy for tackling waiting lists. A multi annual approach allows the PHA’s members to plan ahead, maximising the number of patients that can be treated as quickly as possible – ensuring best value for money and reducing the burden on the taxpayer. You can read more about this and other comments on page 8. Next month’s issue of Hospital Professional News will be a bumper edition to round-off the year in style. We will once again carry our annual Hospital Professional Top 100, as well as in-depth case study profiles of our HPN Award Winners 2016.

Mobile: 0044 7765 236886 CONTRIBUTORS

Marsha L. Tracey | Michael Gilmartin Kate O’Neill | Anthony P. Fitzgerald Sheena M. McHugh Claire M. Buckley Ronan J. Canavan Patricia M. Kearney Douglas James Veale Ursula Fearon

DESIGN DIRECTOR Ian Stoddart Design HospitalProfessionalNews

Furthermore, we will have a look ahead at 2017 with contributed articles from leading professional bodies including the Hospital Pharmacists Association of Ireland, HPRA and the Irish Pharmaceutical Healthcare Authority. You won’t want to miss it!

HOSPITAL PROFESSIONAL NEWS IRELAND Ireland’s Dedicated Hospital Professional Publication HPN • November 2016

4 News

Effective commissioning tool needed says HIQA The Healthcare Information and Quality Aurhority (HIQA) has recommended that the HSE should introduce an effective commissioning model at local and national levels that promotes and addresses the needs of people using services, as well as effective service configuration. Speaking at the recent All Ireland Midwifery Conference, told delegates that a HIQA submission to Oireachtas Committee on the future of healthcare in Ireland asserted that as part of the wider strategic review, Government should consider the introduction of a robust national commissioning model. “In the context of maternity services I believe that such a model can have a positive impact

on effective service provision, governance, financial efficiency and in improving the quality and safety of services,” he said. “Commissioning arrangements explicitly define and separate the roles of purchaser and provider of services; currently both of these functions are usually performed by the Health Service Executive (HSE). An effective commissioning body is responsible for purchasing health and social care services from providers. Procurement is always based on an agreed strategy, assessed need, best available evidence of service efficacy, value for money, and the capacity and capability to deliver a safe and effective service. While cost is, of course, important, quality and the delivery of safe services should be the primary goals.

HIQA CEO, Pheilim Quinn

resources. While procurement decisions are made locally, the service itself is delivered in the most effective, efficient manner, whether in the community or at a national level.

“Commissioning frameworks can provide for national, regional and local procurement arrangements that are person-centred and address local needs. This facilitates a focus on the health and wellbeing of local people and on achieving the best possible outcomes within available

“A national commissioning model would contribute to effective medium- to long-term planning by gathering evidence of current and future service needs. It would also optimise service configuration based on sound strategic planning. The introduction of a standardised framework to commission services would help, by way of example with the implementation of national clinical care programmes and strategies such as the National Maternity Strategy,” he added.

Hospital inspections to improve medication use The HIQA has announced that it is commencing inspections in public acute hospitals to improve patient safety related to medication usage. Phase one of the medication safety monitoring programme will be to conduct one day on-site announced inspections. Hospitals will be notified of an intention to inspect in writing 10 working days in advance. “HIQA will be reviewing medication safety practices in public acute hospitals in Ireland. Hospitals should already have structures in place for medication safety to standardise practices and strive to develop a culture of safety,” said Ms Aoife Lenihan lead inspector on the medication safety monitoring programme. “HIQA inspections will interview staff, speak with patients, observe clinical areas and review documentation in relation to this to gather a comprehensive oversight of medication practices.” A phased approach for monitoring medication safety in public acute hospitals will commence. The first phase will initially focus on the fundamental governance and structure requirements to support a medication safety programme. “Medications are the most commonly used intervention in healthcare, and advances in medication usage continue to play a key role in improving patient treatment success,” said Ms Aoife Lenihan, “However, where medicines are used, the potential for error, such as in prescribing, administering or monitoring, also exists. Medication safety has been identified by a number of bodies in Ireland as a key focus for improvement and it is estimated that on average, at least one medication error per hospital patient occurs each day.”

Junior Doctors threaten strike action With thousands of gardaí and teachers preparing to stage work stoppages, Ireland’s Doctors are the latest group to warn of strike action as pressure on the Government over public service pay reaches crisis levels. The Irish Medical Organisation (IMO) are to take the Government to court over the unilateral abolition of a ¤3,000 living-out allowance for non-consultant doctors appointed since 2012. It said the money was not paid, despite provision for it remaining in contracts with employers. November 2016 • HPN

It is understood the health service has forecast that the State’s potential liability, if it loses the case, could be up to ¤120 million. The IMO said attempts to resolve the row through negotiations had been rebuffed by the Government and industrial action was now being considered. In a statement, the Irish Medical Organisation said, “The payment of a Living Out Allowance to NCHDs is a contractual right under the NCHD Contract which formed part of a Settlement Agreement reached in the High Court in 2010 between the HSE and the IMO.

“This payment was unilaterally removed in 2012 from all new entrant NCHDs despite the fact that it remained in the signed contract between the employer and the NCHD. The IMO and its NCHD members are disappointed that doctors are being forced by the State, for the third time, to take legal action to enforce a written contract.” Dr Paddy Hillery Chair of the NCHD Committee said that “it appears this Government do not want to deal fairly with doctors. Our members core duty is to their patients and while we

have endeavoured to explore all avenues to have this resolved we will now also have to consider industrial action up to and including strike action. “As late as last week we wrote to the Minister for Health to enter talks to resolve the matter but we have received no response. Doctors are demoralised with their working environments and it seems that this Government are happy to preside over the growing emigration of our highly trained doctors to countries that value them and honour legally binding contracts.”


Medicines Agreement on course to save over ¤140m The new pricing Agreement between the Irish Pharmaceutical Healthcare Association (IPHA) and the State which was finalised in July, is on course to save the State over ¤140 million in its first year. Following an analysis of the 948 separate product price changes as listed by the HSE, IPHA is confirming the annual total value of the price reductions since August 1st across all of the IPHA products is on track to provide savings of ¤78.4m annually.

These reductions are due to price realignments and off-patent products facing competition. In addition, an estimated ¤65m in rebates payable by IPHA members to the HSE would bring the total IPHA saving to the State to over ¤140 million in the first 12 month period of the Agreement. “The central purpose of the Agreement is to ensure medicines are supplied at reasonable prices for Ireland and that savings are generated enabling new, innovative medicines to be made available

to Irish patients. The policy goal of providing new medicines to patients is as important as savings, and IPHA will monitor this carefully. Patients and their doctors rightly expect that savings would be applied to providing new medicines to them as quickly as possible,” said Oliver O’Connor, Chief Executive of IPHA. IPHA welcomes indications that the HSE’s intends is to apply the same price cuts and rebates to non-IPHA companies from 1st November, leading

to further savings. It has also been established practice that manufacturers of certain generic products would also face price cuts after an IPHA Agreement and IPHA looks forward to confirmation of this. Coupled with 30% price reductions as biologic products losing patent-protection face competition from biosimilars, the IPHA projection of ¤785 million in total savings under the Agreement is on course.

William Stokes Award for Professor Plunkett Professor Patrick Plunkett was recently awarded the 6th annual William Stokes Award at a ceremony in St James’s Hospital. Professor Plunkett, who was nominated for the award by his colleagues for his contribution to the field of Emergency Medicine, recently retired from his role as the Medical Director of St James’s Hospital after a 28 year-long career with the hospital. A graduate of UCD, Professor Plunkett was appointed Consultant in Emergency Medicine in St James’s Hospital in 1988. He is the Founding Fellow of the Faculty of Accident and Emergency Medicine in Ireland and was on the Education and Examination Committee of this faculty for over 20 years. Professor Plunkett was appointed Medical Director of the Hospital in 2015 until his recent retirement.

Lorcan Birthistle, CEO, St James's Hospital, Professor Plunkett, Health Minister Simon Harris, Paul Donnelly, Chairman, St James's Hospital and Professor Gaye Cunnane, Director of Post-Graduate Education, St James’s Hospital

Clinical Pharmacy and Medicines Production The European Association of Hospital Pharmacists (EAHP) has launched its 2016 survey of practice, aimed at assisting the implementation of the European Statements of Hospital Pharmacy across its 35 member countries. The survey of practice provides the latest insights into the extent to which the vision for hospital pharmacy, represented by the European Statements, is being realized, and where the greatest

challenges and obstacles requiring concerted attention reside. Working in partnership with Keele University's (United Kingdom) Centre for Medicines Optimisation, the results from the survey illuminate where national health systems experience common difficulties in achieving best practices in hospital pharmacy, and therefore give assistance to how EAHP can best pinpoint

the fulfillment of its practice development mission. The six areas of the European Statements of Hospital Pharmacy are surveyed over a two year cycle, with the 2016 survey giving attention to Sections 1 (Governance), 3 (Production and Compounding) and 4 (Clinical Pharmacy services). The 2015 survey addressed: Selection, procurement and distribution; patient safety and quality assurance; and, Education

and research. Amongst its findings were that the most challenging statements to achieve across these areas include those related to: publication of research; management of medicines shortages; and use of computerized decision support systems. The 2016 survey is now in the process of distribution to hospitals across Europe and responses are encouraged by the deadline of 1st November.

HPN • November 2016

6 News

NOR-SWITCH study supports switching to biosimilar from originator At the United Gastro-Enterology (UEG) week in Vienna, the NOR-SWITCH results were presented highlighting that the physician-led switching between medicines containing the originator and biosimilar (CT-P13) versions of infliximab led to the absence of statistical difference in patient outcomes. This result is consistent with the fact that biosimilar medicines are approved to be medically interchangeable with their reference product, under the supervision of a clinical decisionmaker, so that individual patient factors can be duly taken into account (Position Paper). The NOR-SWITCH study is the largest such study to date and its results reinforce the available positive clinical evidence gathered with the use of biosimilar medicines in the last decade in Europe. While there is a large number of ongoing physician-led switching and observational studies involving biologic medicines (originator and biosimilar), it is essential to highlight the uniqueness of the Norwegian framework in which this study was performed: the NOR-SWITCH study forms an integral part of a wider policy framework from the Norwegian government which involved all concerned stakeholders, including patients’ representatives, in the introduction of biosimilar medicines in clinical practice. The study showed that patients’ outcomes were not inferior when switched from this one biologic to a biosimilar. The Irish Pharmaceutical Healthcare Authority (IPHA) has

welcomed the development of biosimilar medicines. ‘They create competition and provide savings in the healthcare budget. IPHA member companies themselves have brought biosimilar medicines to Ireland and will continue to do so,’ says the organisation. NOR-SWITCH is one step in investigating the use of biosimilar medicines. It is specific to the effects of this one medicine, infliximab. As biosimilar medicines are neither identical to the originator nor to other biosimilars, the results of the NOR-SWITCH study pertain only to the set of circumstances set out in the study. They are not applicable more generally to biologic and biosimilar medicines other than the two products concerned. In addition, the study looked at a single change of product (from the originator product to the biosimilar) and not at multiple changes between products. NORSWITCH therefore does not demonstrate that the products are interchangeable. “The decision to switch to a biosimilar should always be a clinical decision made by the treating physician, on an individual patient basis, supported by scientific evidence, and with patient awareness,” Oliver O’Connor, CEO with IPHA told Hospital Professional News.

Continued development of biologic medicines, including biosimilar medicines, creates increased choice for patients and clinicians and increased commercial competition and savings to the State. given that the medicines involved are not interchangeable.” “Continued development of biologic medicines, including biosimilar medicines, creates increased choice for patients and clinicians and increased commercial competition and savings to the State.” As part of the recently completed Framework Supply Agreement with the State, IPHA members agreed to provide a 30% reduction on the price of original biologic medicines when a biosimilar alternative becomes available. This means that the State can immediately make savings to reinvest in

treating new patients or providing new medicines. It also means that patients and clinicians can continue to use the original brand at the reduced price. Adrian van den Hoven, Medicines for Europe Director General commented, “This study is part of the growing body of real world evidence available on EU approved biosimilar medicines which provide alternative treatment options for both physicians and patients in five key therapeutic areas. It reinforces the Biosimilar Medicines Group efforts to ensure acceptance of biosimilar medicines through education and real world evidence gathering.”

“In Ireland, doctors may prescribe biologics and biosimilars, and switch if they judge that clinically appropriate. However, by law, it is not permitted for a pharmacist to substitute or switch a doctor’s prescription on biologics or biosimilars. This is appropriate,

Date for your Diary The Inaugural Biosimilars 360° Symposium event will be held next month in the Royal College of Physicians, Dublin. Leading experts from Ireland and around Europe will be on hand to present the latest scientific and clinical research and developments in biosimilars, in a unique interactive environment. The Symposium will also feature an innovation lounge with oculus rift headsets and digital skeleton technology, to reflect how biosimilars are manufactured and the role biosimilars play in disease management. The keynote address will be given by Professor Larry Egan, Consultant in Gastroenterology, University Hospital Galway whilst speakers will included Sean Barry, Executive Pharmaceutical Assessor, Health Products Regulatory Authority, Ireland talking on ‘Scientific and Regulatory Update: Evolving Landscape on Regulatory Data Requirements to Demonstrate Biosimilarity - Biosimilars Authorisation and Registration’ and Dr Steinar Madsen, Medical Director, Norwegian Medicines Agency, Norway who will look at Biosimilars in Practice - Attitudes, Experiences and Clinical Trials. The event takes place in the Royal College of Physicians, Kildare Street, Dublin 2 on Saturday November 12th and will go on from 10am until 4pm. For more information see Next month’s issue of Hospital Professional News will carry a full report from the event.

November 2016 • HPN

PP-PFE-IRL-0007 Date of Preparation: May 2016

Our commitment to health beyond the patent At Pfizer we are committed to making a meaningful contribution by improving health. Thousands of patients in Ireland are treated with our off-patent medicines each year in areas such as womenâ&#x20AC;&#x2122;s health, epilepsy, serious infections, neuropathic pain and cardiovascular disease. The life of our innovative medicines extends well beyond the life of the patent â&#x20AC;&#x201C; without the Pfizer research and development that led to the discovery of these once innovative medicines, patients in Ireland would not be benefiting from the value they bring today. Pfizer maintains a supply of over 300 products and continues to be sole supplier of medically important and hard-to-manufacture medicines. Thank you for the trust you place in Pfizer and in our medicines.

8 #Budget2017

Serious concerns at the lack of health service investment Budget 2017 response Whilst many have welcomed the increase in next year’s health budget, cautious concerns have also been voiced. The Private Hospitals Association (PHA) said the budget offered a ‘fresh approach’ to waiting lists. The Health Minister has secured at least ¤70m over the next two years to treat patients who have been on waiting lists for unacceptably long periods. The funding will be administered by the National Treatment Purchase Fund (NTPF) which has a track record in procuring patient care efficiently. Speaking after a meeting with the Minister, PHA Chief Executive, Simon Nugent, said, “By securing and announcing funding for 2018 as well as 2017 the Minister has sent a clear signal – to both patients and private hospitals – that he has a long term strategy for tackling waiting lists. A multi annual approach allows the PHA’s members to plan ahead, maximising the number of patients that can be treated as quickly as possible – ensuring best value for money and reducing the burden on the taxpayer. “The PHA assured the Minister that private hospitals across Ireland are ready and able to provide treatment to patients on public waiting lists. We treat about 400,000 patients a year and perform at least 250,000 theatre procedures and have the capacity to see patients quickly, effectively and with high quality outcomes.” Mr Nugent noted that when the National Treatment Fund was

used to tackle waiting lists in the period prior to 2011, it proved very successful – treating up to 20,000 In Patients per annum, being greatly welcomed by patients* and positively evaluated in successive annual reports published by the Office of the Comptroller and Auditor General (C&AG). However, the Irish Hospital Consultants Association (IHCA) has expressed its serious concern that this will not be sufficient to address the growing waiting lists and increased patients demand for healthcare due to demographic and other reasons. In particular, the 2017 Health Budget fails to address the critical capacity constraints that have arisen from years of cuts in acute hospital and health sector capital expenditure, they say. For 2017, the Department of Health will have funding of ¤14,152 for current expenditure and ¤454 million for capital expenditure. This represents an increase of ¤977 million on the 2016 budget for current expenditure and ¤40 million for capital expenditure. The provision for 2017 represents a 7.4% increase on the original Voted Budget for 2016 and a 3.5% increase on the final projected 2016 outturn. Dr Tom Ryan, IHCA President, said that the cumulative cuts of ¤1.7 billion in health sector capital expenditure since 2008 have resulted in an acute health infrastructure that is crumbling, with many hospitals attempting to treat patients with inadequate

capacity and equipment that is increasingly obsolete. He said that it is disappointing that the 2017 Budget has not allocated significantly increased capital funding to address the critical acute hospital and mental health capacity deficits which are preventing consultants and frontline staff from treating patients without delays. Dr Ryan said that the increased NTPF funding to address the unacceptable and growing waiting lists is at best a stop gap measure. He said it is disappointing that the Budget fails to seriously address the root causes of the problems which are inadequate acute and ICU bed capacity and insufficient operating capacity. He said these constraints are not only leading to longer waiting lists but they are resulting in the cancellation of essential surgery with increased frequency. Dr Ryan that it abundantly clear that our acute hospitals do not have enough beds; diagnostic, theatre, staffing and other resources to treat patients without delays. He said that it is critically important that these capacity constraints are addressed in the National Service Plan through the prioritisation of frontline resourcing to enable the delivery of safe high quality care to patients. The Health Minister has said the Budget for 2017 will deliver the highest health budget ever at ¤14.6 billion, but this has been disputed. He said this was ‘demonstrating the Government’s commitment to investing the gains

¤3m for drugs and social inclusion Catherine Byrne TD, Minister of State for Communities and the National Drugs Strategy, has announced the allocation of an additional ¤3m in Budget 2017 to support drugs and social inclusion measures. The extra funding announced will enable the HSE to continue providing interventions aimed at improving the health outcomes of the most vulnerable in society, and will also be used to support the establishment of a pilot supervised injecting facility in Dublin city centre during 2017. Legislation is being drafted by the Department of Health to allow for the establishment and licensing of supervised injecting facilities. Drafting is at advanced stage and it is intended to publish the Bill during the current Dáil session. Minister Byrne said “The establishment of a supervised injecting facility is high on my agenda. This facility is badly needed to address the problem with street injecting in Ireland, which particularly affects Dublin city centre.” “I expect to receive a report from the Steering Committee set up to advise me on the new drugs strategy early in the New Year. Minister Harris and I intend to develop and bring to Government a proposal for multiannual investment in drugs as part of the memorandum for Government on the new strategy.”

November 2016 • HPN

Summary of Key Priority Measures National Treatment Purchase Fund Additional funding of ¤15 million, rising to ¤50 million in 2018, will be used as part of a focused initiative to address waiting lists. The NTPF total 2017 allocation will be over ¤20m to undertake an initiative targeted at those waiting longest. Health & Wellbeing An initial allocation of ¤5 million will kick-start the establishment of a “Healthy Ireland Fund” to support the implementation of Healthy Ireland programmes and projects in a variety of settings, including education, local authorities, workplaces and communities. Older People An additional ¤10m in new development funding is being provided for homecare (including home help and home care package provision) to build on the very significant additional homecare funding provided in 2016. A further sum of ¤3.8m is being made available to support the increased cost of existing services. The budget provides for continuation of the additional ¤30m for homecare announced in July 2016. Furthermore, a sum of ¤24m will be available to support homecare provision from funding made available under the Winter Initiative which will continue next year. ¤2m is being provided in 2017 from within the Department’s Research programme towards a commitment to provide ¤10 million over the years 2017 – 2021 to support the continuation of TILDA, the Irish Longitudinal Study on Ageing. Disabilities The Programme for Government contains a commitment that all 18-year-old school leavers with disabilities should have access to supports and services which meet their needs as they make the transition from school to adult life. Funding is also included for a further ¤12m of additional costs associated with additional services introduced during 2016 and ¤18m in respect of the costs of compliance with national standards and pressures arising from emergency placements.

10 #Budget2017 unable to give clear responses to the health budget and this year is no different,” they said.

from a recovering economy in a better health service.’ “Within these increased resources we can plan for the challenge of increased demand from a growing and ageing population, and begin some significant new developments which will over time deliver real improvements for patients on waiting lists, children with disabilities and older people,” said the Minister. However, the budget in 2008 was closer to ¤16bn. A department official said “on a like-for-like basis” when you take out children (now in a separate department) and the DCA (with Social Protection) the figure did amount to the biggest health budget ever, representing an increase of ¤977m on the 2016 budget (¤500m of this was allocated earlier in the year) for current expenditure and ¤40m for capital expenditure. Mr Harris also announced that the waiting list initiative, the National Treatment Purchase Fund (NTFP), would receive ¤20m in 2017 to target longest waiters, rising to ¤50m in 2018. Recently, NTPF figures showed almost 540,000 on waiting lists. Asked if investment in the NTPF was an admission that public hospitals were not capable of doing the normal routine work, Mr Harris said “I’m afraid not”. However, it was not his intention that the NTPF would outsource all operations to private hospitals — he said he intends to instruct the NTPF to also seek capacity for additional procedures in public hospitals.

Mr Harris also announced plans to recruit 1,000 nurses and midwives including converting agency staff to permanent posts and jobs for graduate nurses some of whom he is meeting this month, after which he intends to announce a plan to retain and attract nurses to work here. However, the Irish Nurses and Midwives Organisation said converting existing agency staff would not increase overall numbers. Asked if any money had been set aside for ¤700m due to hospital consultants under the 2008 consultants’ contract, Mr Harris said no money had been set aside, because the Government intended to defend the claim in the courts following advice from the Attorney General. The Irish Medical Organisation (IMO) has expressed “huge” disappointment at provisions for health in the budget announced. The IMO said that the budget means an increase of just 3.2% in current health spending at a time when the cost of simply standing still are well in excess of that. The Organisation has also taken issue with the claim, made today by the Minister for Health, that the budget represented the largest amount ever given to health as simply incorrect; the ¤14 billion announced today is a lower amount than the 2008 health budget. “We have seen time and time again how the Department are

President of the IMO, Dr John Duddy said that the organisation’s concerns were focussed in particular on the absence of resources and proposals to tackle the inadequate numbers of consultants and the growing trend of our younger doctors to emigrate; “nothing highlights this more than the fact that our doctors continue to be forced to go to Court to fight their employer for their entitlements.” Dr Duddy said that the health services were facing a manpower crisis which this budget has ignored; “while I note the commitment to increasing the number of nurses in the system, a move like this will have little positive impact if we cannot recruit and retain doctors to lead the treatment of patients.” Dr Duddy also criticised the failure to provide any extra resources to support GPs in the community; “politicians talk-the-talk about supporting GP Led Primary Care but they don’t walk-the-walk. We’ve heard more rhetoric today about supporting GPs and Primary Care but no funding details to actually support it. If the talks on a GP contract are to be meaningful, we will need reassurance that there are resources in place to support it.” On capacity, Dr Duddy criticised the lack of beds in the public hospital sector; “the Minister has spoken today of a Bed Capacity Review. The suspicion must be that this is another delaying tactic because there is no reason not to start restoring some of the 1,600 beds that were taken out of the hospital network over the past decade.” Dr Duddy also criticised the spending of public money in private hospitals through the National Treatment Purchase Fund

Health and Wellbeing Minister Corcoran Kennedy said the allocation of additional funding to Health and Wellbeing in Budget 2017 showed the Government’s commitment to the implementation of Healthy Ireland, the National Framework for Improving Health and Wellbeingand to the commitments in the Programme for Government. The Minister described the establishment of the Healthy Ireland Fund as a major initiative. The Fund will allow Government to support innovative, cross sectoral, evidence-based projects, programmes and initiatives that support the implementation of the key national policies in areas such as Obesity, Smoking, Alcohol, Physical Activity and Sexual Health. The Department of Health will announce details of how the Fund will operate before the end of the year. The Minster said she was particularly pleased that she was able to continue the planned extension of BreastCheck to all women aged 50-69 on an incremental basis from 2015-2021. There is also additional funding for vaccination to allow for the introduction of Rotavirus and Meningitis B vaccine for newborns. The Minister pointed out that the extension of Breastcheck and the expansion of the childhood vaccination programme are commitments in the Programme for Partnership Government.

November 2016 • HPN

(NTPF); “the Minister has signalled that ¤70 million is being diverted to the NTPF over the coming years. That money should go to our public hospitals to alleviate problems in them not be diverted to increase the profitability of private sector hospitals.”

Summary of Key Measures Mental Health ¤35 million in new services will be initiated in 2017 in addition to the ¤35m provided in 2016 which remains in the base funding of the Mental Health Services. As in previous years, projects initiated in 2017 will not be completed in that calendar year, however, mental health spending in 2017 will include additional capital funding of over ¤50 million for the award of the contract for the construction of the new National Forensic Mental Health Service in Portrane, the total cost of which is in excess of ¤150 million. Acute Services (including the National Ambulance Service and the National Cancer Control Programme) Implementation of the National Maternity Strategy commenced in 2016, and further investment of ¤3m is provided in 2017. The expansion of Paediatric Services commenced in 2016 will be continued with additional investment in 2017 bringing the total funding available to ¤7.3m in 2017. This includes the development of an All Island Paediatric Cardiology Service. 2016 also saw the rollout of technology upgrades to the National Ambulance Service with an initial investment of ¤2m, increasing to an annual sum of ¤3.6m in 2017. An additional ¤5m is being made available in 2017 for the development of new initiatives within the Acutes Services (including the National Ambulance Service and the National Cancer Control Programme). Additional funding is also provided in 2017 to support the New Children’s Hospital Integration Programme. Funding of ¤50 million is also provided to meet the increased costs of acute hospital services in 2017 associated with changes in the level and complexity of hospital activity.

12 Conference

Equivalent of six large hospitals required according to IHCA Healthcare rationing 'the new norm' Dr Tom Ryan, President, Irish Hospital Consultant's Association

strengthened significantly to be fit for purpose and to enable the development of an integrated, effective and efficient health service in Ireland. The IHCA has questioned whether significant changes in the sources of funding for health care services, which are broadly similar to those used in other countries, are practical in the current economic situation or whether they would deliver sustainable benefits in terms of improved patient care given the risks in changing the model while substantial operational and service delivery issues and problems need to be addressed.

The number of additional acute hospital beds that are required to provide an internationally acceptable health service in Ireland is equivalent to six large hospitals such as the Mater University Hospital or Cork University Hospital or Galway University Hospital according to the Irish Hospital Consultants Association (IHCA). The President of the Association, Dr Tom Ryan, also said that, because of the existing capacity deficits, the public is being forced to accept healthcare rationing as hospitals continue to prioritise balancing inadequate budgets, with the provision of safe and timely care for patients being relegated to a secondary consideration. The IHCA last month held its 28th Annual Conference in Kilkenny, which was attended by the Minister for Health, Mr Simon Harris TD and hospital consultants from across Ireland.

patients. The reductions in acute hospital and ICU beds and the cumulative cuts in investment for equipment and infrastructure have resulted in a stark mismatch between patient needs for care and the means to deliver it. When the first priority of a hospital is to be ‘within budget’, then the result is longer waiting lists, trolley crises, overcrowding, cancellation of essential surgery and poor patient safety and care. "There is an urgent need to strengthen healthcare governance in Ireland. Patient safety should be the first priority in all our hospitals and therefore each hospital and Community Healthcare Organisation should have a board, which includes patient representatives, GPs and practising consultants to which the management is accountable. This is not the case at the moment", said Dr Ryan.

Speaking at the Annual Conference, Dr Ryan said, "The public has become immune to never-ending stories on the ‘crisis’ in our acute hospitals. However the many unresolved problems in our hospitals are now at such a critical level that patient safety is compromised on a daily basis. Many of our hospitals are running at an internationally unacceptable occupancy rate of more than 95% which has an adverse impact on patient safety.

"There is real opportunity in the proposed 10 Year Healthcare Strategy to address the critical shortage of hospital beds, support services and frontline staff, in order to provide care for the increased number of patients arising from our growing and ageing population. The Strategy must include a blueprint outlining the increased capacity and a yearly commissioning timetable. Anything less than this means that the Strategy will be seen as a ‘fudge’ that could set healthcare back for decades", concluded Dr Ryan.

"We have a failing hospital system which is rationing healthcare to

More recently, the IHCA said that a blueprint for the next 10 to 15

November 2016 • HPN

years must outline the increased capacities in acute hospital, mental health and other services that will be in put in place each year to care for the current case load that presents to acute hospitals and for the projected increase in patient numbers. It said that the realistic resourcing of Ireland’s public hospital and mental health services must be prioritised if the country is to have a health service that can provide timely effective care to patients. Years of underfunding and a failure to account for demographic changes have resulted in a health service that has significant capacity, resource and physical infrastructure deficits. The IHCA highlighted these critical concerns in its submission to the Oireachtas Committee on the Future of Healthcare. The Association has also recommended that existing governance arrangements in the health service need to be

According to the Association, a clear set of measures is required to strengthen hospital, hospital group, CHO, HSE, corporate and clinical governance arrangements to ensure that they are fit-forpurpose and ensure best practice. Dr Tom Ryan added: “It is essential that the current focus of governance is rebalanced to facilitate increased clinical governance input at organisational board levels in order to prioritise the delivery of safe, high quality, timely care to patients. In addition, CHO and Hospital Group geographic coverage must also be aligned without delay.” The IHCA has said that the medical profession is keen to engage collaboratively in the development of strategies and plans that will enable the provision of high quality, safe, timely care to patients.

The many unresolved problems in our hospitals are now at such a critical level that patient safety is compromised on a daily basis. Many of our hospitals are running at an internationally unacceptable occupancy rate of more than 95% which has an adverse impact on patient safety.

14 News

Cabinet to formally seek re-location of EMA to Dublin It has been confirmed that Ireland will formally bid to host the European Medicines Agency (EMA) in the aftermath of Brexit. The EMA plays a very important role in the protection and promotion of public health through the scientific evaluation, supervision and safety monitoring of medicines for human and veterinary use in the European Union. The EMA has been based in London since 1995. The Irish Government is concerned about the uncertainty created around the future of this key Agency by the Brexit vote and believes that, once Article 50 has been triggered, an early decision on a new location for the EMA would be helpful in making the transition as smooth as possible. Health Minister Simon Harris said, “Following the UK’s decision to leave the EU, it appears inevitable that the European Medicines Agency will have to be relocated to another EU Member State. The Irish Government believes that Dublin would be a very suitable location and that a move to the Irish capital would minimise the disruption to the business of the EMA, thus ensuring continued protection of EU citizens and providing reassurance to the industries which it regulates.” Over the last 20 years the EMA has built a reputation for excellence within the global pharmaceutical regulatory system. This is in large part due to the expertise and skills of its staff. Minister Harris said

Ireland will formally bid to host the European Medicines Agency (EMA) in the aftermath of Brexit. that it will be particularly important to retain as many of these staff as possible. He believes that relocation to Dublin is the best option in this regard and should prove very attractive to EMA staff and their families. In addition to highlighting Dublin’s strengths in terms of EMA staff retention, Minister Harris also noted that Dublin is an Englishspeaking location and that English is the working language of the EMA and the pharmaceutical industry. The Minister also emphasised the strong support which the Irish medicines regulator – the Health Products Regulatory Authority – would be able to provide to the EMA. While background work on this proposal has been ongoing for a number of months, today’s Cabinet

decision confirms that there will be a whole-of-Government approach to promoting the relocation of the EMA to Ireland. An interdepartmental/interagency group will be established immediately, including the Department of the Taoiseach, Department of Health, Department of Foreign Affairs and Trade, Department of Jobs, Enterprise & Innovation, Department of Agriculture, Food and the Marine, Health Products Regulatory Authority, IDA Ireland, Science Foundation Ireland, and the Health Research Board . The group will develop a detailed proposal by early 2017 and the Government will work to promote the selection of Dublin as the new location for the EMA, in discussion with the EU Commission and other Member States.

The Irish Pharmaceutical Healthcare Association (IPHA) has welcomed the decision. “I would like to congratulate Minister for Health Simon Harris for bringing this issue to Cabinet. Ireland has a very strong case to make: - The HPRA has established an international reputation - Dublin is the best location for business continuity for the EMA - We are a hub of pharmaceutical innovation and research IPHA looks forward to collaborating with the Government and the relevant State agencies to ensure that we maximise our efforts to get this prestigious EU institution re-located to Dublin”, IPHA CEO Oliver O’Connor said.

Intas Pharmaceuticals acquisition of Actavis Intas Pharmaceuticals Ltd. through its wholly owned subsidiary Accord Healthcare Ltd. has announced that it has entered into a definitive agreement to acquire Actavis Ireland & UK from Teva Pharmaceutical Industries Ltd. The transaction is part of the European Commission’s anti-trust divestiture requirements arising from Teva’s acquisition of Allergan’s generics business. Speaking from the Actavis headquarters in Cork, Tony Hynds, November 2016 • HPN

Managing Director, has said, “We are delighted with the great opportunity this presents to build on the strong foundations of our respective organisations; we are excited to join the Intas/Accord family and look forward to an exciting future together.

from Actavis. We are excited to add a range of products to our existing portfolio along with a range of new product launches in both our retail and hospital markets. The move will once again ensure our position as a top 20 generic player globally”.

“The strategic fit between both our organisations means we will continue to provide competition in the Irish market along with the high levels of customer service our customers have come to expect

Actavis Ireland and UK is supported by a strong manufacturing presence in the UK at its Barnstaple site which provides services both to Actavis and other third parties. This

transaction further demonstrates Accord’s commitment to EU manufacturing. The Actavis plant in Barnstaple will become the company’s 4th UK site, ensuring Accord has one of the most extensive local supply chains to service pharmacies, hospitals and wholesalers across Ireland and the UK and also into Europe. The transaction is due to complete in Q4 2016, subject only to regulatory approvals.



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16 Clinical Synopsis

Taking collaboration and patient care in Haematology to the next level The 21st Congress of the European Haematology Association was abuzz with networking between over 10.000 participants who travelled from all over the world to Copenhagen. The EHA Congress combined sessions and a diverse range of topics around Haematology highlighting state-of-the-art clinical practice, recent advances, new data and views from different stakeholders and international organizations. A hot topic this year was the European Reference Networks. Below, Hospital Professional News gives an overview of some of the key clinical presentations. SGN-CD33A Combined with Hypomethylating Therapy Produces High Remission Rates among Older Patients with AML Presenter: Dr Amir Fathi Affiliation: Massachusetts General Hospital Cancer Centre, Boston, USA Acute myeloid leukaemia (AML) is an aggressive form of blood cancer in which the majority of cases express CD33 on the surface of the leukaemia cells. AML is challenging to treat in older patients since intensive chemotherapy is poorly tolerated, and standard therapies, such as the hypomethylating agents (HMAs) azacitidine and decitabine, yield modest response rates. Data are presented from an ongoing phase 1 trial evaluating vadastuximab talirine (SGN-CD33A; 33A) in combination with standard therapies (azacitidine, decitabine) in older AML patients who have declined intensive frontline therapy. 33A is an antibody-drug conjugate (ADC) targeted to CD33, comprising a novel antibody system stably linked to a highly potent cell-killing agent. CD33 is expressed on leukemic blasts in nearly all AML patients and expression is generally consistent regardless of age, risk factors, or disease characteristics. Thus far, 53 AML patients with median age of 75 years have been treated with this combination. Of 49 efficacy-evaluable patients treated with 33A combined with either azacitidine or decitabine, the composite complete remission rate (CR+CRi) was 73 percent, which compares favourably with historical studies of HMA monotherapy in this population. The 30- and 60-day mortality rates were two and eight percent, respectively. The most common Grade 3 or higher treatment-emergent adverse events occurring in 20 percent or more of patients were febrile neutropenia, thrombocytopenia, anaemia and neutropenia. The combination of 33A and HMAs was well-tolerated and yielded encouraging response rates in older AML patients. Genome sequencing of thousands of patients with rare blood disorders Presenter: Dr Ernest Turro Affiliation: University of Cambridge, Cambridge, UK Approximately three million people have a rare bleeding disorder or disease of platelets, which are the cell fragments that help blood clot. The genetic causes of dozens of such disorders are known (e.g. haemophilia), but there are many others yet to be discovered. Because platelets have a role in heart attacks and stroke, they are involved in one in three deaths in the general population and a better understanding of rare platelet diseases may bring benefits to the care of the millions of patients with these common lifethreatening events. Researchers supported by the NIHR-BioResource Rare Diseases (UK) with collaborators worldwide are sequencing the whole genomes of thousands of patients without a genetic diagnosis and collating their clinical information in a research database. Through computational analysis of this information, we are searching for commonalities between patients who also share similar genetic changes to identify new causes of disease and better understand disorders already known to us. So far, we have found a new genetic link between very large platelets and deafness, a genetic change in a well-known cancer gene responsible for fragile bones, scarring of the bone marrow and low platelet count, and a further genetic link between large platelets and heart rhythm problems. Within months of publication, these and other research findings are already benefiting patients through a new cheap, fast and accurate test ( available to patients in the UK and other countries. Daratumumab Shows Remarkable Benefit in Relapsed or Refractory Multiple Myeloma in the POLLUX Study Presenter: Dr Meletios A Dimopoulos Affiliation: National and Kapodistrian University of Athens, Greece Daratumumab is a fully human monoclonal antibody that binds to a novel target on myeloma cells. POLLUX was an open-label, randomised phase 3 study conducted in 18 countries that evaluated the combination of daratumumab and lenalidomide and dexamethasone (daratumumab group) compared with lenalidomide and dexamethasone (control group) in 569 patients with relapsed or refractory multiple myeloma who received at least 1 prior line of therapy. At the pre-planned interim analysis, an unprecedented 63% reduction in the risk of progression or death was shown in the daratumumab group compared with control group, leading to early unblinding of the study. More patients achieved an overall response in the daratumumab group compared with the control group (93% vs 76%, P <0.0001). Deep and durable responses were significantly more frequent in the daratumumab group, with higher rates of very good partial response or better (76% vs 44%, P <0.0001) and a more than doubling of complete response or better November 2016 â&#x20AC;˘ HPN

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18 Clinical Synopsis (43% vs 19%, P <0.0001). Treatment was well-tolerated in the daratumumab group with adverse events consistent with the known profiles of the drugs in the combination. The study establishes a positive benefit/risk profile for daratumumab with lenalidomide and dexamethasone in multiple myeloma patients who have received at least 1 prior line of therapy and suggests that this combination may represent a new standard of care for these patients. The Clot Thickens Presenter: Dr Katherine A High Affiliation: Children’s Hospital of Philadelphia, USA Haemophilia B is a genetic bleeding disorder, affecting approximately 80,000 males worldwide1, caused by an insufficient or dysfunctional blood clotting protein called factor IX (FIX). Whereas normal clotting factor activity levels range from >40% to 150% (or IU/dL), individuals with the severe form of haemophilia B have circulating FIX activity levels of <1% of normal and may experience recurrent joint, muscle, and tissue bleeding, and potentially life-threatening bleeds into a critical closed space (such as the brain) 2,3. Full adherence to FIX protein replacement prophylaxis is effective; however, treatment has not been universally adopted due to the burden of once or twice weekly intravenous infusions4. This ongoing phase 1/2 study is evaluating the safety and tolerability of a single intravenous infusion of SPK-9001, an investigational gene transfer product, designed to allow the body to produce its own factor IX protein by transferring a functioning factor IX gene into the body 5. As of today, enrolment completed for the initial dose level and four subjects have been followed for 7 to 26 weeks after a single intravenous infusion with 5x1011 vg/kg of SPK-9001 without the need for immunosuppression. No product and/or procedure-related serious adverse events (including immune response) have been reported to date and no subjects have required steroids or other medications to suppress the immune system. As of May 22, subjects 1-4 showed plateau factor IX activity levels of 32, 39, 25, and 27% of normal, respectively. All four subjects are no longer infusing FIX protein products; one subject treated himself with a FIX infusion for a suspected ankle bleed two days after the gene transfer administration, otherwise, all subjects have been free from bleeding to date. These results are consistent in terms of kinetics of rise of factor IX, and are well above the threshold of 12% required to reduce the risk of bleeds6. Based on the recommended trough levels6, factor IX activity levels over 12% of normal are likely to reduce significantly the risk of joint bleeds in patients with haemophilia B7. 1. Srivastava et al., 2012; Giangrande 2005 2. Gringeri A et al., 2014 and Jansen et al., 2009 3. Srivastava et al., 2013 and ISTH-SSC, 2011 4. Srivastava et al., 2013, National Hemophilia Foundation 2007, Roberts and Eberst 1993 5. ( 6. den Uijl IEM et al., 2011 7. Madhi A et al., 2015 Immunotherapy delivered by Blinatumomab improves survival in acute lymphoblastic leukaemia patients Presenter: Dr Max S Topp Affiliation: Medizinische Klinik II, Universitätsklinikum Würzburg, Germany Adult patients with acute lymphoblastic leukemia (ALL) can achieve disease control in 90% of cases with intense chemotherapy but only half of these responders will be cured. For patients who are either refractory or relapse after chemotherapy the outcome is dismal despite undergoing more chemotherapy and/or an allogeneic haematopoetic stem cell transplantation. Immunotherapy offers a new treatment option. This can be delivered by the bispecifc antibody construct blinatumomab, which can engage with patients own T cells to fight ALL cells. A single arm Phase II trials with Blinatumomab has shown that 43% of relapsed or refractory (r/r) ALL patients can achieve disease control. The aim of Tower trial was to answer the question if blinatumomab can achieve a survival benefit in adult patients with r/r acute lymphoblastic leukemia compared to standard chemotherapy (SOC). More than 400 r/r ALL patients in Europe, North America, Asia and Australia were randomised 2:1 to receive either blinatumomab or SOC. The trial was stopped prematurely November 2016 • HPN

19 as blinatumomab demonstrated almost doubling of the overall survival when compared to chemotherapy. This benefit was seen in all subgroup of patients including patients who relapsed after an allogeneic haematopoetic stem cell transplantation and/or who have received multiple different chemotherapy regiments. Blinatumomab treatment did not result in more serious side effects than chemotherapy. In conclusion Blinatumomab is the first immunotherapy agent that has proven to extend patients life with relapsed acute lymphoblastic leukemia when compared to chemotherapy. The root of evil: pre-leukemic clones that survive chemotherapy are linked to a higher risk of leukemia recurrence Presenter: Dr Klaus Metzeler Affiliation: (Internal Medicine 3, University Hospital, Ludwig-Maximilians-Universität (LMU) München, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany) Acute myeloid leukemia (AML) is an aggressive form of blood cancer. Treatment with intensive chemotherapy often leads to a period of freedom from overt disease called a remission. However, recurrence of the disease is common. For reasons that are not yet fully understood, older patients have a higher risk of relapse. In some patients, AML originates from a clone of pre-leukemic stem cells. These pre-leukemic stem cells already carry genetic changes (mutations) that are also found in leukemias, but they still can give rise to normal-appearing blood cells. The subsequent gain of additional mutations then causes progression to overt AML. When the AML clone is eradicated by chemotherapy, a pre-leukemic clone remains detectable in some patients. We therefore studied sample pairs collected at the time of leukemia diagnosis, and after chemotherapy while the patient was in remission, from 107 patients with AML. In 36% of these patients, some of the gene mutations found in the leukemia were still present in the remission specimen, indicating the persistence of a pre-leukemic clone. Persisting mutations were more frequent in older patients. Importantly, patients with persisting mutations had a higher risk of subsequent disease recurrence compared to those with no persisting mutation. Multivariate statistical analyses, which also take other known risk factors into account, suggest that the higher incidence of persisting pre-leukemic clones in older patients may be one explanation for the higher risk of AML relapse in this age group. Stopping Tyrosine Kinase Inhibitors in a very large cohort of European Chronic Myeloid Leukaemia Patients: of the Euro-Ski Trial Presenter: Dr Johan Richter Affiliation: Lund, Sweden, Francois-Xavier Mahon, Bordeaux, France and Susanne Saussele, Mannheim, Germany. Tyrosine kinase inhibitors (TKI) have substantially improved survival in patients with chronic myeloid leukemia in chronic phase. However, treatment is in clinical practice considered life-long. Small clinical trials have previously shown that TKI-therapy can be stopped in 40-60% of patients with a very good therapy response. The purpose in EURO-SKI was to determine the proportion of patients keeping their therapy response after stopping TKIs and to determine clinical and biological factors that predict successful TKI-stop. 868 patients at 61 sites in 11 European countries were registered in study. Patients were required to have had at least three years of TKI-therapy and to have had a very good response (MR4) to therapy for at least one year prior to study entry. Only patients who had not failed prior TKI-treatment were included. Results of the trial show that 62% of the patients still maintained treatment response (MMR) 6 months after stopping therapy. This was 56% at 12 months. Duration of TKI therapy and of very good therapy response (MR4) prior to stop was found to predict successful stop. However, neither gender, age or risk score of the disease were linked to likelihood of successful stopping of TKI therapy. Restoring Effective Anti-Tumor Response in Hodgkin Lymphoma with Nivolumab Presenter: Dr Anas Younes Affiliation: Memorial Sloan Kettering Cancer Centre, New York City, United States Hodgkin Lymphoma typically affects young men and women in their 30s. Although it is highly curable with the current combination of chemo and radiation therapy, approximately 20% of patients will not be cured with first line regimens. Second line treatment typically involves different types of chemotherapy followed by a stem cell transplant. However, patients who are not cured with a stem cell transplant have a very poor prognosis. Accordingly, the development of new agents for patients with relapsed Hodgkin Lymphoma is of high priority. A few years ago, Brentuximab Vedotin was the first drug to be approved by the FDA for treatment of relapsed Hodgkin Lymphoma. In more than three decades, Nivolumab is the second drug that is now expected to be approved for this indication.” The registrational trial, Checkmate 205, is a Phase 2 evaluating Nivolumab with classical Hodgkin lymphoma (cHL). Reported here are the results from one cohort: patients with cHL after failure of both ASCT and subsequent brentuximab vedotin treatment. The primary endpoint of objective response rate (ORR) per an independent radiologic review committee (IRRC) was 66.3% and 73% by investigator response (secondary endpoint). Median time to response was 2.1 months, and median duration of remission was 7.8 months (95% CI: 6.6-NE). The majority of responses (62.3%) were ongoing at the time of analysis. In patients who had no prior response to most recent prior brentuximab vedotin (n=43), nivolumab treatment resulted in an IRRC-assessed objective response rate of 72%. The safety profile of nivolumab was consistent with previously reported data in this tumour type.

HPN • November 2016

20 News

Equipping Government to cope with health challenges The Lancet has published the most up-to-date analysis on the state of the world's health to equip Governments with evidence to identify national health challenges and priorities for intervention. This massive effort brings together 1870 independent experts in 127 countries and territories as part of the Global Burden of Disease, Injuries, and Risk Factors (GBD) 2015 study collaboration, published in one special issue. New estimates reveal the key drivers of ill health, disability, and death in individual countries. Globally, people's health is improving, but progress has been far from universal, highlighting areas where improvements must be made. For the first time, GBD 2015 includes a measure of development (the SocioDemographic Index, or SDI, which is based on income per capita, educational attainment and total fertility rate) in order to assess a country's observed performance compared to their expected performance based on their stage of development. GBD 2015 analyses 249 causes of death, 315 diseases and injuries, and 79 risk factors in 195 countries and territories between 1990

and 2015. Four capstone papers are published alongside two on child and maternal mortality. These are summarised below, followed by key regional, national findings. The world population has gained more than a decade of life expectancy since 1980, rising to 69.0 years in men and 74.8 years in women in 2015. An important contributor to this has been large falls in death rates for many communicable diseases particularly in the last 10 years, including HIV/AIDS, malaria, and diarrhoea. The rate of people dying from cardiovascular disease and cancers has also fallen, although at a slower pace. The number of annual deaths has increased from roughly 48 million in 1990 to almost 56 million in 2015. 70% (40 million) of global deaths in 2015 were due to noncommunicable diseases (NCDs including ischaemic heart disease, stroke, diabetes, chronic kidney disease, Alzheimer's disease and other dementias, and drug use disorders). In 2015, an estimated 1.2 million deaths were due to HIV/ AIDS (down 33.5% since 2005), and 730500 were due to malaria (down 37% since 2005). Although healthy life expectancy

has increased steadily in 191 of 195 countries (by 6.1 years) between 1990 and 2015, it has not risen as much as overall life expectancy (10.1 years), meaning people are living more years with illness and disability. The burden of ill health (measured in disability-adjusted life years, or DALYs ie, the burden of years lost to premature death and disability) has shifted from communicable, maternal, neonatal, and nutritional disorders (eg, HIV/AIDS, malaria, lower respiratory infections, diarrhoeal diseases, measles, and malnutrition) to disabling NCDs (eg, drug use disorders (particularly opioids and cocaine), hearing and vision loss, and osteoarthritis)-mainly due to increases in population numbers and ageing, a trend with massive implications for health systems and the costs of treatment. High blood pressure, smoking, high blood sugar, high body mass index, and childhood undernutrition were the world's leading risk factors for premature death and ill health in 2015. Since 1990, there have been particularly large and concerning increases in exposure to high BMI, drug use, occupational carcinogens

(eg, diesel exhaust and benzene), ozone pollution, and high blood sugar, which affect the burden of conditions like diabetes, heart disease and cancers. Each of these papers reveals wide differences across regions and countries in terms of their overall progress, but also wide variations between the progress observed in countries compared to what would be expected based on that country's level of development. Europe • In 2015, premature death due to drug use disorders surpassed expected levels in Scotland, and Norway; whilst premature death from alcohol use was worse than expected in Denmark and Finland. • Deaths in children under 5 surpassed expected levels in Scotland and Wales in 2015. • Many Western European countries including the UK, Spain, and France performed better than expected at reducing premature deaths from stroke - potentially reflecting improved prevention and care (eg, smoking cessation, control of blood pressure, acute stroke units), and diagnosis.

Sharing innovation in paediatric oncology Dr Michael Capra, Consultant Paediatric Oncologist, OLCHC and Chair of the Local Organising Committee

For the first time, Ireland has hosted the global conference of the International Society of Paediatric Oncology (SIOP). Over 2,200 delegates from 97 countries were in attendance. SIOP is a global organisation of healthcare professionals, scientists and researchers dedicated to increasing knowledge of all aspects of childhood cancer, and aims to improve and optimise treatments throughout the world. November 2016 • HPN

The annual SIOP Congress, which took place from 19th- 22nd October 2016 in The Convention Centre, Dublin (CCD), delivered a high quality scientific programme tailored to the entire SIOP community focusing on all aspects of childhood and young adult cancer. The multidisciplinary meeting facilitated the exchange of innovative ideas and advancements in paediatric

oncology, with a number of engaging sessions given by world renowned experts for delegates to attend. Founded in the late 1960s, the Society has developed into a dynamic and vibrant multidisciplinary organisation including; paediatric oncologists, surgeons, radiation oncologists, nurses, psychologists, survivors and their families, young investigators, and practitioners working in developing countries. The Local Organising Committee for the event included staff from the Department of Haematology Oncology at Our Lady’s Children’s Hospital, Crumlin (OLCHC), together with representation from

colleagues in Cork and Belfast, and the Childhood Cancer Foundation (CCF). Dr Michael Capra, Consultant Paediatric Oncologist, OLCHC and Chair of the Local Organising Committee said, “We were delighted to work with SIOP this year in hosting the Annual Congress in Dublin for the first time. It is such an important global event for all members of SIOP and an excellent opportunity for healthcare professionals working with children and adolescents affected by cancer to learn from each other and progress further advancements in the field. Hosting the congress here in Dublin helped to reinforce and bring home the important role that each and every Irish young patient plays when they enroll on a clinical trial as the results of these trials help us to improve our treatment for all. This underpins the philosophy of SIOP – the collaborative effort of individuals in order to collectively improve the outcome for all children with cancer.”


Bon Secours launch ambitious 2020 Plan Bon Secours Health System launched its Inaugural Conference entitled “Patients, Partnership and Planning”. The Conference brought together health leaders from around the world including the Mayo Clinic, UPMC, RCSI, the NHS and all major Private Health Insurers and Public Hospital CEO’s, to share their knowledge and expertise with one aim, how to improve services for patients. The Conference was opened by the American Ambassador, Mr Kevin O’ Malley who stressed the importance of healthcare links between Ireland and the United States and the importance of partnership working. “Creative thinkers will, through the use of technology and collaborations, make our healthcare systems stronger, more connected and more efficient, with the result of generating better and longer lasting outcomes for patients everywhere,” he said. Bill Maher, CEO, outlined the importance of partnerships particularly with colleagues in the Public Sector so that we can collectively meet the challenges facing the Health System and deliver service for patients. Speaking at the Conference, Mr Maher, launched the Bon Secours Health System’s ambitious ‘2020 Plan’ to develop services for

Mr Bill Maher, CEO, Bon Secours Health System

patients and to continue to invest in Advanced Medicine Exceptional Care. He said, “The ‘2020 Plan’ outlines our strategic goals and initiatives which will see a ¤150m capital investment across all hospitals in our group, in Cork, Dublin, Galway, Tralee and the Care Village in Cork. As Ireland’s largest Private Healthcare provider, headquartered in Cork and a not for profit organization, our aim remains to provide “good help to those in need” and invest in our staff and services for the future.” There were a number of other major announcements at the Conference as part of the ‘2020 Plan’ which included news of a joint venture with UPMC to establish the Radiotherapy Centre in Cork. Speaking at the

Conference, Mr Chuck Bogosta, President of UPMC International announced the joint venture to provide one of the country’s most advanced radiation therapy centres for cancer patients. “The new centre will combine the expertise of BSHS, with UPMC’s world-renowned model of cancer care that brings the latest and best radiation therapy treatments to patients. We’re excited to work with such a highly regarded clinical partner as Bon Secours Hospital Cork to reach more patients in Ireland with world-class care close to home,” said Mr Bogosta. Echoing Mr Bogosta’s statement, Mr Maher said “This partnership builds upon the world-class medical and surgical oncology services we already offer in Cork

and, in partnership with UPMC, we will soon enhance our cancer services by providing access to leading-edge radiation technology and clinical protocols.” The Radiotherapy Centre will be built on the Bon Secours campus in Cork as part of a new, six-story expansion currently under construction. The new Radiotherapy Centre will open in January 2019 and expects to treat patients with two advanced Varian TrueBeam Radiotherapy System, providing image-guided radiation therapy (IGRT) and intensity-modulated radiation therapy (IMRT). Used for a variety of cancers, these approaches are designed to improve patient outcomes while minimizing side-effects.

Potential new way of treating aggressive cancer Scientists here have found a potential new way to treat one of the most aggressive and difficult to treat forms of breast cancer. Researchers from BREAST-PREDICT, an Irish Cancer Society Collaborative Cancer Research Centre, have shown that a new drug – APR-246 – can prevent the growth of triplenegative breast cancer cells. If found to be successful in clinical trials, APR-246 has the potential to save lives for patients with a form of breast cancer which is currently difficult to treat. The research was carried out by PhD student Naoise Synnott, under the supervision of Professor Joe Duffy and Professor John Crown, and was recently published in the International Journal of Cancer. It involved laboratory tests in combination with current

Based in St Vincent’s University Hospital and UCD, the research team now hopes that APR-246 can be tested among patients in clinical trials which, if successful, could lead to the drug being made available for patients with triplenegative breast cancer.

“I decided to focus my BREAST-PREDICT research on triple-negative breast cancer because it was clear that work needed to be done to provide better and more targeted treatment for these patients. I hope that the work of me and my colleagues in St Vincent’s and UCD will be a big step in providing better treatment and hope to future triple-negative breast cancer patients.”

Commenting on the findings, Naoise said, “At the moment the only form of drug treatment available to patients with triple-negative breast cancer is chemotherapy. While this will work well for some patients, others may find that their cancer cells don’t respond as well as might be hoped to chemo, leading to patients suffering the side effects of this treatment without any of the desired outcomes.

The outcome for patients with breast cancer has greatly improved in recent years. Today, survival rates for breast cancer have increased to 85% over five years. Newer, more personalised treatments have played a huge role in this high survival rate, with drugs such as Herceptin and hormone therapies like Tamoxifen attacking the three important ‘biomarkers’ which are detectable in most strains of the disease in patients -

chemotherapy treatments and was funded by BREAST-PREDICT and the Clinical Cancer Research Trust.

estrogen receptors, progesterone receptors and HER2. Triple-negative breast cancers lack these targets. While the disease often responds well to older chemotherapy drugs, there are currently limited options in terms of more targeted and less toxic treatments. A mutation of the p53 gene does, however, occur in around 80% of these triple-negative breast cancers. Naoise and her colleagues have now shown that APR-246 can act by correcting or neutralising the mutant form of p53, thereby stopping the growth of triple-negative breast cancer cells which have been grown in the laboratory. Head of Research at the Irish Cancer Society, Dr Robert O’Connor, hailed the development as a significant milestone in the ongoing work of BREAST-PREDICT. HPN • November 2016

22 Clinical News

Advances in Breast Cancer come to the Fore The recent introduction of gene analysis to determine how effective chemotherapy would be as part of an individual cancer patient’s treatment plan has led to more personalised treatment for many women with early stage breast cancer. Since the ‘Oncotype DX’ test was introduced in Ireland in 2011, the use of chemotherapy has dropped significantly in those women.

Early detection, more personalised treatment and more knowledge about the causes and risk factors behind breast cancer mean that more people are surviving the disease than ever before. Forty years ago the outlook for a breast cancer patient was vastly different from today. In 1976, almost half of women diagnosed with breast cancer died from the disease. Today, survival rates for breast cancer have increased to 85% over five years. The Irish Cancer Society has recently looked back on forty years of breast cancer in Ireland to see the advances that have been made in the prevention, diagnosis, treatment and survivorship associated with this disease. According to Dr Catherine M Kelly, Consultant Medical Oncologist and Breast Cancer Specialist at the Mater Misericordiae University Hospital and Mater Private Hospital in Dublin, “There is no doubt that the picture of breast cancer in Ireland is a much brighter one than that of 40 years ago. Much of this is down to huge advances in research. As a breast cancer researcher I’ve been at the forefront of some of these advances and can attest to the hope they bring to patients. “While increasing survival rates are hugely significant, we must not become complacent in our battle with this disease. Better breast cancer research means better patient care, better outcomes, and one step closer to eventually beating this disease for good.” Forty years ago breast cancer was rarely detected early. No breast cancer screening systems were in place anywhere in the world. It was only in 1976 that mammography was recommended as a screening tool by the American Cancer Society. Fast forward to 2016 and the prevalence of breast cancer screening programmes across Ireland means that early diagnosis is far more common. In Ireland the BreastCheck screening programme began in February 2000 and since then over 450,000 women have been screened. The public now has

November 2016 • HPN

Dr Catherine Kelly, Consultant Medical Oncologist, MMUH

There is no doubt that the picture of breast cancer in Ireland is a much brighter one than that of 40 years ago. Much of this is down to huge advances in research. more information than ever before about the signs of breast cancer, meaning that increasingly women will find a lump themselves and contact their doctor. In 1976 mastectomy was the only surgical option recommended to women with breast cancer, involving removal of the full breast, underarm lymph nodes and chest wall muscles. Now, a simpler lumpectomy is the more common surgery, directly removing the tumour and having less impact on the patient’s body. Partial mastectomies and breast reconstruction post-surgery are now options for patients that could only be dreamed of 40 years ago. In the 1970s the causes and characteristics of breast cancer were only beginning to be understood. But when researchers found that the hormones oestrogen and progesterone are commonly linked to breast cancer growth, testing soon began on the drug Tamoxifen, which helps prevent the disease returning by blocking the effects of oestrogen. From Irish oncologist and radiotherapist Dr Moya Cole pioneering a clinical trial of the

drug to 46 women with advanced breast cancer in 1969, Tamoxifen is now routinely used as part of a treatment plan after surgery, chemotherapy and radiation are finished. In 1998, after researchers discovered that high levels of the human epidermal growth factor 2 (HER2) protein was found in cancer cells in 25-30% of cases, the first targeted anti breast cancer drug – Herceptin – was introduced to treat this HER2-positive breast cancer. Used with chemotherapy, Herceptin can lower the risk of HER2-positive breast cancer recurring by about 50% compared to chemotherapy alone. Understanding the links between breast cancer and genes has also been a huge factor in treating the disease more successfully. In the mid-1990s scientists discovered that women who have changes in the genes BRCA1 and BRCA2 have a 50-80% increased risk of developing breast cancer and ovarian cancers. As a result, clinical trials are underway on new drugs that may be able to treat cancers that involve these genetic mutations.

The last five years alone have seen research discoveries that will profoundly change the way scientists see cancer in the future. In 2012 researchers announced an important finding- that the majority of breast cancers can be grouped into a number of subtypes. This molecular classification of breast cancers is a huge advance because it allows better prediction of the likely outcome for the patient and points the way for new treatments that will work better in those particular sub-types. In 2016 breast cancer patients are being diagnosed earlier, undergoing less invasive surgery and receiving more targeted therapies. We now know that every breast cancer is different. Future research will focus on personalised treatment that is even better equipped to save lives and get patients back to full health. The Irish Cancer Society is funding a ¤7.5 million collaborative cancer research centre called BREAST-PREDICT that is working to achieve the development of personalised medicine. BREAST-PREDICT commenced in 2013 and is made up of approximately 50 breast cancer researchers based all around Ireland. BREAST-PREDICT aims to test new treatment strategies for breast cancer patients, understand how patients respond to certain medicines, study the evolution of breast cancer and determine if exposure to commonly utilised medicines has an impact on breast cancer patient outcomes. This world class research is giving us a better understanding of why patients respond differently to treatments and helping to develop treatments based on each individual patient.

CPD 26: Parkinson’s disease Continuing Professional Development


Biography - Sinead Ryan graduated from the University of Brighton in 2008, and completed her pre-registration in Chelsea and Westminster Hospital NHS Foundation Trust, London. She worked in a number of clinical positions in London before returning to Ireland in 2011. She completed her higher diploma in community pharmacy from Trinity College Dublin in 2014. Sinead is currently working as a community pharmacist in Limerick.

1. REFLECT - Before reading this module, consider the following: Will this clinical area be relevant to my practice?

3. PLAN - If I have identified a knowledge gap - will this article satisfy those needs or will more reading be required?

2. IDENTIFY - If the answer is no, I may still be interested in the area but the article may not contribute towards my continuing professional development (CPD). If the answer is yes, I should identify any knowledge gaps in the clinical area.

4. EVALUATE - Did this article meet my learning needs - and how has my practise changed as a result? Have I identified further learning needs?

60 Second Summary Parkinsons Disease (PD) is a progressive neuro-degenerative condition resulting from the death of the dopamine containing cells of the substantia nigra. There is no consistently reliable test that can distinguish PD from other conditions that have similar clinical presentations. The diagnosis is primarily a clinical one based on the history and examination. Patients with PD classically present with the symptoms and signs associated with parkinsonism, namely hypokinesia (ie poverty of movement), bradykinesia (ie slowness of movement), rigidity and rest tremor. Currently, there is no cure for PD. Management focuses on relieving the motor and non-motor symptoms of the condition. The treatments for the motor symptoms (for example levodopa, dopamine agonists and monoamine-oxidase B inhibitors) work by increasing dopamine in the central nervous system. In general, selective serotonin reuptake inhibitors (SSRIs) are used to manage depression for patients with PD. Psychosis is usually managed using atypical antipsychotics. Rivastigmine is used first line for the treatment of PDrelated dementia. Patients should be counseled on the importance of adherence to PD medications, the possible side effects and possible treatment options available. Patients and caregivers may need to be signposted to supportive services and Parkinson support groups.


5. WHAT NEXT - At this time you may like to record your learning for future use or

assessment. Follow the 4 previous steps, log and record your findings. Published by HPN, sponsored by MSD. Copies can be downloaded from Disclaimer: All material published is copyright, no part of this can be used in any other publication without permission of the publishers and author. MSD has no editorial oversight of the CPD programmes included in these modules.

Parkinson’s disease Parkinson’s Disease (PD) is a chronic, progressive, neurodegenerative condition that generally affects adults in middle to late life and is characterized by bradykinesia, tremor, rigidity, gait disturbances and postural instability.1 Parkinson’s disease is the second most common neurodegenerative disease in the world. It affects 1% of the population over 65 years of age, rising to 2% for those over 80 years. More than 10 million people worldwide are living with Parkinson’s disease. It has a prevalence of 150 per 100,000 under the age of 70 and increasing sharply in those over 70 years. The incidence of PD increases with age, but an estimated 4% of people with PD are diagnosed before the age of 50.1,2 There is a higher prevalence of PD in male patients.3 There is no consistently reliable test that can distinguish PD from other conditions that have similar clinical presentations. The diagnosis is primarily clinical, based on a history and examination.1 PATHOLOGY In idiopathic PD, the progressive degeneration of pigmented neurons in the substantia nigra leads to a pigmented neurones in the substania nigra leads to a deficiency of the neurotransmitter dopamine.1 The resulting neurochemical imbalance in the basal ganglia causes the characteristic signs and symptoms of the illness. In PD, the substantia nigra lobe of the brain undergoes progressive neuronal degeneration; inclusion bodies called Lewy bodies develop. The pathological hallmark of PD is the Lewy body. There is a loss of dopamine and melanin that correlates with cell loss and the degree of akinesia the patient experiences. There is a remarkable degree of “reserve” within the nigrostriatal system, in that up to 80% of dopaminergic neurons are lost before the cardinal clinical features of PD begin to appear. SIGNS AND SYMPTOMS The combination of tremor, rigidity and akinesia develops slowly, over months to several years,

together with changes in posture. Common initial symptoms are tremor and slowness. Limbs and joints feel stiff and they ache. Fine movements become difficult. Slowness causes difficulty rising from a chair or getting into or out of bed. Writing becomes small (micrographia) and spidery. Idiopathic PD is almost always initially more prominent on one side. The diagnosis is usually evident from the overall appearance.  Tremor The characteristic pill-rolling tremor at rest (movements between thumb and forefinger) typically decreases with action. Tremor is often asymptomatic at first.  Rigidity Stiffness develops throughout movements and is equal in opposing muscle groups this is in contrast to the selective increase in limb tone found in other movement disorders. Extrapyramidal rigidity (socalled “lead pipe” and “cog-wheel”) and postural instability are mainstay clinical features of PD.  Akinesia Slowing of movement (bradykinesia) is an additional sign of PD as distinct from rigidity. There is difficulty-initiating movement. There is difficulty initiating movement. Rapid fine finger movements, such as piano playing, become indistinct, slow and tremulous. Facial immobility gives a mask-like appearance. Frequency of spontaneous blinking diminishes, producing a serpentine stare.  Postural and gait changes Stooping is characteristic. Gait becomes unsteady with shuffling and poor arm swinging. The posture is sometimes called simian to describe the ape-like forward flexion, immobility and lack of animation. Balance deteriorates and falls are common in later stages.  Speech Pronunciation is initially a monotone and progresses to tremulous slurring dysarthria, which is the result of akinesia, tremor and rigidity. Eventually, speech may be lost (anarthria).

HPN • November 2016


CPD 26: Parkinson’s disease

 Cognitive Changes Cognitive decline may occur early in the condition and is rarely absent in advanced disease. Depression is common.  Gastrointestinal and other symptoms These include constipation, sometimes an early symptom, heartburn, dribbling, dysphagia and weight loss. Urinary incontinence is common, especially in men. Skin can be greasy and prone to excessive sweating. PD worsens over the years, beginning as a mild inconvenience but slowly progressing. Remissions are unknown except for rare, remarkable short-lived periods of release. These can occur at times of emotion, fear or excitement, when the sufferer is released for seconds or minutes and able to move quickly. While bradykinesia and tremor worsen, power remains normal until immobility makes its assessment difficult. Patients often complain of limb and joint discomfort. There is no sensory loss. The rate of progression of symptoms is very variable, with a benign form running over several decades. Usually the course is over 10-15 years, with death resulting from bronchopneumonia with immobility and cognitive impairment. DIAGNOSIS There is no definite test to diagnose PD; diagnosis is made by recognizing physical signs and distinguishing idiopathic PD from other Parkinsonian syndromes. Conventional brain imaging is normal initially but atrophy develops over time. Dopamine transporter (DAT) imaging is abnormal but discriminates poorly between PD and other akinetic-rigid syndromes. Patients with suspected PD should be referred to a specialist to confirm the diagnosis; the diagnosis should be reviewed every 6-12 months. “Early PD” refers to PD in patients who have developed functional disability and require symptomatic therapy. “Later PD” refers to PD patients on levodopa who have developed motor complications. DIFFERENTIAL DIAGNOSIS A number of other neurological brain disorders can cause features of PD i.e. slowing, rigidity and tremor seen in idiopathic PD. Examples are Alzheimer’s disease, multi-infarct dementia, repeated head injury and late-effects of severe hypoxia or CO poisoning. Slowing also occurs in hypothyroidism, and in certain forms of depression. Features resembling those of Parkinson’s disease can occur in diseases such as progressive supranuclear palsy and multiple system atrophy, but they do not normally show a sustained response to the drugs used in the treatment of idiopathic PD. SHORT-TERM IMPLICATIONS OF PD In the short-term, the prospect for good symptom control, with minimal impact upon lifestyle, is good in the majority of patients. Although medically, PD may be well controlled in the short-term, the psychological impact of facing a lifelong, chronic, progressive illness cannot be underestimated. Depression is a common yet under-diagnosed facet of PD but it is eminently treatable. A prevalence of 40 to 50 per cent has been suggested for depression in PD, although estimates in various studies vary widely. There is some evidence that depression

November 2016 • HPN

in PD represents an endogenous component of the illness, presumably through involvement of monoaminergic systems (serotoninergic, dopaminergic and noradrenergic have all been implicated). In a Global Parkinson’s Disease Survey, a multicentre international study that assessed quality of life in a cohort of 1,000 patients with PD, depression was the primary factor, after motor disability and medication, to have an impact upon the daily life of the patients. LONG – TERM IMPLICATIONS OF PD PD patients and their carers may face a number of problems in the longer term. They include motor deterioration, neuropsychiatric symptoms and autonomic dysfunction. Motor problems evolve at a rate of approximately 10 per cent of patients per year, so that 10 years into the illness, virtually all PD patients will have developed motor fluctuations. For the first four to five year period post diagnosis there is typically a period of good symptom control. At this point it is common for the patient to begin to notice a wearing off of the medication effect before the next dose is due. Increasing the medication leads to peakdose dyskinesias at this stage, which comprise fidgety movements (chorea) or more sustained abnormal muscle contractions and postures (dystonia). As PD progresses over the next few years, the alterations in motor performance becomes more profound and the patient fluctuates between marked dyskinesias and periods of complete immobility. These episodes can occur suddenly and unpredictably and are known as freezing episodes. Falls become more common as the disease advances and, like the freezing episodes, these are difficult to treat.4 TREATMENT Medication therapy does not prevent disease progression, but it improves most patients’ quality of life. While medication alters little, if at all, the natural history of PD, levodopa and /or dopaminergic agonists produce striking initial improvements. Medications are avoided until clinically necessary because of delayed unwanted side effects. In addition, to the difficulties common to other disabling neurological conditions, the management of Parkinson’s disease must take into account the fact that the mainstay of pharmacological treatment, levodopa, can eventually produce dyskinesia and motor fluctuation. Particular care needs to be taken with elderly patients as Antiparkinsonian drugs can cause confusion in the elderly. It is particularly important to initiate treatment with low doses and to increase the dose gradually. Levodopa, dopamine-receptor agonists or monoamine-oxidase-B inhibitors can be administered for initial treatment in early PD. According to the NICE guidelines for PD, it is not possible to identify a universal first-choice drug therapy for patients with early PD. The choice of drug first prescribed should take into account the patients clinical and lifestyle characteristics and patient preference, after the patient has been informed of the short and long term benefits and drawbacks of the drug therapies. Therapy with two or more antiparkinsonian drugs may be necessary as the disease progresses. Most patients eventually require levodopa and subsequently develop motor complications.

LEVODOPA Levodopa has been the gold standard treatment for PD since it was introduced in the 1960s. Having commenced Levodopa treatment, patients experience rapid improvement in their symptoms and quality of life. However, this period is followed by decreased efficacy and levodopa-related motor disturbances, known as dyskinesias. The time this takes to occur can vary from months to years – approximately half of all patients experience dyskinesias after five years of levodopa treatment, and it is suspected that this effect may occur more rapidly in younger patients. Due to this effect, and the availability of other proven first-line options, many clinicians reserve levodopa for later in the course of the disease. Levodopa is initiated at low doses and titrated according to its clinical effect and tolerability. Modified-release preparations of levodopa were developed in an effort to provide more stable plasma levels, thereby reducing motor complications. However, variable absorption means that these advantages have not been realized. Despite this, modified-release preparations have been useful in simplifying drug regimens and providing relief for patients with night-time symptoms. Levodopa can be given in combination with Carbidopa, which prevents the nausea that can be caused by levodopa alone. This combination enables a significantly lower dose of levodopa to be administered and helps reduce the side effects of nausea and vomiting.  Carbidopa/Levodopa: In adult patients Carbidopa 25mg/Levodopa 100mg combination (Sinemet CR®), is prescribed and initially one tablet is taken orally three times a day and is increased by one tablet daily or every other day up to a maximum of eight tablets (200mg Carbidopa) daily. It can be taken with or without food, but high fat meals can delay absorption.7  Carbidopa/Levodopa/Entacapone: In adult patients there are various combinations of Stalevo® Preparations on the market. The dose is titrated to the desired response. The maximum daily amount of tablets varies between the preparations.7 DOPAMINE AGONISTS Dopamine agonists are commonly used as initial treatment of PD when levodopa therapy is delayed (especially for younger patients) and as adjunctive therapy with levodopa in later PD. Dopamine agonists are less effective than levodopa at controlling motor symptoms but are considerably less likely to cause dyskinesia. They have a direct action on postsynaptic dopamine receptors and have been in use since the 1970s. Initial treatment of PD is often with the dopamine-receptor agonists Pramipexole (Mirapexin®), Ropinirole, Rotigotine (Neupro® Transdermal Patch). The ergot-derived dopamine-receptor agonists Bromocriptine, Cabergoline (Dostinex®) and Pergolide are rarely used because they are associated with cardiac valve and pulmonary fibrotic effects. The dopamine-receptor agonists are also associated with more psychiatric side-effects than levodopa. Dopamine-receptor agonists are also used with levodopa in more advanced disease. If a dopamine-receptor agonist is added to

25 levodopa therapy, the dose of levodopa needs to be reduced. SPECIAL CONSIDERATIONS - IMPULSE CONTROL DISORDERS Treatment with dopamine-receptor agonists and levodopa is associated with impulse control disorders, including gambling, binge eating and hypersexual urges.5 Some studies suggest it is more common in young males and those with a history of mood disorders, alcohol abuse and obsessive compulsive disorder. There is no evidence that ergot or non-ergot derived dopamine-receptor agonists differ in their propensity to cause impulse control disorders, so switching between dopaminereceptor agonists to control these side-effects is not recommended. If the patient or caregiver notices the development of an impulse control disorder, the dopamine-receptor agonist or levodopa should be withdrawn or the dose reduced until the symptoms resolve. Pharmacists are ideally placed to counsel patients and their caregiver regarding these effects and explain why the decision has been made for the causative medicine to be tapered off or discontinued. MAO-B INHIBITORS Rasagiline (Azilect®) and Selegiline (Eldepryl®) are MAO-B inhibitors. They increase the amount of dopamine at receptors in the striatum by preventing its metabolism. They are used as initial therapy, especially if dopamine agonists should be avoided, or as levodopa-sparing medicines in later disease. Rasagiline is more commonly used because selegiline is associated with hallucinations, insomnia and confusion. When combined with levodopa, selegiline should be avoided or used with great caution in patients with postural hypotension. Both medicines have the potential to interact with many medicines due to their inhibition of monoamine oxidase, which may not be fully selective for MAO-B.

off fluctuations should be monitored in these patients and the control of motor symptoms reviewed. PSYCHOSIS Psychosis can affect between 30 and 40% of PD patients. Psychosis can be triggered by the introduction of new medicines or by changes in the doses of existing anti-Parkinsonian medicines. Therefore, PD therapy should be reviewed for all patients who develop psychosis and the doses reduced where possible. Mild psychotic symptoms in people with PD may not need to be actively treated if they are tolerated by the patient and carer. In PD patients that require treatment atypical antipsychotic medicines (e.g. Clozapine) should be chosen. Typical antipsychotic drugs must not be used because they exacerbate the motor features of PD. DEMENTIA PD related dementia affects 20-40% of patients with PD and the incidence increases by approximately 14% each year for patients aged 70-79 years. Cholinesterase inhibitors are used, as dementia in PD patients is associated with a reduction in cholinergic functioning within the brain. Rivastigmine (Exelon®) is used first line to improve cognition. A significant clinical benefit occurs in approximately 15% of cases. Donepezil (Aricept®) and Galantamine (Reminyl®) have demonstrated some limited efficacy in the management of dementia in PD patients. SLEEP DISTURBANCES Approximately 60 to 90% of PD patients experience sleep disturbances. These can include daytime sleepiness or an inability to sleep at night due to nocturia, tremor or dyskinesia. Depression can also aggravate existing sleep disturbances. Off-label use of Modafinil may provide a therapeutic option for patients with daytime sleepiness.1



Beta-adrenergic antagonists may be used in the symptomatic treatment of selected people with postural tremor in PD, but should not be drugs of first choice.

Patients who develop autonomic dysfunction, such as postural hypotension, urinary dysfunction or constipation, should receive symptomatic support.

MANAGING NON-MOTOR SYMPTOMS OF PD Patients with PD can develop non-motor symptoms as the disease progresses. The non-motor features of PD include depression, psychosis, dementia, sleep disturbances and autonomic dysfunction. DEPRESSION Depression has been reported to affect 4050% of patients with PD. However, this may be an underestimate because diagnosing mild depression in patients with PD is complicated by the fact that many of the clinical features of mild depression are also motor features of PD. PD-related depression is generally managed using selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs). The choice of treatment is dependent on patient characteristics and other medicines that the patient is using (e.g. SSRIs can be used for patients receiving rasagiline but TCAs should be avoided). Mood swings and anxiety are possible symptoms of the “off” state of PD. On-

LATER-STAGE DISEASE Over time a patient’s response to initial treatments will decline. When this occurs, patients experience “switching off”, also referred to as “wearing off” or “off time”, as plasma drug concentrations reach a trough (this manifests as akinesia and rigidity). In addition, motor complications, such as dyskinesia and dystonia, occur at peak serum levels. Patients can fluctuate rapidly or erratically between these two states – this is known as the “on-off” phenomenon. Wearing off can be countered by increasing the dose of a patient’s medicines or shortening the interval between doses. However, increasing the dose can induce or worsen motor complications, especially with levodopa. If amendments to dosing regimens fail to correct the problems, combinations of drugs will be necessary. CATECHOL-O-METHYLTRANSFERASE INHIBITORS The catechol-O-methyltransferase (COMT) inhibitors, Entacapone (Comtess®) and Tolcapone (Tasmar®) prevent the peripheral breakdown of levodopa, by inhibiting catecholO-methyltransferase, allowing more levodopa to reach the brain. They are licensed for use as an adjunct to co-beneldopa or co-careledopa for patients with PD who experience ‘end-ofdose’ deterioration and cannot be stabilized on these combinations. The dose of levodopa may need to be reduced when a COMT inhibitor is added because increased levodopa levels can worsen dyskinesia. COMT inhibitors are rarely used with levodopa as initial therapy because the combination has been shown to shorten the time to onset of dyskinesia. COMT inhibitors can worsen dyskinesia, cause abdominal discomfort and colour the urine. Due to risk of hepatotoxicity, Tolcapone should be prescribed under specialist supervision only, when other COMT inhibitors combined with co-beneldopa or co-careldopa have produced an inadequate response. Entacapone is available in a combination product with levodopa and carbidopa (Stalevo®). The use of this product may improve adherence and the range of strengths available enables small adjustments of levodopa dose.

Table 1 Options for initial pharmacotherapy in early PD Initial therapy First-choice Symptom control for early PD option

Risk of side effects Motor Other adverse complications events

Levodopa Yes Good degree Evidence of of symptom control increased motor complications Dopamine Yes Moderate degree Evidence of agonists of symptom control reduced motor complications

Evidence of increased other adverse events

MAO-B Yes Limited degree inhibitors of symptom control

Evidence of reduced motor complications

Evidence of increased other adverse events



Lack of evidence

Lack of evidence

Lack of evidence



Lack of evidence

Lack of evidence

Lack of evidence



Lack of evidence

Lack of evidence

Lack of evidence

Evidence of increased other adverse events

HPN • November 2016


CPD 26: Parkinson’s disease


with apomorphine should remain under specialist supervision.

Antimuscarinic drugs exert their antiparkinsonian action by reducing the effects of the relative central cholinergic excess that occurs as a result of dopamine deficiency. Antimuscarinic drugs such as Procyclidine (Kemadrin®), Orphenadrine and Trihexyphenidyl can be useful in drug induced parkinsonism, but they are generally not used in idiopathic PD as they are less effective than dopaminergic drugs and they are associated with cognitive impairment. Generally, the use of these drugs is now limited to younger patients with severe tremor and dystonia in their feet, and patients with later-stage disease and dyskinesia (for these patients it is useful because the mode of action does not involve dopaminergic stimulation). There are no important differences between the antimuscarinic drugs, but some patients tolerate one better than another. Procyclidine can be given parenterally and is effective emergency treatment for acute druginduced dystonic reactions. If treatment with an antimuscarinic is ineffective, intravenous diazepam can be given for life-threatening acute drug-induced dystonic reactions.



• Counsel patients that the practice of withdrawing patients from their antiparkinsonian drugs (so called ‘drug holidays’) to reduce motor complications should not be undertaken because of the risk of neuroleptic malignant syndrome.

Amantadine is a weak dopamine agonist with modest antiparkinsonian effects. It is mainly used for the management of levodopa-induced dyskinesia. Tolerance to its effects may develop and confusion and hallucinations may occasionally occur. LAST-LINE TREATMENTS Despite optimal management some patients’ disease progresses such that dyskinesia and “off” periods become unmanageable and conventional treatment is ineffective. For such patients, management options could include Apomorphine and Levodopa intestinal gel. APOMORPHINE It is a potent dopamine-receptor agonist that is sometimes helpful in advanced disease for patients experiencing unpredictable “off” periods with levodopa treatment. Treatment

Duodopa is a soluble gel form of levodopa and carbidopa that is administered directly into the duodenum via a percutaneous gastrostomy tube. Because of its expense and the invasive route of administration, the use of Duodopa is limited to those with severe motor fluctuations that are not managed by other drug therapies. PHARMACIST ADVICE • When initiating treatment, patients should be advised about its limitations and possible side effects. About 5-10% of patients when PD respond poorly to treatment.

• Patients may need to be signposted to supportive therapies such as occupational therapy, speech and language therapy or physiotherapy services as PD progresses. CLASSICAL FEATURES OF PARKINSON’S DISEASE Bradykinesia Slowness of movement. Rest Tremor A rhythmic movement with a frequency of 4-6 Hz noticed in patients at rest (the characteristic “pill-rolling movement”).

• Advise patients that Antiparkinsonian drug therapy should never be stopped abruptly as it carries a small risk of neuroleptic malignant syndrome.

Extrapyramidal rigidity An increase in muscle tone, which may be likened to bending a piece of lead piping, often with a superimposed “ratchety” feeling (cogwheel).

• Patients initiating treatments of co-careldopa, co-beneldopa, and dopamine-receptor agonists should be warned of the risk and to exercise caution when driving or operating machinery. Those who have experienced excessive sedation or sudden onset of sleep should refrain from driving or operating machines until these effects have stopped occurring. • NICE guidance recommends “a review of all medication and avoidance of any medication that may affect sleep or alertness, or may interact with other medication (for example, selegiline, antihistamines, H2 antagonists, antipsychotics and sedatives).1

First - Symptom control Risk of side effects option choice Motor complications Other adverse events

Dopamine Yes Moderate degree Evidence of reduced agonists of symptom motor complications control

Evidence of increased adverse events

COMT Yes inhibitors

Moderate degree Evidence of reduced of symptom control motor complications

Evidence of increased adverse events

MAO-B Yes inhibitors

Moderate degree Evidence of reduced of symptom control motor complications

Evidence of increased adverse events

Amantadine No

Non-significant result

Evidence of reduced motor complications

Evidence of increased adverse events

Apomorphine No

Limited degree of symptom control

Evidence of reduced motor complications

Evidence of increased adverse events

November 2016 • HPN

• The NICE guidelines for PD do not recommend PD patients take Vitamin E or Co-enzyme Q10 as neuroprotective therapy.1

• Counsel new patients that treatment is not usually started until symptoms cause significant disruption to daily activities.

Table 2 Options for adjuvant pharmacotherapy in later PD Adjuvant therapy for later PD

• As patients with PD may develop impaired cognitive ability, a communication deficit and/or depression, they should be provided with both oral and written communication throughout the course of the condition.

Postural Instability Usually a late feature of the disease, which comprises impairment of righting reflexes with a tendency to fall. REFERENCES 1. National Institute for Health and Clinical Excellence. Parkinson’s disease: national clinical guidelines for diagnosis and management in primary and secondary care. June 2006. 2. Olanow CW, Stern MB, & Sethi K: The scientific and clinical basis for the treatment of Parkinson disease. Neurology 2009 3. Scottish Intercollegiate Guidelines Network, Diagnosis and pharmacological management of Parkinson’s disease. January 2010. 4. Kostic V, Przedborski S, Flaster E, Sternic N. Early development of levodopa-induced dyskinesias and response fluctuations in young-onset Parkinson’s. Neurology 1991. 5. British National Formulary 67. 6. Monthly Index of Medical Specialities (MIMS). July 2016. 7. Summary of Product Characteristics for all medicines accessed online from: www. September 2016. 8. Dell’Agnello G, Ceravolo R, Nuti A, et al. SSRIs do not worsen Parkinson’s disease: evidence from an open-label, prospective study. Clinical Neuropharmacology 2001. 9. Dunsmure L, Kearney D. Parkinson’s Disease Management. Clinical Pharmacist. December 2011.

News 27

No apology from Harris on delayed discharges Minister for Health Simon Harris has told Emergency Medicine consultants that he “makes no apology for being obsessed” with placing strong emphasis on the need to solve the problem of delayed discharges in hospitals. Speaking to delegates at the Irish Association for Emergency Medicine Annual Scientific Meeting, which was held in Dublin last month, the Minister said progress has been made regarding delayed discharges as a result of weekly meetings his Department is having with the HSE to drive the implementation of measures to address pressures and overcrowding in emergency departments (EDs). “As a result of those weekly meetings I mentioned earlier, we have made some recent progress in this area, but the number of patients in this unenviable position is still 604,” according to Minister Harris. “I think we need to think about

that as being equivalent to another Mater Hospital. I want to see a greater focus on this and to encourage a culture of greater cooperation between primary, acute, and social care to address it.” The Minister pointed out the number of patients on trolleys has reduced by almost five per cent in 2016 to date, compared with the same period in 2015. Also, Compliance with the national Patient Experience Time (PET) target, which aims to eliminate waiting periods of over 24 hours in EDs, has improved from 95 per cent to 97 per cent this year. “In acknowledging this I am in no way attempting to diminish the challenge we face, particularly in the season ahead, or deflect from the unacceptably high numbers of patients still on trolleys and the impact that has on them,” Minister Harris said. “However, the improvements we have seen have resulted from your hard work and also

from a concerted and integrated approach across primary care, acute hospitals and social care.” Minister Harris spoke about the recently launched HSE Winter Initiative 2016 – 2017, which provides ¤40 million of additional funding to manage the expected winter surge in demand for hospital care. He said timely patient discharge from hospital is being enhanced by increasing overall homecare and home help provision, and also 950 extra homecare packages targeted at nine specific hospitals. The Clinical Lead for the HSE’s National Clinical Programme for Older People Dr Diarmuid O’Shea, told the Irish Association for Emergency Medicine Annual Scientific Meeting that identifying the problem of “frailty” is vital in the assessment of older patients. Frailty is a common clinical syndrome in older adults that carries an increased risk for poor health outcomes, including falls,

incident disability, hospitalisation, and mortality. Dr O’Shea said it is important for physicians to realise that frailty is a “distinctive health state”. “We need to think about it, we need to recognise and understand it, and we need to do something about it,” according to Dr O’Shea. He said the gold standard for the management of frailty in older patients is comprehensive geriatric assessment, which identifies medical, psychosocial, and functional limitations of a frail older person in order to develop a co-ordinated plan to maximise overall health with ageing. The President of the Irish Association for Emergency Medicine (IAEM) Dr Mark Doyle, has said that staff working in emergency departments are still under severe pressure, in spite of recent statistics showing fewer patients waiting on trolleys compared to last year.

Alarming increase in Obesity rates for Ireland National Strategy launched in Ireland The policy and action plan aims to reverse obesity trends, to prevent health complications and reduce the overall burden for individuals, families, the health system and the wider society and economy. It was launched by Minister for Health, Simon Harris TD, together with the Minister for Children and Youth Affairs, Dr Katherine Zappone TD, and the Minister of State for Health Promotion, Marcella Corcoran Kennedy TD. In the past two decades, levels of overweight and obesity in Ireland have doubled (Morgan et al, 2008). Only 40% now have a healthy weight. Levels of overweight and obesity are much higher in disadvantaged groups. Overweight and obesity are significant risk factors for many chronic non-communicable diseases. The links between obesity and heart disease, cancers, type 2 diabetes, mental ill-health, respiratory problems and musculoskeletal conditions are well established (WHO/FAO Joint Expert Consultation, 2003; National Obesity Observatory,

2011). The burden of adult obesity in financial terms has been estimated as ¤1.13 billion per annum (safefood, 2012). Rising levels of overweight and obesity are placing an increasing burden on individuals and society. Currently, six in ten adults and one in four children are overweight or obese (Department of Health, 2013; Layte and McCrory, 2009; 2011). According to World Health Organisation (WHO) forecasts, Ireland could top the European league tables in the coming years (WHO, 2015). Obesity-related chronic diseases are dominating hospital activity to the point that this will become unsustainable unless action is taken. The Ministers announced a range of actions which would be undertaken over the coming years to address the growing concerns about overweight and obesity. These include • Development of a Nutrition Policy • A new clinical Lead for Obesity will be appointed in the HSE

Obesity rates in Europe • Prioritisation of Obesity services in the HSE service plans for 2017 and subsequent years • Support for introduction of a Sugar Levy to encourage a reduction in the rates of consumption of sugarsweetened beverages

• Agreement on food reformulation targets with the food industry and establishment of a forum for engagement with industry on best practice initiatives towards a healthy food environment

HPN • November 2016

28 Feature

Epidemiology of diabetes and complications among adults in the Republic of Ireland 1998-2015: A systematic review and meta-analysis Marsha L. Tracey1*, Michael Gilmartin2, Kate O’Neill1, Anthony P. Fitzgerald1, Sheena M. McHugh1, Claire M. Buckley1,3, Ronan J. Canavan4 and Patricia M. Kearney1 Diabetes is a serious global public health issue which has been described as the most challenging health problem in the 21st century.1, 2 Cases of diabetes have progressively increased worldwide; between 1980 and 2008 there was a two-fold increase in the number of adults with diabetes.3 Type 2 diabetes is the main driver of the epidemic, accounting for approximately 90 % of all cases.2 The increasing burden of diabetes is driven primarily by rising levels of obesity and an ageing population.2, 4 To date there is no national surveillance programme, or national population-based survey of diabetes in Ireland. Therefore it is difficult to quantify or monitor the impact of diabetes at a national level. Estimates from the International Diabetes Federation (2013) suggest that the prevalence of diabetes is in line with global trends. In 2000, the IDF estimated that the prevalence of diabetes was 3.2 % [5], this had increased to 6.5 % in 2013 [2]. Diabetes places a significant burden of care on the individual, health care professionals and the wider health system.1, 6 Individuals with diabetes are two to four times more likely to develop cardiovascular disease relative to the general population and have a two to five-fold greater risk of dying from these conditions.7, 8 Diabetes is a significant cause of blindness in adults, non-traumatic lower limb amputations and end-stage renal disease resulting in transplantation and dialysis.2 Understanding the epidemiology of diabetes is essential to identify public health priorities. Accurate estimates of the burden of diabetes are essential for future planning and evaluation of services. While the IDF provides prevalence estimates for countries and regions, there are substantial variations in time trends as estimates are based on imputations.9, 10 To date, estimates of diabetes prevalence in Ireland have been largely based

November 2016 • HPN

on data from the 2007 National Survey of Health and Lifestyles in Ireland (SLÁN).11 Country specific prevalence rates have also been reported in the grey literature;2 however these estimates have been extrapolated using data from the UK. The Euro Diabetes Index (2014) stated that there was a lack of reliable data to monitor diabetes related complications in Ireland.12 To date, a comprehensive overview of the diabetes situation in Ireland has not been carried out. Therefore the rationale for carrying out this systematic review is to provide a comprehensive understanding of the diabetes situation in Ireland and to highlight current gaps in existing knowledge to inform future research. The aims of this review are 1) to systematically identify and summarise studies describing the prevalence of diabetes and the most common microvascular (retinopathy, neuropathy and nephropathy) and macrovascular complications among adults in Ireland between 1998 and 2014; and 2) to explore trends in diagnosed diabetes prevalence between 1998 and 2015. Methods This review was produced according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines for systematic reviews and meta analyses.13 Key words and study eligibility criteria were determined a priority. Search strategy Both peer-reviewed journal articles and reports were considered for this review. A systematic literature search was carried out in PubMed and Embase databases to identify relevant studies reporting the prevalence of diabetes, microvascular or macrovascular complications among adults within the Republic of Ireland.

Keywords and Medical Subject Headings (MeSH) terms included Ireland, prevalence, diabetes, microvascular, retinopathy, neuropathy, nephropathy, macrovascular and cardiovascular disease. Keywords were combined using the AND or OR operators (Additional file 1). Reference lists of articles were also examined to identify potentially relevant studies. In addition, a Google search was conducted using the keywords prevalence, diabetes, retinopathy, neuropathy, nephropathy and Ireland to identify relevant grey literature. Searches were carried out between January 2014 and March 2014. A second search was carried out in December 2015 to ensure the review included all up to date relevant information. Inclusion criteria Studies were eligible for inclusion if they met the following criteria: (1) conducted in the Republic of Ireland between 1998 and 2014; (2) cross-sectional study design or baseline data from longitudinal studies; (3) prevalence estimates reported for adults aged ≥ 18 years, including men and women; (4) data provided on diabetes prevalence (including a self-report of a previous doctor diagnosis and undiagnosed diabetes) and/ or the prevalence of microvascular complications (retinopathy, neuropathy, nephropathy) or macrovascular complications (myocardial infarction, congestive heart failure, stroke or TIA) in persons with diabetes; (5) if prevalence data were not reported, sufficient detail to calculate the numerator and denominator was provided; (6) the total sample size was ≥ 200; (7) adequate information was reported on the methods used. Exclusion criteria Studies containing participants from Northern Ireland, restricted to a specific sub-population (including hospital based studies),

solely focused on type 1 diabetes, prediabetes or gestational diabetes were excluded from this review. Model estimates of prevalence were also excluded. If multiple articles provided information on a single study, the article detailing the most comprehensive data was selected. Full text articles were retrieved for all potentially eligible studies and were independently reviewed by three authors (MT, MG, and KON). Data abstraction and quality assessment For each eligible study, three reviewers (MT, MG, and KON) individually collected relevant information using a structured data extraction form. The methodological quality of each included study was assessed using a critical appraisal checklist for studies used in systematic reviews addressing questions of prevalence.14 This appraisal tool was developed to specifically examine the internal and external validity of prevalence data included in systematic reviews. Methodological quality was considered ‘low’ if three or less criteria were met, ‘moderate’ if four to six criteria were met and ‘high’ if seven to nine criteria were met. Articles were not excluded on the basis of quality. Any inconsistencies in data abstraction and quality assessment between reviewers were resolved through consensus. Statistical analysis A meta-analysis was carried out using STATA version 13.1 (StataCorp, College Station, TX, USA). Studies were grouped into four categories: diagnosed diabetes among adults aged 18+ years; diagnosed and undiagnosed diabetes among adults aged 45+ years; diagnosed diabetes among adults aged 45+ years; undiagnosed diabetes among adults aged 45+ years. Pooled estimates of diabetes prevalence and 95 % confidence intervals (95 % CI) were calculated. Trends

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Presentation Abasaglar is a clear, colourless, sterile solution of 100 units/ml (equivalent to 3.64mg) insulin glargine (rDNA origin), available as either 3ml cartridge or 3ml KwikPen. Each cartridge/pen contains 300 units of insulin glargine in 3ml solution. Uses Treatment of diabetes mellitus in adults, adolescents, and children aged 2 years and above. Dosage and Administration The dose regimen (dose and timing) should be individually adjusted. In patients with Type 2 diabetes mellitus, Abasaglar can also be given together with orally active antidiabetic medication. Abasaglar has a prolonged duration of action, and should be administered once daily at any time, but at the same time each day. It should only be given by subcutaneous injection and should not be administered intravenously. Injection sites must be rotated within a given injection area from one injection to the next. Abasaglar must not be mixed with any other insulin or diluted. When changing from another intermediate or long-acting insulin treatment regimen to Abasaglar, a change of the dose of the basal insulin may be required and the concomitant antidiabetic treatment may need to be adjusted (dose and timing of additional regular insulins or fast-acting insulin analogues, or the dose of oral antidiabetic medicinal products). Contraindications Hypersensitivity to insulin glargine or any of the excipients. Warnings and Special Precautions Abasaglar is not the insulin of choice for the treatment of diabetic ketoacidosis. In case of insufficient glucose control, or tendency to hyper- or hypoglycaemic episodes, other relevant factors must be reviewed before dose adjustment is considered. Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand, type, origin, and/or method of manufacture may result in the need for a change in dose. In rare cases, insulin antibodies may necessitate dose adjustment. The time of occurrence of hypoglycaemia may change when the insulin regimen is changed, depending on the action profile of the insulins used. Caution and intensified glucose monitoring are advised in patients for whom

hypoglycaemia might be of particular clinical relevance. Patients should be aware that warning symptoms of hypoglycaemia may be changed, less pronounced, or absent in certain circumstances, including: markedly improved glycaemic control; when hypoglycaemia develops gradually; in the elderly; after transfer from animal to human insulin; autonomic neuropathy; long history of diabetes; psychiatric illness; use of certain medications such as beta-blockers. This may result in severe hypoglycaemia. The prolonged effect of insulin glargine may delay recovery from hypoglycaemia. If HbA1c is low, consider possibility of recurrent, unrecognised hypoglycaemia. Adherence of the patient to the dose and dietary regimen, correct insulin administration, and awareness of hypoglycaemia symptoms are essential to reduce risk of hypoglycaemia. Factors increasing risk of hypoglycaemia require particularly close monitoring and may necessitate dose adjustment. Intercurrent illness requires intensified monitoring. Testing for ketones and dose adjustment may be necessary. Patients with Type 1 diabetes must continue to consume at least small amounts of carbohydrate and must never omit insulin entirely. The cartridges should only be used in a pen recommended for the use with Lilly insulin cartridges. The insulin label must always be checked before each injection to avoid medication errors. Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin. If the combination is used, patients should be observed for signs and symptoms of heart failure and pioglitazone discontinued if any deterioration occurs. Pregnancy and Lactation No clinical data from controlled studies are available. Data from >1,000 pregnancy outcomes indicate no specific adverse effects of insulin glargine on pregnancy and no specific malformative nor feto/neonatal toxicity. The use of Abasaglar may be considered during pregnancy, if necessary. Insulin requirements may decrease during the first trimester and generally increase during the second and third trimesters. Immediately after delivery, insulin

requirements decline rapidly. Careful monitoring of glucose control is essential. Driving, etc The patient’s ability to concentrate and react may be impaired as a result of hypo- or hyperglycaemia, or visual impairment. This may constitute a risk in situations where these abilities are of special importance (eg, driving a car or operating machines). Undesirable Effects Hypoglycaemia is very common. Injection site reactions and lipohypertrophy are common. Immediate-type allergic reactions are rare, but may be life-threatening. For full details of these and other side-effects, please see the Summary of Product Characteristics, which is available at Legal Category POM Marketing Authorisation Numbers and Holder EU/1/14/944/003 EU/1/14/944/007 Eli Lilly Regional Operations GmbH Kölblgasse 8-10 1030 Vienna Austria Date of Preparation or Last Review May 2015 Full Prescribing Information is Available From Eli Lilly and Company Limited, Lilly House, Priestley Road, Basingstoke, Hampshire, RG24 9NL. Telephone: Basingstoke (01256) 315 000. E-mail: ukmedinfo@lilly. com or Eli Lilly and Company (Ireland) Limited, Hyde House, 65 Adelaide Road, Dublin 2, Republic of Ireland. Telephone: Dublin (01) 661 4377, E-mail: ukmedinfo@lilly. com. ABASAGLAR® (insulin glargine) is a registered trademark of Eli Lilly and Company. KWIKPEN™ is a trademark of Eli Lilly and Company. October 2015 IE/aba/00027b 1. ABASAGLAR® Summary of Product Characteristics. December 2014. Adverse events and product complaints should be reported. To report an adverse event or a product complaint about a Lilly medicine, please call Lilly on: 01 664 0446. Adverse events and product complaints may also be reported to the Health Products Regulatory Authority. Reporting forms and information can be found at This medicinal product is subject to additional monitoring.

30 Feature in pooled prevalence could not be explored as there was a lack of available data from different time points; therefore an overall estimate was provided for each group. Heterogeneity between studies was assessed by the Chi-square based Q test and I2 statistic. Potential publication bias was evaluated by the Begg’s test. A two-tailed p <0.05 was regarded to be statistically significant. High heterogeneity was found among studies reporting diabetes prevalence (I2 ≥ 75 %, p-value < 0.01) hence, pooled estimates were calculated using randomeffects model using the method of DerSimonian and Laird.15 The results from the meta-analysis were presented in a forest plot. To determine the robustness of the results, a sensitivity analysis, based on high quality studies, was carried out. A meta-analysis of the prevalence of diabetes complications was inappropriate; factors which influence prevalence estimates (e.g. time since diabetes diagnosis, type of diabetes, method of diagnosis) either varied between studies or were not reported. Instead a narrative synthesis provides a summary of relevant data. Trends in diagnosed diabetes As trends in diabetes prevalence could not be calculated by metaanalysis, original datasets from four national population based studies,16–19 identified during the literature search were obtained and analysed. In each dataset, diabetes was defined by a self-report of a previous doctor diagnosis. A detailed description on study methodology can be found elsewhere.18, 20 Using data from these national surveys, multivariate Poisson regression models were undertaken to impute annual gender and age-specific (18–39 years, 40–69 years, ≥70 years) rates of diagnosed diabetes and to assess trends over time. The dependent variable was the number of cases of diagnosed diabetes and the exposure variables were year of data collection and age group. An interaction term between calendar year and age group was considered to explore whether the rates of change over time differed across age groups; a non-significant interaction indicated a common linear trend in prevalence. The predict command was used post analysis to calculate the expected rates of diagnosed diabetes for each

November 2016 • HPN

calendar year of the study. The gender and age-specific predicted rates were applied to 2004–2015 population data so the absolute number of diabetes cases could be obtained. Annual population estimates were obtained from the Central Statistics Office (CSO), Ireland.21 A census took place in Ireland in 2002, 2006 and 2011; data for other study years were CSO inter-censal estimates.21 Prevalence was calculated by dividing the number of expected cases of doctor diagnosis of diabetes by the total study population and was expressed as a percentage with 95 % CI. Prevalence estimates were presented graphically in Excel.

Figure 1

Results Study selection Results of the literature search and the selection process are summarised in Fig. 1. One report [22] provided two estimates for diabetes prevalence from two separate studies.16, 17 In total, 15 studies were eligible for inclusion; eight reporting estimates on diabetes prevalence and seven reporting estimates on complication prevalence. Of the included studies, the methodological quality was considered moderate in nine studies and high in the remaining studies (Additional file 2). Characteristics of selected studies Characteristics of studies that reported the prevalence of diabetes or diabetes complications are presented in Tables 1 and 2. In all included studies, data collection were carried out between 1998 and 2011. Studies varied in terms of the study design, setting (national vs. regional), sampling approach and study quality. Of the 8 studies reporting on diabetes prevalence (Table 1), five articles had been published in peerreviewed journals,11, 23–26 while three estimates were reported in were reported in two national reports.22, 27 Of the 7 studies reporting diabetes complications (Table 2), six had been published in peer reviewed journals,28–33 while one audit34 provided data on the prevalence of diabetes related complications. Five studies utilised an objective data source to ascertain the prevalence of complications.28–30, 33, 34 The diagnostic criteria for complications was unclear in three studies31, 31, 34 whereas the remaining four used validated

Figure 2

31 diagnostic criteria to identify cases,28–30, 33 however these criteria differed between studies reporting on the same complication. Prevalence of diabetes in included studies Table 3 reports the prevalence of diabetes by study. Individual and summary estimates, based on a random-effects meta-analysis are illustrated in Fig. 2. There was significant heterogeneity in all groups. Sensitivity analysis only showed lower heterogeneity in combined prevalence rates for undiagnosed and diagnosed diabetes among adults aged over 45 years (I2 ≥ 25 %, p = 0.36); with a pooled prevalence of 9.2 % (95 % CI: 8.6–9.8) (Additional file 3). According to the Egger’s test, there was no evidence of publication bias (p = 0.27). Trends in the prevalence of diagnosed diabetes over time In adults aged 18 years and over, the prevalence of diagnosed diabetes increased from 2.2 % (95 % CI: 1.7 %– 2.7 %) in 1998 to 5.2 % (95 % CI: 5.1 %–5.3 %) in 2015 (ptrend = <0.001); representing an absolute mean increase of 0.17 % per year. In 2015, the incidence of diagnosed diabetes was 0.2/100 population. Figure 3 illustrates the age-specific prevalence of self-reported diagnosed diabetes from 1998 to 2015. In adults aged between 18 and 39 years, the prevalence of self-reported doctor diagnosed diabetes remained stable between 1998 and 2015 in both men and women; ptrend >0.05. However, there was a significant increase in prevalence among men aged 40 to 69 years between 1998 (3.5 % [95 % CI: 3.4–3.6 %]) and 2015 (6.6 % [95 % CI: 6.5–6.7 %]; ptrend <0.001). The prevalence of diabetes also increased among women in the same age group over the same time period (1998– 2.5 % [95 % CI: 2.4– 2.5 %] to 2015- 4.2 % [95 % CI: 4.1–4.3 %]; ptrend <0.001). In those aged 70 years and over, an upward trend in prevalence among both men (1998–8.2 % [95 % CI: 8.0–8.3 %] to 2015- 15.1 % [95 % CI: 14.8– 15.2 %]) and women (1998- 4.7 % [95 % CI: 4.5–4.8 %] to 2015- 10.7 % [95 % CI: 10.5–10.8 %]) was also observed; ptrend <0.001 Discussion This systematic review is the first study to compile all available evidence reporting the prevalence

of diabetes (diagnosed and undiagnosed) and related complications (microvascular and macrovascular) among adults in Ireland between 1998 and 2015. Fifteen studies (eight describing diabetes prevalence and seven describing complication prevalence) were included.

Figure 3

Similar to other systematic reviews;35–37 comparability between studies was limited due to differences in study population, sampling methods and diagnostic criteria. Additionally, substantial statistical heterogeneity was detected between studies reporting the prevalence of diabetes; therefore our pooled estimates have to be interpreted with caution. Sensitivity analysis, based on study quality, lowered the heterogeneity of combined prevalence rates for undiagnosed and diagnosed diabetes among adults aged over 45 years. However, this may reflect variability between prevalence estimates rather than study quality. Trends in diabetes prevalence could not be explored by metaanalysis, therefore, original data from four population based national studies16–19 were obtained to explore time trends in doctor diagnosed diabetes prevalence between 1998 and 2015. Over a seventeen year period, we observed an important increase in the national prevalence of self-reported diagnosed diabetes in Ireland. Consistent with previous research38–40 trends in the prevalence of self-reported diagnosed diabetes remained constant in adults aged 18 to 39 years, while an increasing prevalence was observed in the older age groups. We were unable to distinguish between the various types of diabetes in this review; however it can be assumed that type 2 diabetes is driving the increase in prevalence as it accounts for 90 % of all diabetes cases.1, 2 The prevalence of diabetes was consistently higher in males compared to females. Evidence suggests that men are at a higher risk of developing type 2 diabetes as they develop diabetes at a lower BMI, are more predisposed to central fat deposition and are more prone to insulin resistance.41 Therefore, men are more likely to develop type 2 diabetes in response to increasing levels of obesity.42 On the other hand, the higher prevalence in the male population may reflect preferences in

diagnostic methods. Evidence has highlighted that the prevalence of FPG diagnosed diabetes is higher among men, whereas women are more commonly diagnosed by a 2-h plasma glucose test.43 While it is not possible to determine the method of diabetes diagnosis in this review; it is important to consider how these gender differences may influence diagnosed diabetes prevalence estimates over time. Similar to diagnosed diabetes, trends in the prevalence of undiagnosed diabetes could not be explored by meta analysis as only two nationally representative studies had relevant data.11, 25 The prevalence of undiagnosed diabetes, based on HbA1c, decreased from 2.8 % in 2007 to 0.9 % in 2009–2011 among adults aged ≥45 years and ≥50 years, respectively. While the prevalence of diagnosed diabetes increased from 6.1 % in 200711 to 8.6 % in 2009–2011.25 This shift from undiagnosed to diagnosed diabetes prevalence has also been observed in a study carried out in Germany.10 This decrease in undiagnosed diabetes prevalence may be attributable to earlier detection of diabetes.10 In Ireland, screening high risk patients for type 2 diabetes has been encouraged since the introduction of national guidelines for diabetes care in 2002.44 Another study based on 29144 adults aged 45–75 years with private health insurance, reported the prevalence of undiagnosed diabetes to be 1.8 % in 2009–2012.45 However this estimate was derived from FPG; evidence suggests that the use of HbA1c may underestimate diabetes prevalence compared with estimates using FPG.38, 43, 46

The prevalence of diabetes complications varied substantially between studies therefore comparisons between studies have to be interpreted with caution. These variations may be attributable to differences in disease duration or study population (type 1 and type 2 diabetes vs. type 2 diabetes), study setting (primary care vs. population-based) or heterogeneity in the criteria used to diagnose macrovascular and microvascular complications. Objective data describing the national prevalence of diabetic retinopathy was not available however, regional data on diabetic retinopathy showed that approximately 25 % of primary care patients with type 1 and type 2 diabetes had been diagnosed with this condition [33, 34]. This estimate is higher than a previous hospital-based study based on patients with type 2 diabetes (14.8 %) [47] and primary care data from the UK (19.6 %) [48] but lower than global prevalence estimates (34.6 %) [49]. Though, caution has to be applied when interpreting the results as both regional studies included in this review reported a low uptake rate of retinopathy screening at approximately 50%.33, 34 Additionally, characteristics between attenders and non-attenders were not compared in either study; hence it is possible that there were systematic differences between the two groups. Healthier people are more likely to participate in research; therefore the prevalence of diabetic retinopathy may have been underestimated. As a national screening programme for diabetic retinopathy was introduced in 2013,50 future

HPN • November 2016

32 Feature estimates based on this national programme may be more reliable.

to determine the prevalence of diabetes related complications.


This approach is prone to misclassification bias which can result in an inaccurate estimation of prevalence.52 When compared to medical records, data from self report have been shown to underestimate the prevalence of diabetic retinopathy.53 However, moderate to high levels of agreement between diabetes prevalence and self report have been shown in several studies.54â&#x20AC;&#x201C;56 Although only data on self-reported diabetes were available, results from trend analysis are in line with other developed countries. Secondly, without the inclusion of undiagnosed diabetes in our trend analysis, we acknowledge that diabetes prevalence is underestimated. Finally, significant increases in diagnosed diabetes prevalence were observed over time but these increases may be attributed to heightened awareness among patients, changes in clinical practices, including increased screening for

The strengths and limitations of this systematic review should be noted. Both peer-reviewed articles and estimates detailed in the grey literature were included to limit the impact of publication bias. Original data from four national studies were obtained so trends in diagnosed diabetes prevalence could be examined over a 17 year period. Although response rates were below the optimal rate of 70 %, the representativeness of each study has been demonstrated previously,18, 51 so it can be assumed that the results presented can be generalised to the Irish population. However, several limitations need to be acknowledged. Firstly, studies included in this review were of moderate to high quality; however, six of the included studies relied on self-reporting to determine the prevalence of diagnosed diabetes and one study relied on self-reporting

November 2016 â&#x20AC;˘ HPN

type 2 diabetes, and better survival rates for patients with diabetes.57 However, there is a lack of data on mortality rates among people with diabetes in Ireland; therefore it is not possible to determine whether our increasing trends in prevalence are due to improved health outcomes in those with diabetes. Conclusion This review provides the first comprehensive overview of the burden of diabetes in Ireland. In the absence of a national diabetes register, the findings in this review provide a robust estimate of the trends in prevalence of doctor diagnosed diabetes among the adult population in Ireland. Findings from this review are in accordance with the Euro Diabetes Index (2014);12 there is a lack of information relating to the prevalence of undiagnosed diabetes, macrovascular and microvascular complications. Interpretation of available data was limited due to inconsistencies in reporting, limited availability of objective data and standardisation

in diagnostic criteria. We suggest that the true burden of diabetes in Ireland is underestimated.58 In 2010, the National Clinical Programme in Diabetes was established to improve and standardise patient care in Ireland.59 Reliable baseline data are needed to monitor improvements in care over time at a national level. Therefore, we suggest that a comprehensive national diabetes register is urgently needed in Ireland. Author details 1Department of Epidemiology and Public Health, University College Cork, Western Gateway Building, Cork, Republic of Ireland. 2Department of Medicine, Royal College of Surgeons, Dublin, Republic of Ireland. 3Department of Public Health, Heath Service Executive (HSE) South, Cork, Republic of Ireland. 4Department of Endocrinology, St. Vincentâ&#x20AC;&#x2122;s University Hospital, Dublin, Republic of Ireland.

News 33

IMO set out their views of Doctors in Ireland As Hospital Professional News was going to press, the Irish Medical Organisation presented to the Oireachtas Committee on the Future of Healthcare. The three key challenges which must be overcome to deliver on a Universal Health System were addressed. • The requirement for enhanced health services to meet the needs of a growing population • The current inability to recruit or retain doctors to our health services • The absence of a planned funding model to support the Health Services Dr Peadar Gilligan, Chair of the Consultants Committee addressed the members and stated that the written submission made by the IMO to the Committee provides recommendations on a wide range of health service activities, but added that he wanted to focus on central aspects of the future of Irish healthcare with regards to capacity, staffing, and the role of general practice. “These are system wide issues that, unless appropriately resolved, will inhibit development in other areas of the health service,” he said. “The media coverage of Irish healthcare frequently centres on acute or secondary care, and in particular emergency department over-crowding,” he said. “As an Emergency Medicine Consultant I have been witness to the very

real impact on patient care that cuts in health service funding have had. Our ability to provide high quality care to patients in a timely manner is truly compromised in Ireland, as manifested by admitted patients spending in excess of twelve hours in emergency departments following a decision that admission is necessary, and the increasing waiting lists for planned care delivery. One of the most significant reductions made within the health service was to bed capacity and the effect of this is evident in every acute hospital in the country on a daily basis. “There are about 12,800 acute beds within the hospital system, 800 fewer than in 2007. Of these, 10,800 are in-patient beds, 1,300 fewer than in 2007. Contrast those 10,800 in-patient beds with the 14,700 in-patient beds the Department of Health said back in 2003 that we would need by 2011, or the approximately 14,600 in-patient beds we would have if we adopted the west European average. “To put it bluntly, acute beds currently available within the acute hospital system are too few to provide care to patients in a safe manner and, unless urgent steps are taken to remedy this shortfall, patients will continue to experience significant delays, and preventable deaths will continue to happen. We have heard repeated promises of a bed capacity review, but no action appears to have been taken. Such a review is needed to determine precisely

how many, and what types of, beds should be placed within the acute hospital system to provide adequate capacity on a medium to long-term basis. However, in the short-term, in-patient beds must be restored to the system at a faster rate than is currently occurring.” He added, “Deficits in medical staffing restrict patients’ access to care, and the quality of that care. The 2003 Report by the National Task Force on Medical Staffing, when applied to our current population, sets out a requirement for 4,400 consultants in the health service. Today, however, there are just over 2,700, and as a result we have long-waiting lists for outpatients and procedures across virtually all medical specialties. Comprehensive manpower planning must be under taken to develop a consultant-delivered health service. “At present, however, we are being forced to cope with a grossly understaffed hospital system where the patient experience of care is not as their doctors would wish. Both consultants and non-consultant hospital doctors, the next generation of consultants, are being pressed into excessive levels of service provision which diminish their educational opportunities, and jeopardise patient care through the generation of unacceptable clinical workloads. It is little wonder that few doctors see working in Ireland as an attractive choice, or one compatible with their professional

development. Accordingly, we have one of the lowest numbers of practising doctors per capita in the EU, at just 2.8 per 1,000 population, compared to an EU average of 3.4. “As a directly result of a failure to honour consultant and trainee contracts, public sector cuts, and the further catastrophic 30% reduction in salary to all new consultants imposed in 2012, there are in excess of 250 unfilled consultant posts in Ireland, with one quarter of advertised consultant posts receiving no applicants. This does not auger well for the future of hospital care in Ireland. Irish-trained doctors continue to leave the country in significant numbers. Figures gathered by the OECD reveal that Ireland has the highest reliance on foreign-trained doctors of any country in the EU. Our own research has found that just 40% of Ireland’s medical graduates plan to practise in Ireland, while studies by the Medical Council demonstrate that health service understaffing is the leading reason why our doctors consider practising abroad. Until these issues, are satisfactorily resolved we will struggle to fill medical posts in our health service. “Inadequate resourcing of hospitals in Ireland has compromised patient care and as a result patients, and the staff caring for them, are suffering,” he concluded.

Celebrating 40 years of Orthopaedic Nursing The Nursing Department in Cappagh National Orthopaedic Hospital is celebrating 40 years of Orthopaedic Nursing Education with over one hundred guests gathering for an official reception in the Lady Martin Auditorium in Cappagh.

Sr Anne Curry, Sisters of Charity. Sr Anne was a Nurse Tutor in the 70s-80s in Cappagh Hospital

Guests included representatives of the Royal College of Surgeons, Religious Sisters of Charity, Nursing & Midwifery Planning & Development, past and current educational instructors and current and past nurses. “During the past 40 years, the body of nursing knowledge has increased exponentially. As a result of this ever-expanding body of knowledge, nurses have tended to

gravitate to individual specialities and to concentrate their expertise in one area. While orthopaedic nurse education started here in

the 60’s, the formal accredited programmes commenced in 1976 and we are delighted to be celebrating this milestone” said

Ms. Kathy O’Sullivan, Director of Nursing in Cappagh National Orthopaedic Hospital.

HPN • November 2016

34 HMI Conference

Making Better Choices Coverage from the Heath Managers Institute Annual Conference By Maureen Browne, Editor, Health Manager HMI President, Lucy Nugent opened the 6th Annual HMI Conference by welcoming HMI Members, guests, speakers and delegates. Senior health managers from all over the country packed the one day conference which was held in The Concert Hall in the RDS in Dublin, on September 29 with the theme “Getting it Right – Making Better Choices.” The HMI is the professional body for healthcare managers across all sectors of the health services in Ireland. Its aim is the continuous development of standards of management competence and practice. It achieves this aim through informing, educating and involving its members and stakeholders in professional development and networking event. Ms. Nugent said that during the coming year, HMI planned to introduce a number of key issue research groups to help understand the forces driving health service delivery in Ireland and internationally and to make recommendations with regard to policies and best practice. “We invite you and your organisations to participate in this initiative.” “The title of this year’s conference is GETTING IT RIGHT. The theme reflects the opportunities which managers have to enhance healthcare delivery. In this conference we focus on some of the key choices which managers have to make in terms of improving the quality of service delivery, increasing operational performance and efficiency, utilising technology and enhancing management competencies.” “At all times, we must keep our eye on ensuring that the decisions we make about care delivery and service improvements have the patient at the centre of our thoughts. This afternoon session will focus on you as managers: your role as leaders, managing the stresses of your roles and the importance of taking human factors into account as we manage our people.”

November 2016 • HPN

Lucy Nugent, HMI President

“Being a member Institute, we are conscious of the need to meet with our members and to disseminate relevant information about the key issues in healthcare delivery. The principal way we do this is through our conference and our regional events. These could not happen without the support we receive from our sponsors. I would like to thank GSK, which is the main sponsor here today and, just as important, also support our regional events. Their continued support for our events and conference assists greatly the work of the Institute.” EReferral will save ¤2.6 million Moving to 100% electronic general referral will result in a saving of ¤2.6 million a year, Richard Corbridge, Chief Information Officer HSE and Chief Executive Officer eHealth Ireland and Ms Gemma Garvan, HSE told the Conference. Mr Corbridge and Ms Colette Garvan and made a joint presentation on “Enhancing capability, knowledge and timely access to information. They said that over 40% of

GPs were now using electronic referral everyday with consequent savings. “It is phenomenal without additional investment or resources and shows that digital can make a difference and how enthusiastic Irish healthcare is for digital. It will also ensure that waiting lists become accurate. EHealth should be seen as an enabler and not as a cost to the health service.” They emphasised that the successful delivery of eHealth required clinical leadership. Clinical systems must be integrated and speak to each other. An electronic healthcare record was the ultimate goal. Integrated care was only possible with digital change as a catalyst. They were also anxious to point out that solutions achieved for the public healthcare system could also be used in the private system. Epilepsy geonomic sequencing being included in an EHR could hopefully save many lives. They said that eHealth Ireland vision’s was “To improve population wellbeing, health service efficiencies and economic

opportunity through the use of effective and innovative digitally enabled solutions.” EHealth Ireland would be the:  Accreditation Body for eHealth  Design Authority for eHealth solutions  Delivery Vehicle for strategic eHealth Programmes and Projects  Commissioner of eHealth Services  Custodian trusted broker for Electronic Health information  Driver for Innovation in eHealth  Demonstrator of clinical leadership They added that HSE Director General, Tony O’Brien had five key priorities for EHealth Ireland between now and Christmas:  To deliver a digital identify to all staff by December 23.  Provide support to roll out the national Medical Laboratory Information System at St. James’s Hospital.

Gemma Garvan and Richard Corbridge

35  Propose a solution to address the waiting list challenge set by Minister Harris by October and put it in place by Christmas.

Dr Brian Turner, University College, Cork

 Put a solution in place for GPs to remove “tractor” hardware.  All aspects of the Maternal and Newborn Clinical Management system (MNCMS) to go live on time. Mr Corbridge said the Secretary General of the Department of Health had a vision that EHealth would become the single custodian of health information. The Individual Health Identifier (IHI) would use personal data to accurately identify a specific individual. This data would include; name, gender, PPSN, date of birth, address and nationality. The IHI central function was now live, it had the demographic information allowed in the health identifiers act and a unique number for every patient in Ireland. The IHI delivered the key to accessing information, without it information remained local. Impenetrable data that could never drive change and certainly would not enable a learning health care system. The IHI changed the outlook for integrated care, allowing a patient to begin to understand what integrated means. In the next 4 – 6 weeks they would start connecting systems to the unique health identifier. A number of programmes of work were currently being undertaken – Epilepsy geonomic sequencing being included in an EHR could hopefully save many lives. Sixty people under the age of five died in Ireland last year due to circumstances related to epilepsy. With a budget of ¤1.2 million it was hoped that genomic sequencing could save 60 lives and ¤5 million a year. Deploying Ireland’s first health care supply chain management solution to patients ‘ homes could save over ¤20m in first the three years. Ireland’s health ranking in the OECD Ireland is not doing too badly in spending on healthcare – it is now in the eighth position in the OECD, behind the US, Japan, Switzerland, Sweden, Netherlands, Germany and France - Dr Brian Turner, Lecturer in Economics, University College, Cork, told the Conference.

However, he warned that, based on 4.76m population, we would require over 2,800 additional doctors and over 9,000 additional hospital beds to bring us up to the OECD average. Speaking on “The reality of health economics in Ireland,” he said Ireland’s position was now more comparable with other OECD countries, as there had been change in the definition of what constituted healthcare and greater share of what was previously considered social care was now considered healthcare. We had exceeded the OECD average since 2008, due more to our falling GDP rather than rising health spending. Our spending as a percentage of our gross national income ranked us seventh in the OECD. However, with the increase in our GDP Ireland’s ranking would fall unless spending was greatly increased. In the EU-15, Ireland now had the third highest proportion of money on health spending coming from private sources and this had implications for equity. Dr Turner said that the majority of health spending in Ireland– 69% – came from the government. Voluntary health insurance contributed only 13%, despite the fact that nearly half the population was covered, 15% came from out of pocket expenses and 3% from other sources. Private funding had increased in recent years, from 21% in 2008 to 31% in 2014. In the EU-15, Ireland now had the third highest proportion of money on health spending coming from private sources (only Portugal and Greece were higher) and this had implications for equity. Where providers were concerned, the largest share of the money – 35 % – went to hospitals, 20% went to ambulatory care, 19% to long term residential care 14% to retailers of medical goods and 12% to other areas.

According to OECD Health at a Glance 2015,Ireland had fewer doctors per 1,000 population than OECD average. (2.7 vs. 3.3) and we had a particular shortage of specialists. Where functions were concerned 54% went on curative/ rehabilitative services, 22% on long term care (health), 15% on medical goods, 3% on preventive care and 6% on other areas. Our public and private health systems operating side by side – a public system funded by taxation and a private system where roughly half the population bought private health insurance and this was allocated largely on a fee for service basis. The difficulty was that the providers were largely one and the same and if one was being allocated funding on a block basis and the other on a fee per item basis there was an incentivewhich might not be acted on – to treat private patients. While a mixture of public and private funding and delivery were not unusual internationally, the degree of overlap in Ireland was significant. Prior to 2011 – when the National Treatment Purchase Fund was at its peak – public patients who were waiting significant times to get into public hospitals because beds were taken up by private patients could go to private hospitals and have their care there paid for by state. This was unique in an international context. By international standards Ireland has a high number of people who had to pay out of pocket expenses for primary care. Approximately 38% of the population have medical cards and approximately 9% have GP Visit cards. The remainder faced significant out of pocket expenses and some might put off going to

the GP on cost grounds and could end up going into more expensive hospital care. There was a take-up rate of 46% for private health insurance. There had been significant inflation of premia until 2014, when it moderated, but it was now accelerating again. The exit from the market when the economy was struggling was concentrated on the younger age groups. The large number of older people contributed to the increase in premia between 2008 and 2014. The fact that the market contracted by only 12% cent during the economic downturn was an expression of how people really valued their health insurance and wanted to hang on at all costs. Dr Turner said the Irish health system had not fully recovered from cutbacks in 1980s/1990s. The number of hospital beds was approximately one third lower than in 1980, despite a population increase of approximately one third and an increase in the over-65 population of approximately two thirds over the same timeframe. He said we needed to manage expectations in terms of what we could achieve. According to OECD Health at a Glance 2015, Ireland had fewer doctors per 1,000 population than OECD average. (2.7 vs. 3.3) and we had a particular shortage of specialists. We had fewer hospital beds per 1,000 population than the OECD average (2.8 vs. 4.8). The fact that the market contracted by only 12% cent during the economic downturn was an expression of how

HPN • November 2016

36 HMI Conference Eric De Roodenbeke, Director General, International Hospital Federation

people really valued their health insurance and wanted to hang on at all costs.

world and the profession of healthcare management needed a greater voice in decision making.

To bring these figures into line with the OECD average would require (based on 4.76m population) over 2,800 additional doctors and over 9,000 additional hospital beds.

Mr de Roodenbeke said the IHF was created by national organisations representing healthcare providers from around the world.

However, we were getting some things right and we were not alone in our health problems other countries faced exactly the same issues. Irish life expectancy at birth was above the OECD average, our mortality rates from ischemic heart disease, though still above the OECD average (136 vs. 117 deaths per 100,000 population), fell at a faster rate (down 59% vs. 45% from 1990-2013). We must professionalise healthcare management Healthcare professionals need professionalisation and the International Hospital Federation is creating a web based platform which will allow healthcare professionals to assess themselves, Eric de Roodenbeke, Director General of the IHF told the Conference. He said healthcare management was not recognised as a profession in many parts of the

The profession of healthcare management needed a greater voice in decision making. “Our vision is a world of well managed organisations delivering high quality services, efficiently, safely and with good access for all people,” he said. “Management is a critical pillar of our goal as an organisation. Management is not bureaucracy. It is a fundamental task of management to ensure people are capable of performance. Leadership is a component of management.” Mr de Roodenbeke said healthcare service delivery organisations were very complex organisations and leadership and management were critical. There was some evidence on the relationship between management performance and organisational performance. The IHF had established a consortium from all over the world

to lead the development of global competencies for managers. The key principles were the need for a contemporary model that connected with the health needs of society that would help focus on the developmental needs of individuals. “In this regard, I want to pay tribute to the contribution of HMI President, Lucy Nugent who has been on the journey with us since the early beginning, in 2011,” he said. He also paid tribute to the work of Gerry O’Dwyer HMI Director of Education and President of the European Association of Hospital Managers. Mr de Roodenbeke said there was international agreement on the fundamental competencies (knowledge, skill and attitudes) for healthcare managers. It was also necessary to define healthcare management as a profession in countries where it had not been recognised, and to promote the formation and acceptance of Health Management Associations within countries & regions. A Competency Directory was needed because there were various leadership/management frameworks with a lot of ownership behind them which no one wanted to give up. However, the good news was that they

had the same core content. The difference was in frameworks articulating competencies under different categories and outcomes. The Global Healthcare Management Competency Directory was a crosswalk and consolidation of content from existing competency frameworks throughout the world. It had been validated through field review and two rounds of expert feedback. There is a total of 81 competencies. There was agreement on five key domains:  Leadership  Communication and Relationship Management  Professional and Social Responsibility  Health and Healthcare Environment  Business Within each there are Domains and Subdomains, examples of which are for the first two domains are:  Leadership  Leadership Skills and Behaviours  Engaging Culture and Environment  Leading Change  Driving Innovation  Communications and Relationship Management  Relationship Management  Communication Skills and Engagement  Facilitation and Negotiation

Advances in personalised care within oncology Trinity College Dublin' has played host to the 2016 International Cancer Conference, with the theme “New Frontiers in Personalised Cancer Care”. The conference, held in the Trinity Biomedical Sciences Institute, was opened by Trinity Provost Dr Patrick Prendergast and RTÉ Northern Editor and cancer survivor, Mr Tommie Gorman. An outstanding group of international speakers gave talks on advances in cancer prevention,

November 2016 • HPN

immunotherapy, surgical oncology, radiotherapy and targeted therapeutics. The Burkitt Lecture “Cancer Prevention: from Denis Burkitt to the Human Genome Project” was delivered by the 2016 Burkitt Medal Awardee, Dr Paul Brennan, Head of the Genetics Section of the International Agency for Research on Cancer (IARC), Lyon, France. Dr Brennan was honoured at the conference dinner on 17 October when he was awarded the 2016 Burkitt Medal.

Professor John O’Leary, Chair of Pathology, Cancer Theme Leader, Trinity College Dublin, talked on the Irish Perspective and specifically plans by Trinity College and St James’s Hospital to take it to next level by working towards the establishment of a comprehensive cancer centre – a cancer institute. Professor O’Leary said, “While the current Trinity/St James’s cancer ecosystem is very broad and has performed excellently in the external peer review process, the

institute will be more focused in terms of research, integration of cancer care and research, improvements of the broad education agenda and access to best cancer practices. It will be similar to best international exemplar models setting a new standard for cancer care in Ireland.”

News 37

Calls for more Irish experts to develop International Standards The Chief Executive of the National Standards Authority of Ireland (NSAI) has called for more Irish biotechnology firms, researchers and manufacturers to participate in the development of the world’s first international standards for the biotechnology sector.

Maurice Buckley, Chief Executive, NSAI

Best practice guidelines have already been established for various fields of biotechnology, but there are still no clear set of agreed internationally accepted standards.

Maurice Buckley’s call came as over 120 experts from 26 countries around the world gathered in Dublin Castle to continue their work developing new standards for the biotechnology industry. The ISO Technical Committee established in December 2013, developing standards in key areas of Biotechnology such as bio banking, bioprocessing, analytical methods, and data processing. There is just one active Irish participant on this committee from Ireland. Emma Snapes is Biobank Manager at the INFANT Centre in University College Cork. This is Ireland’s first dedicated perinatal research centre. Addressing the delegates in Dublin Castle, Maurice Buckley said these new international standards will contribute to society, the economy,

tracks and more importantly you will be able to have your say on international best practice which will affect your industry, “he added.

“I’ve worked in biobank facilities all over the world and scientists everywhere have the same concerns,” said Emma Snapes, Biobank Manager at the INFANT Centre in UCC. the regulatory environment and the further enhancement of the biotechnology industry. “Ireland must be a key player in the development of these new international standards, because Ireland is home to many of the world’s top biopharmaceutical firms and experts,” said Mr Buckley. “9 of the world’s top 10 pharmaceutical companies are based here and the industry employs over 50,000 people directly in Ireland. Therefore it

is essential Irish biotechnology researchers and specialists play a pivotal role and have their say on these new standards, which could shape the market or regulations in the future. “There may also be some financial benefits. According to a study by the French standards body, AFNOR, companies involved in standardization saw an extra 20% growth in annual sales. By actively participating in standards development you will be able to see what is coming down the

“Are we doing things in the right way? Can we be doing things a little bit better? There are over 80 best practices guidelines. This leads to a very confusing area, particularly for new and emerging biobanks. Which guideline is best? How do we seek the right information for setting up and improving our processes for bio banking? By standardizing the mechanisms and introducing international benchmarks of excellence; research methodologies will become more rigorous, enhancing the quality of the research,” she added.

Hospital Pharmacists – Catalysts for Change Registration is now open for Europe's largest hospital pharmacy education event, the 22nd Congress of the European Association of Hospital Pharmacists (EAHP). Taking place in Cannes, France, from 22nd to 24th March 2017, the event will take as its overall theme: 'Hospital pharmacists – catalysts for change'. Keynote speeches will emphasise major future-focused talking points

within the profession, such as: 'New medicines at any cost?'; 'Big Data: hype or help?'; and, 'Introducing the Common Training Framework'. Almost 30 seminars will explore a diversity of practice and science topics such as: performance management; hospital accreditation; the growing role of hospital pharmacists in the outpatient setting; health technology assessment;

automation; predicting the future of healthcare; Immuno-Oncology; and, the Falsified Medicines Directive. Interactive sessions will provide hospital pharmacists with opportunities to engage very directly in learning about the creation of business plans for clinical pharmacy services, designing pharmacy practice research studies, and developing and implementing deprescribing guidelines.

Workshops will provide hints and tips on successful publication, quality management, and the art of writing an abstracts. An evergrowing programme of additional satellite events, exhibitions, poster displays, presentation sessions, and bespoke events, such as the Congress Student Programme, compliments the formal Congress programme.

RCSI Dean’s Award 2017 Professor Celine Marmion and Cara McVeigh have been named as this year's winners of the Royal College of Surgeons of Ireland Dean's Award. The announcement was made at the annual Faculty of Medicine and Health Sciences Dinner, which took place on Friday, 21st October. Professor Celine Marmion, Associate Professor of Bioinorganic Chemistry in the Department of Pharmaceutical & Medicinal Chemistry, received the Academic Award while Cara McVeigh, Conference & Events Manager, Conference and Events Department, was the recipient of the Support Award. The Dean's Award scheme was created as a way of acknowledging the diverse and essential contributions of all staff members at RCSI. Both winners were presented with a commemorative award by Professor Hannah McGee, Dean of the Faculty of Medicine and Health Sciences. Pictured right are Professor Celine Marmion, Professor Hannah McGee and Celine McVeigh. HPN • November 2016

38 News

Lack of adequate rehab facilities for stroke patients Three out of four of the country’s rehabilitation hospitals admit they are unable to provide stroke patients with the recommended level of therapy they need, according to a HSE audit. Just one in four has a dedicated stroke unit and 60 per cent lack a stroke specialist to oversee rehabilitation. Less than one in three units has access to psychological services. In addition, the vast majority of the 26 hospitals that took part in the study have no access to community rehabilitation teams to continue therapy that is essential to assist recovery for patients after they are discharged home. The study by the Irish Heart Foundation (IHF) and the HSE’s national stroke programme is the first to examine post-stroke care in Ireland and follows on a national audit of stroke care published earlier this year. This showed a 25 per cent reduction in deaths from the condition in seven years but also pointed to deficits in staffing. Almost two thirds of those facilities surveyed, 60%, did not have a stroke specialist.

77% of hospitals had no dedicated stroke unit compared to just a quarter in the UK while 61% had no access to a Community Rehabilitation team.

Professor Joe Harbinson, Lead Consultant Stroke Physician and Senior Geriatrician, St James's Hospital, Dublin National Clinical Lead in Stroke Medicine

The audit team recommended investment to provide more beds, more staff and community teams to deal with the problems highlighted in the report. HSE's Professor Joe Harbison said there is a need for around 250 extra therapists to tackle the problems. Professor Harbison said: “The incidence of stroke in Ireland is rising by about 350 extra cases every year, but we still have a severe shortage of stroke unit beds to accommodate patients, or the specialist nursing, therapy and medical staff we need to care for them,” said the HSE’s National Clinical Lead for Stroke, Professor Joe Harbison. “We have only about half the acute stroke unit beds we need to meet international standards, and this audit shows an even lower proportion of specialist rehabilitation beds."

Dr Paul McElwaine, Stroke Research Fellow, National Clinical Programme for Stroke added, “It makes no sense at all that we have significant investment of expertise and resources to save patients’ lives after a stroke, but then fail to follow through with basic therapy services that will help them recover. “Ireland is at the cutting edge of developing lifesaving treatments such as thrombectomy and thrombolysis to treat stroke.

"But we waste much of the benefit of these innovations by failing to provide the therapy that doesn’t just promote recovery and a better quality of life for patients, but also reduces overall health service costs by keeping patients out of nursing homes.” Next month’s issue of Hospital Professional News will carry full details of the report in our Stroke Rehabilitation Feature Special.

COST Action on medicines shortages Over 35 experts, from 22 countries, across a wide mix of disciplines, recently met in Bucharest, Romania, for the second meeting of the COST Action on medicines shortages. A COST Action is an initiative of the long-standing European programme 'Co-operation in Science and Technology'. Operating for over 40 years, the programme gives scientists the opportunity to embark upon bottom-up, multidisciplinary cooperation across all science and technology domains. A COST Action on the topic of medicines shortages launched in April 2016 and set itself the tasks of: • Improving understanding of the medicines shortages landscape in Europe (led by Prof Dr Isabelle Huys, Belgium); November 2016 • HPN

• Investigating medicines shortages with API and manufacturing related shortages (led by Professor Dr Claude Farrugia, Malta); • Understanding more about the nature of procurement related disruptions (led by Mr David Stead, United Kingdom); • Exploring the Clinicopharmacological needs related to medicines shortages (led by Mr Nenad Miljkovic, Serbia); and, • Measuring the impact of shortages on outcomes (led by Dr Mina Gaga, Greece). The second meeting of the COST Action, held in Bucharest on Thursday 29th September, was an opportunity for the respective

Working Groups taking up these challenges to meet and further plan activities.

will also be placed on integrating national research into the COST Platform."

Speaking after the meeting, Professor Helena Jenzer, Chair of the Action, remarked, "The meeting was a productive coming together of researchers, practitioners and other interested parties from across Europe impacted by medicines shortages. The way ahead for the various Working Groups was clarified, and the Action is now well positioned to expand its reach to other stakeholder communities, such as Early Career Investigators. If there are PhD and MSc candidates working in the area of medicines shortages, we want to hear from them! The Action will also continue to make outreach to industrial, manufacturing and patient interests. An ongoing focus

Initial expressions of interest in being involved in the COST Action should be made to Expressions of interest in involvement are especially welcomed from: • Currently unrepresented European countries such as Bulgaria, the Czech Republic, Estonia, Finland, Hungary, Iceland, Italy, Luxembourg, the Netherlands and Norway; • Early Career Investigators; and, • The pharmaceutical industry.

Feature 39

What makes psoriatic and rheumatoid arthritis so different? Douglas James Veale,1,2 Ursula Fearon1,2

Clinical and Anatomical Features On the surface, the most striking similarity is that of arthritis: tender, soft tissue swelling of the joints, and in the majority of cases (psoriatic arthritis (PsA) 70%; rheumatoid arthritis (RA) 80%) the same joints are involved, symmetrical synovitis of the proximal interphalangeal and metacarpophalangeal joints of the hands. However, even though there are superficial similarities, several differences are evident on closer inspection. The first description of subtle differences in the clinical features of joint swelling came in 1973 when Professor Verna Wright in Leeds suggested that PsA displayed features consistent with spondyloarthopathy, distinct from RA.1 This was followed up with studies of hereditability of psoriasis in over 100 index cases,2 and accompanied by detailed radiographic examinations based on the distinct patterns of bony abnormality and joint erosion described previously by Avila et al.3 It was noted that the characteristic bony lesion in PsA is a large erosion of the bony cortex, poorly demarcated, in a paraarticular site compared with the often neatly demarcated articular margin of the RA erosion, but the PsA erosion also appeared to be closely associated with new bone formation. Recent developments in MRI and microcomputerised tomography have defined these changes more precisely in patients with PsA comparing them with RA erosions and osteoarthritis osteophytes.4 Interestingly, the advent of MRI has also enabled detailed studies of the site of inflammation in the small joints of the hands, leading to the concept of enthesitis alongside synovitis that explains some differences of clinical examination originally described on the surface of these joints.5 McGonagle has further expanded the concept of enthesitis examining the anatomical detail

Table 1 Summary of key differences in PsA and RA

Psoriatic arthritis

Rheumatoid arthritis


 DIP joint and axial arthritis

 MCP and wrist joints

 Often asymmetrical

 Predominantly symmetrical

 Enthesitis common


 HLA Cw6 and B27

 IL23 receptor


 Absence of circulating autoantibodies

 Distinct vascular pathology


 Circulating autoantibodies RF/ACPA  T-lymphocyte and B-lymphocyte infiltrate

 T-lymphocyte predominance growth factors

 Early expression of vascular growth factors

Response to therapy

 DMARDs, eg, methotrexate

 DMARDs, eg, methotrexate

 TNF inhibitors

 TNF inhibitors

 Abatacept

 Abatacept

 Ustekinumab

 Rituximab

 Secukinumab

 Tocilizumab

of the ligamentous insertions around the distal interphalangeal (DIP) joints to explain some of the clinical features in PsA. MRI also revealed the extent and distribution of synovial tissue inflammation within the joints6 although the synovium has been the subject of several studies focused on the pathogenesis of RA and PsA. The clinical and radiological changes strongly support a pattern of joint inflammation and damage in PsA, distinct from RA, that match findings in the seronegative spondyloarthropathies. Theassociation with erosive disease highlights the importance of early diagnosis and aggressive treatment to maximally maintain function (table 1).

ACPA, anticitrullinated protein antibodies; DIP, distal interphalangeal; DMARDs, disease modifying anti-rheumatic drugs; HLA, human leucocyte antigen; IL, interleukin; MCP, metacarpophalangeal; RF, rheumatoid factor; TNF, tumour necrosis factor. Additional differences in the pattern of joint involvement were also described at an early stage. The original Moll and Wright classification of PsA proposed that DIP joints were frequently inflamed in PsA in direct contrast with RA. While they described up to 60% of patients with DIP joint disease alone, today the figure is reported to be 20% of cases. Another

 Late expression of vascular

notable difference from RA, is the involvement of the axial skeleton, including the sacroiliac joints and the lumbosacral spine, similar to but not identical to ankylosing spondylitis, this has led to PsA being included in the spectrum of spondyloarthopathies. These features, of course, support the concept of enthesitis in this family of diseases, and is further strengthened by the association with the major histocompatibility complex (MHC) class I antigen human leucocyte antigen (HLA) B27, as opposed to the MHC class II shared epitope, HLA DRB1, associated with RA, and therefore clearly defines a difference in genetic susceptibility

HPN • November 2016

40 Feature Figure 1

and pathogenesis of PsA and RA.7 Recently, several genes associated with ankylosing spondylitis and inflammatory bowel disease have been identified in a significant proportion of patients with PsA including the interleukin (IL) 23 receptor, CARD9 and ERAP1.8 Interestingly, a recent study in an animal model of spondyloarthropathy by Sherlock et al,9 demonstrated a unique population of entheseal resident T cells expressing the IL23 receptor. In vivo expression of IL23 led to production of IL17 and IL22 from these cells and the development of enthesitis characterised by entheseal new bone formation in the absence of synovitis. Pathogenesis and Pathophysiology Early studies of the synovial tissue at a microscopic level used a Parker-Pearson needle to obtain biopsies ‘blindly’ from the suprapatellar region under local anaesthetic. Initial studies in RA defined the microscopic features of synovitis, such as villous formation, increased mononuclear cell infiltrate, and increased vascularisation. The first studies to perform detailed microscopic examinations in PsA revealed changes that were quite different. The most significant histological changes were vascular, characterised by endothelial swelling and vessel wall thickening.10 Subsequent studies compared directly synovial tissue biopsies from patients with PsA and RA that demonstrated a less cellular infiltrate, more vascular tissue in PsA than RA, in addition, the characteristic

November 2016 • HPN

hyperplasia of the lining layer of cells observed in RA was less marked in PsA synovium.11 The increased vascular staining using factor VIII-related von Willebrand Factor antibodies by immunohistochemistry and immunofluorescence (figure 1) was assumed to represent increased numbers of new blood vessels in PsA synovium. Consistent with this finding, several studies demonstrated increased expression of angiogenic growth factors, such as vascular endothelial growth factor (VEGF), angiopoietin 2 (Ang2), and basic fibroblast growth factor (BFGF) in PsA synovium compared to RA.12 13 Furthermore, in PsA, increased expression of vascular adhesion molecule 1 (VCAM1) and intercellular adhesion molecule 1 (ICAM-1), along with reduced expression of E-selectin are described. Figure 1 Immunofluorescent staining of blood vessels in (A). Rheumatoid arthritis compared with (B). Psoriatic arthritis (PsA), illustrating increased immature blood vessels in PsA synovium. It has been suggested that fewer T and B cells are found in PsA compared with RA, although, as aforementioned, specific subsets of T cells, such as Th17 cells, may be over-represented and responsible for driving inflammation. 14 The role of T cells in PsA synovium has been highlighted by the beneficial effects on T-cell therapies, such as ciclosporin and abatacept in the treatment of synovitis in PsA.15 16 B-cell aggregates have been noted in PsA and RA synovial biopsies, occasionally forming lymphoid follicles, this raised the question

‘What B cells are doing in the synovium of patients with PsA?’11 PsA has not been associated with circulating antibodies, in contrast to those in RA. Indeed, there has been considerable controversy around the diagnosis of PsA, and the presence or absence of rheumatoid factor (RF) in the circulation. Some argue that a positive RF does not outrule the diagnosis of PsA, while others suggest a positive RF should rule out the diagnosis of PsA. The publication of the landmark CASPAR study and related criteria does conclude that RF has a significantly high discriminant value, such that a negative result forms one of five possible criteria, three of which are required to make a diagnosis of PsA.17 It has been subsequently confirmed that PsA is not usually associated with circulating autoantibodies, including anticitrullinated protein antibodies (ACPA).18 It may be hypothesised that the B cell in the synovial tissue are fulfilling a T-cell activating or cooperative role; however, this remains to be proven, and it is not yet known if the presence of B cells in PsA synovium predict response to anti-B-cell targeted therapies, such Rituximab; however, reports of case studies to date have not shown efficacy in PsA.19 Despite the site-specific differences noted on MRI as described above, direct visualisation using arthroscopy initially suggested significant similarity in the joints of patients with RA and PsA. Arthroscopy using small (<2.9 mm) needle telescopes introduced under local anaesthesia was performed by a small number of rheumatologists in many countries worldwide in the 1990s.20

Prior to that time, few rheumatologists undertook arthroscopic examinations. At first, the synovium appeared similar in both conditions— erythematous, hypervascularised with villi ‘frond-like’ proliferations or granular swelling into the joint cavity. It was assumed that all inflammation was the same. It was not until the latter part of that decade that observations in relation to the vascularisation of the synovial tissue were described in detail, that again suggested significant differences between PsA and RA.21 In this study, Reece et al described a significant difference in the pattern of new blood vessels in PsA and RA, indicating that ‘not all inflammation is the same’! This distinct pattern of new blood vessel formation in PsA and the seronegative spondyloarthropathies has been confirmed in subsequent studies.22 In the former, the vessels form a hypervascularised network of elongated, tortuous vessels suggesting the proliferation of existing vessels by extension only, while in RA, the vessels show regular branching (figure 2) similar to the neovascularisation seen in diabetes. Furthermore, at a microscopic level, the increased vessels previously noted on immunohistology in PsA synovium may be due to the elongation and increased tortuosity of existing vessels, rather than an increase in the actual number of new vessels. These observations are supported by the findings on a molecular level of different vascular growth factor expression patterns, especially VEGF and Ang2, found at high levels in synovial tissue of the early stage of PsA. This compares with moderate levels of VEGF and Ang1 in the early phase of RA, increasing in the later stages of the disease.13 23 Additionally, the blood vessel changes in the joints in PsA are very similar to those noted in the dermis of the skin in psoriasis.24 In RA, a very different systemic vascular response may also be observed, that of a small– medium vessel vasculitis associated with a leucocytoclastic perivascular infiltrate. While the systemic response in both conditions suggests an active inflammatory immune reaction, evidence for this is more often found in RA, presumed to match

Hospital Professional

Dynamic 100 Call for Nominations

HPN is seeking your nominations for the 2016 Hospital Professional Dynamic 100 The Professional Dynamic 100 is a unique look at the 100 key individuals, working within Hospital multidisciplinary teams, Hospital Pharmacy and the healthcare industry. The aim is to celebrate the most influential individuals in Irish hospitals today, recognises the contribution made by 100 key players in this fast changing arena. Inclusion in the Hospital Professional Dynamic 100 significantly is an acknowledgement of the expertise, unique capabilities and individual’s preeminent status for consistently enhancing healthcare within Ireland to enhance outcomes for colleagues, peers and the general public, the patients.  Who has inspired you this year?  Who deserves special recognition for an initiative or project completed this year?  Who has shown the ability to drive forward their profession? Nominations are being sought for individual contributions of excellence, innovation, best practice and progressive thinking in the Hospital sector. This may include (but is not limited to) CEO’s, Professors, Chief Pharmacist, Hospital Pharmacists, Consultants, Hospital Doctors, CEOs and Senior Management from Hospitals, Governing bodies and the Pharmaceutical Industry.

Please email your nominations to HPN Editor Kelly Jo Eastwood at before 17.11.2016

42 Feature Figure 2

placebo-controlled study of over 200 patients with RA.33 34 Secukinumab, a fully human antiIL17A Mab has also been shown to have some efficacy in a small proof-of-concept study in the treatment of patients with PsA.35

the autoimmune nature of RA characterised by production of autoantibodies as outlined above. In PsA, the systemic immune response may also be apparent, however, it is often less marked than in RA. Figure 2 Macroscopic appearance of synovial membrane vascularity in (A). Rheumatoid arthritis (RA) compared with (B). Psoriatic arthritis (PsA), illustrating straight, branching blood vessels in RA compared with a tortuous vascular pattern in PsA synovium. In many clinical studies and trials, it is noted that the mean rise in circulating markers of inflammation, such as erythrocyte sedimentation rate, C reactive protein (CRP), or serum amyloid A, is significantly lower in the PsA population in contrast with patients with RA.25 This observation, along with the absence of specific autoantibodies has led to the hypothesis that PsA is an autoinflammatory disease lacking evidence of specific autoimmune reactivity. Similarities in this respect have been drawn between PsA and other systemic conditions characterised by disturbance of the inflammasome.26 Therapeutic Responses First-line disease modifying anti-rheumatic drugs (DMARDs), such as methotrexate (MTX) and leflunomide are effective in the management of both RA and PsA although there is a wealth of clinical trial evidence for the use of MTX in RA, whereas in PsA, the evidence is sparse. The introduction of tumour necrosis factor inhibitors (TNFi) led to a major shift in the treatment of RA and PsA irrespective of

November 2016 • HPN

the diagnosis.27 Indeed, this comparative study in patients with PsA and RA matched for disease activity, suggested that the remission rate was higher in PsA (60%) than in RA (44%). The benefit of TNFi in PsA, includes an effect on spinal symptoms present in up to 25%, and in dactylitis and nail disease manifest in 20% of patients, while synthetic DMARDs show little efficacy.28 There are now five TNFi agents approved for use in patients with PsA, all showing equivalent efficacy in the treatment of joint disease, while recent data suggests relevant clinical effects as early as 24 weeks.29 The major difference between synthetic DMARDs and TNFi is the effect on inhibition of bone damage, suggesting that use of TNFi early in the disease course is potentially of greater benefit to patients. PsA is not a benign disease, as progression and joint damage are observed over time. A cohort of patients with PsA attending an early arthritis clinic, and receiving treatment with synthetic DMARDs, demonstrated significant bone erosions over a 2-year period.30 Several new biological agents targeting novel molecules implicated in the inflammatory pathway have now been developed and are available. The interesting observation thus far is that some of these treatments are highly effective in RA but have shown little benefit in the treatment of patients with PsA. In particular, monoclonal antibodies (Mab) against CD20 molecule expressed on B cells and the IL6 receptor, appear to be effective in patients with RA but not in patients with PsA. This may not be surprising, as noted above,

there is an absence of circulating autoantibodies in PsA. Moreover, the acute-phase marker CRP, which may reflect IL6 production, is often lower in patients with PsA compared with patients with RA; however, there is no evidence that the IL6R Mab is effective in patients with PsA who do have a high CRP. One biological agent, a fusion protein against CTLA-4 (abatacept) results in down modulation of T-cell activation, however, does show similar activity in both patients with PsA and RA. Recent advances in our understanding of the pathophysiology of PsA, as outlined above, has led to a focus on the IL17, IL12/IL23 pathway as a potential therapeutic target. Several Mab targeting this key regulatory pathway have now been developed and studied in the setting of PsA and psoriasis. A fully human anti-IL12/ IL23 Mab, ustekinumab, has been studied in two large, phase III randomised clinical trials to show safety and efficacy in the treatment of PsA.31 32 The ustekinumabstudies included over 600 patients with active PsA and showed significant responses compared with placebo over a 52-week study period, and may therefore offer a specific, alternative, biological, therapeutic mechanism for the treatment of PsA. Ustekinumab studies in RA have been completed but not yet published, another anti-IL17 Mab, (AIN457) secukinumab, was reported to be efficacious in psoriasis, uveitis and rheumatoid arthritis, and the effect in RA has been confirmed, with a stable adverse event profile, in a double-blind, randomised,

This study included 42 patients over a 24-week period, and it failed to meet the primary end point; however, significant improvements in secondary measures were observed. Finally, two anti-IL17 receptor antibodies, brodalimumab and ixekizumab, were shown in short phase II studies to be significantly beneficial in plaque psoriasis.35 36 Brodalimumab, which is an antiIL17 receptor Mab has now been shown to be efficacious in PsA in a 52-week randomised, doubleblind, placebo-controlled study.37 In conclusion, this review outlines the similarities and the differences in PsA and RA. In many respects, the similarities may be superficial and restricted to the clinical or ‘macro’ view of the diseases. By contrast, the differences may be more than skin deep! Significant differences have been observed at the clinical, immunological, cellular and molecular levels. Specifically, the most defined differences focus around the absence of autoantibodies, RF and ACPA, the vascular morphology and angiogenic growth factor expression in the synovial tissue, and the pattern of periarticular inflammation, bone erosion and formation at the entheseal complex of peripheral and spinal joints. Finally, while some synthetic and biological DMARDs appear to be effective in both patients with PsA and RA, again, specific differences in response to new targeted therapies are being observed which may be explained by specific differences in the molecular pathogenesis of PsA compared with RA. References supplied on request. The Centre for Arthritis and Rheumatic Diseases, EULAR Centre of Excellence, St Vincent’s University Hospital, Dublin Academic Medical Centre, Dublin, Ireland


The Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland


Feature 43

Imperfect HIV adherence links to more inflammation and immune activation Research involving men taking antiretroviral therapy, all with an undetectable viral load, has shown that imperfect adherence to therapy is associated with higher levels of key markers of inflammation and immune activation. The study is published in the online edition of Clinical Infectious Diseases. The authors believe their findings could explain the residual inflammation observed in people taking HIV therapy who have a suppressed viral load. “To our knowledge, this is the first report in which suboptimal cART [combination antiretroviral therapy] adherence has been associated with heightened levels of inflammation and immune activation despite suppressed HIV viremia using standard clinical assays,” comment the investigators. “cART adherence variations could have significant biological consequences despite apparent HIV suppression, since persistent inflammation and immune activation are associated with increased morbidity and mortality among HIV-infected persons.” Low level HIV replication due to imperfect adherence could, the investigators suggest, be an explanation. Improvements in treatment and care mean that many people with HIV now have a normal or near-normal life expectancy. Starting antiretroviral therapy and attainment of an undetectable viral load (below 50 copies/ml in most test assays, with some modern tests having a threshold of 20 copies/ml) is associated with reductions in markers of systemic inflammation and immune activation. However, viral suppression does not reduce levels of inflammation and immune activation to those observed in the HIVnegative population. Persistent inflammation and immune activation may have serious clinical consequences and have been linked to the development of serious non-AIDS-related illnesses including cardiovascular, renal and liver disease, cognitive decline, frailty and malignancies.

The reasons for the low-level inflammation and immune activation observed in people who have a suppressed viral load are not yet fully understood, but it is plausible that imperfect adherence and ongoing low-level viral replication may have a role. Investigators from the ongoing Multicenter AIDS Cohort Study (MACS) therefore undertook a prospective, longitudinal study to assess whether adherence to HIV therapy below 100%, even when it attained viral suppression (below 50 copies/ml), was associated with residual inflammation and immune activation. The study population comprised 912 men who received care between 1998 and 2009. The men provided information about adherence to their HIV therapy in the four days just before their sixmonthly follow-up visits and were asked whether it was typical of the previous six months. Participants in the study were also tested for 24 biomarkers of inflammation and immune activation. Biomarker levels were compared between participants with 100% adherence and those with less than perfect

adherence. Two sets of analysis were performed, comparing four-day adherence (100%; 85 to 99%; below 85%) and six-month adherence (100% vs below 100%). Participants contributed a total of 2816 study visits (median 3 per person). Their median age was 48 years and median CD4 count was 584 cells/mm3. Perfect and imperfect six-month adherence was reported at 87% and 13% of study visits, respectively. Analysis of four-day adherence showed that 100% adherence was reported at 88% of visits, 85 to 99% adherence at 4% of visits and below 85% adherence at 8% of visits. In the six-month adherence analysis, imperfect adherence (compared to 100% adherence) was associated with higher concentrations of 21 out of the 24 biomarkers, with significantly higher levels of c-reactive protein (CRP)(21%, p = 0.006), IFNgamma (15%, p = 0.008), IL-2 (14%, p = 0.022), IL-6 (12%, p = 0.014), TNF-alpha (11%, p <

0.001), IL-10 (11%, p =0.023). After adjustment for multiple confounders, imperfect adherence remained significantly associated with higher concentrations of TNF-alpha. In the four-day adherence model, adherence between 85 and 99% was not associated with higher concentrations of any biomarkers compared to 100% adherence, with the exception of TNF-alpha (10% increase, p = 0.019). However, adherence below 85% was associated with significantly higher levels of six biomarkers, compared to perfect adherence: CRP (22%, p =0.01), IL-2 (20%, p = 0.011), IFN-gamma (17%, p = 0.012), IL-6 (16%, p = 0.01), IL-10 (13%, p = 0.035) and TNF-alpha (10%, p = 0.001). As with the six-month analysis, TNF-alpha remained significant in models taking into account multiple confounders. Models adjusting for statin use did not significantly affect the study’s principal findings.

HPN • November 2016

44 News

Calls for Reimbursement for Genetic Emphysema (Alpha-1) The Alpha One Foundation has called for the reimbursement of the life-changing therapy, Respreeza (Zemaira), for genetic emphysema, also known as alpha-1 antitrypsin deficiency (AATD) or Alpha-1. The call was made as its annual conference got underway in the Marino Institute of Education in Dublin, with patients being updated on the latest developments taking place in new therapies, screening and research. Respreeza, which is made by CSL Behring, is an augmentation therapy that targets the underlying condition, rather than the symptoms of severe Alpha-1. The therapy is currently being assessed by the National Centre for Pharmacoeconomics (NCPE).

Alpha-1 is the most common genetic lung disorder in Ireland. In fact, Ireland has an unusually high prevalence of the condition - amongst the highest in Europe. Alpha-1 antitrypsin is a protein whose main function is to protect the lungs from infection and irritants such as tobacco smoke. A deficiency of this protein can lead to symptoms such as breathlessness, wheezing and cough with phlegm, and can cause severe lung, liver and skin problems. The majority of people with Alpha-1 present with emphysema or chronic obstructive pulmonary disease (COPD). Currently, almost 350 people have been diagnosed with the severe form of Alpha-1 in Ireland, however, it is estimated that around 3,000 people across

the island of Ireland have it. Diagnosis is through a simple blood test which can thus enable early medical intervention and lifestyle changes such as smoking cessation meaning, in some cases, the prevention of lung disease. As Alpha-1 is a genetic condition, the Alpha One Foundation strongly recommends that first-degree family members of people diagnosed with Alpha-1 should be tested as part of the National Alpha-1 Targeted Detection Programme, as well as the following: - All people with emphysema and chronic obstructive pulmonary disease (COPD)

- People with liver disease where the cause is unknown - People with reduced serum levels of alpha-1 antitrypsin - People with the panniculitis skin disease Since a clinical trial of Respreeza – known as the RAPID study – began in Ireland in 2006, a total of 21 people have been offered access to the therapy by its maker on a compassionate-use basis. Some patients have been receiving this treatment for almost a decade. In addition to those patients currently in receipt of the therapy, it is estimated that a further 40 patients would benefit.

- All people with asthma that is non-responsive to usual treatment

New appointments at Bon Secours Dublin The hospital team at Bon Secours Hospital Dublin have welcomed two new Consultant appointments. Dr James Forde has recently commenced private practice at the Bon Secours Hospital Dublin. Dr Forde, an honours medical graduate of UCD (2005), completed his specialist urological training in Ireland in 2015. In 2010 he was awarded an M.D from Trinity College Dublin. He became a Fellow of the Royal College of Surgeons in Ireland in Urology in 2014. Dr Aoibhlinn O'Toole has also recently commenced practice at the Bon Secours Hospital Dublin. Dr O'Toole graduated from

Dr Aoubhlinn O'Toole, Consultant Gastroenterologist

University College Dublin in 2004. She completed her Specialist training in Gastroenterology and General Internal Medicine in St Vincent's University Hospital, Sligo General Hospital and Beaumont Hospital. She was the UCD Newman Scholar in Inflammatory Bowel disease

and obtained an MD from UCD for her research on colorectal cancer and immune evasion. She subsequently moved to Boston.

She returned to Dublin in 2015 to join the Gastroenterology team in Beaumont Hospital.

The call was made as the umbrella body for 15 local COPD support groups announced its first-ever "Save Your Breath" national patient conference in the Royal College of Physicians.

able to participate in a range of COPD lifestyle and well-being workshops and there was also a rare opportunity to quiz politicians directly on their COPD health policies.

and allied healthcare colleagues in both the public and private health sectors are being urged to consider what they can do to help raise awareness.

The conference had patients hear first-hand from leading Irish and UK experts of the progress being made in COPD treatment and care. Attendees were also

It is estimated that there are 380,000 people with COPD in this country, yet the vast majority of people are unaware that they may have the disease. Pharmacy

Be Aware of COPD Ahead of World COPD Day on Wednesday November 16, COPD Support Ireland is urging hospital staff and those in community pharmacies across the country to help tackle COPD and consider organising their own activities to raise awareness of the disease. World COPD Day is organised by the Global Initiative for Chronic Obstructive Lung Disease, also known as GOLD. November 2016 • HPN

The event was supported by A. Menarini, GSK and Novartis.



One proven treatment for COPD patients,with patients,with * or without 3,4† exacerbations, demonstrating consistent superiority vs Salmeterol/Fluticasone1‡ 1,2

ULTIBRO® BREEZHALER® is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD).5 * Patients had at least one moderate or severe exacerbation in the previous 12 months. † Patients had no moderate or severe exacerbation in the previous 12 months. ‡ Fluticasone/Salmeterol 500/50 mg BID. Ultibro Breezhaler ▼This This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 of the SmPC for how to report adverse reactions. ABBREVIATED PRESCRIBING INFORMATION Please refer to Summary of Product Characteristics (SmPC) before prescribing. Presentation: Ultibro® Breezhaler® 85mcg / 43mcg inhalation powder hard capsules containing indacaterol maleate and glycopyrronium bromide respectively and separate Ultibro® Breezhaler® inhaler.Indications: A maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). Dosage and administration: Recommended dose is the inhalation of the content of one capsule once daily, administered at the same time of the day each day, using the Ultibro® Breezhaler® inhaler. Capsules must not be swallowed. No dose adjustment required in elderly patients, for patients with mild and moderate hepatic impairment or for patients with mild to moderate renal impairment. No data available for use in patients with severe hepatic impairment and should only be used in patients with severe renal impairment or end-stage renal disease requiring dialysis if the expected benefit outweighs the potential risk. No relevant use in the paediatric population. Contraindications: Hypersensitivity to the active substances or to any of the excipients. Warnings/Precautions: Not to be administered concomitantly with medicinal products containing other LABA’s or LAMA’s. Asthma: ♦ULTIBRO® BREEZHALER® SHOULD NOT BE USED FOR TREATMENT OF ASTHMA. Acute use: ♦Not indicated for treatment of acute episodes of bronchospasm. Hypersensitivity: ♦Immediate hypersensitivity reactions have been reported after administration of indacaterol or glycopyrronium. If signs suggesting allergic reactions occur (in particular, angioedema, difficulties in breathing or swallowing, swelling of the tongue, lips and face, urticaria or skin rash), treatment should be discontinued immediately and alternative therapy instituted. Paradoxical bronchospasm: ♦If paradoxical bronchospasm occurs, Ultibro® Breezhaler® should be discontinued immediately and alternative therapy instituted. Anticholinergic effects related to glycopyrronium: ♦To be used with caution in patients with narrow-angle glaucoma and in patients with urinary retention. Patients with severe renal impairment: ♦Should only be used in patients with severe renal impairment, including those with end-stage renal disease requiring dialysis, if the expected benefit outweighs the potential risk. These patients should be monitored closely for potential adverse reactions. Cardiovascular effects: ♦To be used with caution in patients with cardiovascular disorders (coronary artery disease, acute myocardial infarction, cardiac arrhythmias, hypertension), in patients with known or suspected prolongation of the QT interval or patients treated with medicinal products affecting the QT interval and in patients with unstable ischaemic heart disease, left ventricular failure, history of myocardial infarction, arrhythmia (excluding chronic stable atrial fibrillation), a history of long QT syndrome or whose QTc (Fridericia method) was prolonged. ♦LABA’s may produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, blood pressure, and/or symptoms, ECG changes. In case such effects occur, treatment may need to be discontinued. Hypokalaemia: ♦ LABA’s may produce significant hypokalaemia in some patients, which has the potential to produce cardiovascular effects. In patients with severe COPD, hypokalaemia may be potentiated by hypoxia and concomitant treatment which may increase the susceptibility to cardiac arrhythmias. Hyperglycaemia: ♦Inhalation of high doses of LABA’s may produce increases in plasma glucose. Upon initiation of treatment with Ultibro® Breezhaler® plasma glucose should be monitored more closely in diabetic patients. ♦ Ultibro® Breezhaler® has not been investigated in patients for whom diabetes mellitus is not well controlled. General disorders: ♦To be used with caution in patients with convulsive disorders or thyrotoxicosis, and in patients who are unusually responsive to LABA’s. Excipients: ♦ Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Pregnancy and Lactation: ♦Ultibro® Breezhaler® should only be used during pregnancy if the expected benefit to the patient justifies the potential risk to the foetus. ♦Not known whether indacaterol, glycopyrronium and their metabolites are excreted in human milk. Use of Ultibro® Breezhaler® by breast-feeding women should only be considered if the expected benefit to the woman is greater than any possible risk to the infant. Interactions: ♦Concomitant use is not recommended with beta adrenergic blockers, anticholinergics or sympathomimetic agents. ♦Concomitant hypokalaemic treatment with methylxanthine derivatives, steroids, or non-potassium-sparing diuretics may potentiate the possible hypokalaemic effect of beta2-adrenergic agonists, therefore use with caution. ♦Inhibition of the key contributors of indacaterol clearance, CYP3A4 and P-gp, does not raise any safety concerns given the safety experience of treatment with indacaterol. ♦No clinically relevant drug interaction is expected when glycopyrronium is co administered with cimetidine or other inhibitors of the organic cation transport. Adverse reactions: ♦Very common: upper respiratory tract infection. ♦Common: nasopharyngitis, urinary tract infection, sinusitis, rhinitis, dizziness, headache, cough, oropharyngeal pain including throat irritation, dyspepsia, dental caries, gastroenteritis, musculoskeletal pain, pyrexia, chest pain. ♦Uncommon: hypersensitivity, angioedema, diabetes mellitus and hyperglycaemia, insomnia, paraesthesia, glaucoma, ischaemic heart disease, atrial fibrillation, tachycardia, palpitations, paradoxical bronchospasm, epistaxis, dry mouth, pruritus / rash, muscle spasm, myalgia, pain in extremity, bladder obstruction and urinary retention, peripheral oedema and fatigue. ♦Please refer to SmPC for a full list of adverse events for Ultibro® Breezhaler®. Legal Category: POM Pack sizes: Cartons containing 10 capsules (1x10 capsule blister strips) and one Ultibro® Breezhaler® inhaler or 30 capsules (3x10 capsule blister strips) and one Ultibro® Breezhaler® inhaler. Marketing Authorisation Holder: Novartis Europharm Limited, Frimley Business Park, Camberley GU16 7SR, United Kingdom. Marketing Authorisation Numbers: EU/1/13/862/007 & 003. Full prescribing information is available on request from Novartis Ireland Ltd, Vista Building, Elm Park Business Park, Dublin 4. Tel: 01 2601255 or at www. Date of Revision of API Text: 9th February 2016 References: 1. Wedzicha JA, Banerji D, Chapman KR, et al. Indacaterol–glycopyrronium versus salmeterol–fluticasone for COPD. N Engl J Med. 2016. 374:2222-2234. 2. Wedzicha JA, et al. Lancet Respir J 2013:1:199–209. 3. Mahler DA, et al. Eur Respir J 2014;43:1599–1609. 4. Vogelmeier CF, et al. Lancet Respir Med; 2013:1:51–60. 5. Ultibro® Breezhaler®. Summary of Product Characteristics. Accessed on, October 2016.

Date of Preparation: October 2016 IE02/ULT16-CNF057q

46 News

Increasing use of caesarean section reflects a worsening risk profile Leading researchers and practitioners in the field of maternal health were brought together at a conference recently to discuss the increasing use of caesarean section in Ireland and the associated risks for mothers and infants. Speakers at the conference at the ESRI discussed recently published and ongoing research from a collaboration between researchers from the ESRI, Trinity’s Department of Sociology and the UCD Centre of Human Reproduction at the Coombe Women and Infants University Hospital. The proportion of births delivered by caesarean section (CS) is increasing across OECD countries and Ireland is no exception. Here the proportion of births by CS has increased from 7% in 1984 to 13% in 1993 and 30% by 2014 (the latest year available). The option of using CS is a major reason why deaths among mothers and children in childbirth are a fraction of what they were in the past. Still, there are now concerns that the benefits of CS may be outweighed by the increased clinical risks and economic costs that it carries. Joint research between the ESRI, Trinity and UCD has investigated the factors driving the increasing use of CS using data on births recorded in the 19 Irish maternity units over the last 17 years. By focusing on variation in the use of

CS across units, the researchers sought to understand what clinical and sociodemographic factors are driving the CS trend and thus contribute to the development of safe and cost-effective services for mothers and babies. The primary reason why use of CS has increased over time is that medical advances have made the operation much safer for the mother but the research also shows that factors like the increasing average age of mothers, particularly first time mothers and the clinical risks that this brings are crucial. The research also shows that maternity units still vary in the use of CS after the characteristics of mothers have been accounted for. Research findings from the joint research initiative:  In 1984 just 7% of deliveries were by CS. This was 13% in 1993 rising to 30% by 2014, a fourfold increase in 30 years.  Ireland’s CS rate is average to high within the OECD where countries like the Netherlands have rates almost 50% lower than Ireland. Italy has the highest rates of CS in Europe.  The average age of mothers has increased from 30 in 1999 to 32 in 2014.  The proportion of births to women aged 35 plus has increased from 20% in 1999 to 33% in 2014, a 65% increase.

Prof Michael Turner,UCD Centre for Human Reproduction

 After adjusting for the risk profile of mothers, significant differences remain in the likelihood of a woman experiencing CS across maternity units in Ireland. Policy Implications

 The proportion of first births in the total decreased from 41% in 1999 to 39% in 2014  The proportion of mothers with high blood pressure (including pre-existing) increased from 3.7% in 2005 to 4.4% in 2014.  The proportion of mothers with gestational diabetes increased from 1.3% in 2005 to 5.5% in 2014.  Use of vaginal birth after CS has fallen significantly over time.  Overall variation across maternity units in proportion of births by CS has fallen since 1999 but the absolute difference between the units with the highest and lowest rates has increased. Units with high proportions in 1999 have increased the most.

 The number of births in Irish maternity units increased from 54,000 in 1999 to over 76,000 in 2009 before falling to 68,000 in 2014, a 26% increase.  The average level of risk associated with mothers giving birth in Irish hospitals is increasing.  However, funding and staffing levels in maternity services has not kept pace with either the number of births or the risk profile. Prof Michael Turner, UCD Centre for Human Reproduction commented that, “Although many of the obstetric trends in Ireland are challenging, Irish maternity units continue to deliver results which are among the best in the world. If we wish to maintain this record we will need to invest to take account of adverse trends whilst constantly striving to coordinate and improve practice in Irish maternity services.”

Health CIOs set to meet at Executive Leadership Summit Tony O’Brien, Director General for the Health Service Executive (HSE), Richard Corbridge, CIO for HSE, Will Smart, CIO for NHS England and Andrew Griffiths, CIO for NHS Wales will open an Executive Leadership Summit event with a lively discussion focused on the CIO and corporate leadership. The event, hosted by HIMSS Europe and the HSE in association with KPMG, will invite around 100 influential chief information officers, chief clinical information officers and industry leaders to discuss the bigger picture topic of ‘Leading through times of change.’ Richard Corbridge, CIO HSE, CEO, eHealth Ireland said, “The HIMSS event is the culmination of a week of events that will showcase digital innovation to the public of Ireland. This will allow us to begin to understand how by embracing the concepts of digital and innovation, health and wellbeing can be supported to be safer, more efficient and with the patient at the centre.” It comes at a pivotal time for Ireland as the country looks to deliver on its ¤875m electronic health record strategy. The Executive Leadership Summit will take place at the Royal Dublin Society on the 24th November. Speakers and participants throughout the day will compare and contrast strategies and approaches across the different geographies in an effort to move forward the digital health agenda. To request an invitation please contact

November 2016 • HPN

Prescribing Information (Ireland) ▼ Vargatef® 100 mg and 150 mg soft capsules Soft capsules containing 100 mg or 150 mg nintedanib (as esilate). Indication: Vargatef is indicated in combination with docetaxel for the treatment of adult patients with locally advanced, metastatic or locally recurrent non-small cell lung cancer (NSCLC) of adenocarcinoma tumour histology after firstline chemotherapy. Dose and Administration: Treatment with Vargatef should be initiated and supervised by a physician experienced in the use of anticancer therapies. The recommended dose of nintedanib is 200 mg twice daily administered approximately 12 hours apart, on days 2 to 21 of a standard 21 day docetaxel treatment cycle. Vargatef must not be taken on the same day of docetaxel chemotherapy administration (= day 1). If a dose of nintedanib is missed, administration should resume at the next scheduled time at the recommended dose. The individual daily doses of nintedanib should not be increased beyond the recommended dose to make up for missed doses. The recommended maximum daily dose of 400 mg should not be exceeded. Patients may continue therapy with nintedanib after discontinuation of docetaxel for as long as clinical benefit is observed or until unacceptable toxicity occurs. For posology, methods of administration, and dose modifications of docetaxel, please refer to the corresponding product information for docetaxel. Dose adjustments should be considered in case of adverse events of pre-specified severity: diarrhoea, vomiting, nausea and other non haematological or haematological adverse reactions, and aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) and bilirubin elevations – as initial measure for the management of adverse reactions treatment with nintedanib should be temporarily interrupted. Please refer to the Summary of Product Characteristics (SPC) for further information including when to discontinue treatment. Paediatric population: Safety and efficacy in children aged 0-18 years have not been established. Elderly patients (≥ 65 years): No overall differences in safety and efficacy were observed for elderly patients. No adjustment of initial dosing required on the basis of a patient’s age. Race and body weight: Based on population pharmacokinetic analyses, no a priori dose adjustments necessary. Safety data for Black and African American patients are limited. Renal impairment: Less than 1 % of a single dose of nintedanib is excreted via the kidney. Adjustment of the starting dose in patients with mild to moderate renal impairment is not required. The safety, efficacy and pharmacokinetics have not been studied in patients with severe renal impairment (< 30 ml/min creatinine clearance). Hepatic impairment: Nintedanib is predominantly eliminated via biliary/faecal excretion (> 90%). Exposure increased in patients with hepatic impairment (Child Pugh A, Child Pugh B). No adjustment of the starting dose is needed for patients with mild hepatic impairment based on clinical data (Child Pugh A). The safety and efficacy have not been investigated in patients with hepatic impairment classified as moderate (Child Pugh B) and severe (Child Pugh C). Treatment of patients with moderate to severe hepatic impairment is not recommended. The capsules must be taken orally, preferably with food, swallowed whole with water, and must not be chewed or crushed. Contraindications: Hypersensitivity to nintedanib, peanut or soya, or to any of the excipients. Warnings and Precautions: Patients with gastrointestinal disorders including diarrhoea, nausea and vomiting may require interruption, dose reduction or discontinuation of therapy. Diarrhoea should be treated at first signs with adequate hydration and anti-diarrhoeal medicinal products, e.g. loperamide. Supportive care for nausea and vomiting may include medicinal products with anti-emetic properties, e.g. glucocorticoids, anti-histamines or 5-HT3 receptor antagonists and adequate hydration. In the event of dehydration, administration of electrolytes and fluids is required. Plasma levels of electrolytes should be monitored, if relevant gastrointestinal adverse events occur. Combination treatment with docetaxel is associated with a higher frequency of neutropenia of CTCAE grade ≥ 3 as compared to treatment with docetaxel alone. Subsequent complications such as sepsis or febrile neutropenia have been observed. Blood counts should be monitored during therapy, please refer to SPC. Hepatic function: treatment is not recommended in patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment. Based on increased exposure, the risk for adverse events may be increased in patients with mild hepatic impairment (Child Pugh A). Nintedanib was associated with an elevation of liver enzymes (ALT, AST, ALKP, gamma-glutamyltransferase) or bilirubin, with a potentially higher risk for female patients. These increases were reversible in the majority of cases. Transaminase, ALKP and bilirubin levels should be investigated before initiation of combination treatment and monitoring continued as required. If relevant liver enzyme elevations are measured, interruption, dose reduction or discontinuation of the therapy with Vargatef may be required, please refer to the SPC. VEGFR inhibition might be associated with an increased risk of bleeding. Vargatef is not recommended in patients with recent pulmonary bleeding (> 2.5 ml of red blood) as well as patients with centrally located tumours with radiographic evidence of local invasion of major blood vessels or radiographic evidence of cavitary or necrotic tumours. Patients taking concomitant anticoagulation, such as warfarin or phenprocoumon should be monitored regularly for changes in prothrombin time, international normalized ratio (INR), and clinical bleeding episodes. Patients with stable brain metastasis should be closely monitored for signs and symptoms of cerebral bleeding. Treatment not recommended for patients with active brain metastasis. Patients should be closely monitored for thromboembolic events and Vargatef should be discontinued in patients with life-threatening venous thromboembolic reactions. Caution should be used when treating patients with a higher cardiovascular risk including known coronary artery disease. Treatment interruption should be considered in patients who develop signs or symptoms of acute myocardial ischaemia. Based on the mechanism of action patients treated with Vargatef may have an increased risk of gastrointestinal perforations. Particular caution should be exercised when treating patients with previous abdominal surgery or a recent history of a hollow organ perforation. Treatment should only be initiated at least 4 weeks after major surgery. Therapy should be permanently discontinued in patients who develop gastrointestinal perforation. Nintedanib may impair wound healing. Treatment should therefore only be initiated or, in case of perioperative interruption, resumed based on clinical judgement of adequate wound healing. Caution should be exercised in patients who may develop QTc prolongation. Dietary soya products are known to cause allergic reactions including severe anaphylaxis in persons with soya allergy. Patients with known allergy to peanut protein carry an enhanced risk for severe reactions to soya preparations. Nintedanib exposure increased linearly with patient age, was inversely correlated to weight, and was generally higher in patients of Asian race which may result in a higher risk of developing liver enzyme elevations; close monitoring is recommended in patients with several of these risk factors. Close monitoring is recommended in patients weighing < 50 kg. Interactions: Interaction studies have only been performed in adults. P-glycoprotein (P-gp): Nintedanib is a substrate of P-gp. If co-administered, potent P-gp inhibitors e.g. ketoconazole or erythromycin may increase exposure to nintedanib. Patients should be monitored closely for tolerability of nintedanib. Potent P-gp inducers e.g. rifampicin, carbamazepine, phenytoin and St. John’s Wort may decrease exposure to nintedanib. Co-administration should be carefully considered. Cytochrome (CYP)- enzymes: Likelihood of drug-drug interactions with nintedanib based on CYP metabolism considered to be low. Other medicinal products: The potential for interactions with hormonal contraceptives was not explored. Fertility, Pregnancy and Lactation: Nintedanib may cause foetal harm in humans; women should avoid becoming pregnant while receiving this treatment and use adequate contraception during and for at least 3 months after the last dose of Vargatef. Since the effect of nintedanib on the metabolism and efficacy of contraceptives has not been investigated, barrier methods should be applied as a second form of contraception, to avoid pregnancy. There is no information on the use of Vargatef in pregnant women, but pre-clinical studies have shown reproductive toxicity and therefore nintedanib should not be used during pregnancy unless the clinical condition requires treatment. Pregnancy testing should be conducted at least prior to treatment. Female patients should be advised to notify their doctor or pharmacist if they become pregnant during therapy. If the patient becomes pregnant while receiving Vargatef, she should be apprised of the potential hazard to the foetus. Termination of the treatment with Vargatef should be considered. There is no information on the excretion of nintedanib and its metabolites in human milk. Pre-clinical studies showed that small amounts of nintedanib and its metabolites (≤ 0.5 % of the administered dose) were secreted into milk of lactating rats. A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Vargatef. Based on preclinical investigations there is no evidence for impairment of male fertility. There are no human or animal data on potential effects of nintedanib on female fertility available. Undesirable effects: The most frequently reported adverse reactions specific for nintedanib were diarrhoea, increased liver enzymes (ALT and AST) and vomiting. Very common (≥ 1/10): Neutropenia (includes febrile neutropenia), decreased appetite, electrolyte imbalance, peripheral neuropathy, bleeding, diarrhoea, vomiting, nausea, abdominal pain, alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, mucositis (including stomatitis), rash. Common (≥ 1/100 < 1/10): Febrile neutropenia, abscesses, sepsis, dehydration, venous thromboembolism, hypertension, hyperbilirubinaemia, gamma-glutamyltransferase increased. Prescribers should consult the Summary of Product Characteristics for further information on side effects and recommended measures. Pack sizes: 100 mg 120 capsules; 150mg 60 capsules. Legal category: POM. MA numbers: 100 mg: EU/1/14/954/002; 150 mg: EU/1/14/954/004. Marketing Authorisation Holder: Boehringer Ingelheim International GmbH, Binger Strasse 173, 55216 Ingelheim am Rhein, Germany. Prescribers should consult the Summary of Product Characteristics for full prescribing information. Additional information is available on request from Boehringer Ingelheim Ireland Ltd, The Hyde Building, The Park, Carrickmines, Dublin 18. Prepared in September 2016

EXTENDING WHAT’S POSSIBLE VARGATEF®, the only triple angiokinase inhibitor for advanced adenocarcinoma of the lung after first-line chemotherapy1 VARGATEF® is indicated in combination with docetaxel for the treatment of adult patients with locally advanced, metastatic or locally recurrent non-small cell lung cancer of adenocarcinoma tumour histology after first-line chemotherapy1

This medicinal product is subject to additional monitoring. Adverse events should be reported to the Health Products Regulatory Authority at or by email to Adverse events should also be reported to Boehringer Ingelheim Pharmacovigilance on 01 291 3960 or by email to

Reference: 1. VARGATEF® 100/150mg Summary of Product Characteristics. Available at: Accessed September 2016. IRE/VAR-161124a Date of preparation: September 2016

48 Event Gallery

Workshop on Drug Transporters in the Lungs The School of Pharmacy and Pharmaceutical Sciences at Trinity College Dublin recently hosted the first Workshop on Drug Transporters in the Lungs at the Panoz Institute. The Workshop was financially supported by the SFI ISCA Japan initiative and co-sponsored by the Japanese Society for the Study of Xenobiotics (JSSX). An international group of 28 scientists from academia and the pharmaceutical industry undertaking research in inhalation biopharmaceutics attended the event. Participants heard about a series of studies focussing on new targets for the treatment of lung diseases, a particularly important topic as a result of new pipeline drug development and novel clinical entities which may have a narrow therapeutic index or be too toxic for systemic delivery. Improving the efficiency of inhaled aerosol delivery by targeting drug to the appropriate lung regions/sites, may improve the therapeutic response and minimise potential adverse effects. Other topics covered in vitro and ex vivo models of the air-blood barrier and advances in analytical technology.

RCSI Hospitals Group launches Healthy Ireland Implementation Plan Barry McGinn, Head of Planning Performance & Programme Management, Health & Wellbeing Division, HSE; Dr Cate Hartigan, Assistant National Director of Health Promotion & Improvement, HSE; Emer Smyth, A/Health Promotion & Improvement, HSE DNE Health & Wellbeing Division, HSE; Emer Smyth, A/Health Promotion & Improvement, HSE DNE Health & Wellbeing Division, HSE; Minister Marcella Corcoran Kennedy, Minister of State for Health Promotion; Brian Fenton, Dublin GAA Player and Physiotherapist, Beaumont Hospital; Sheila McGuinness, COO RCSI Hospitals Group; Ian Carter, CEO RCSI Hospitals Group and Cathal Kelly, CEO/Registrar Royal College of Surgeons in Ireland (RCSI)

The Minister for Health Promotion, Marcella Corcoran Kennedy TD, launched the RCSI Hospitals Group Healthy Ireland Implementation Plan 2016 – 2019 at the end of last month (October). Joining the Minister for the launch were Mr Ian Carter, CEO of the RCSI Hospitals Group, Dr. Stephanie O’Keeffe, National Director, Health and Wellbeing, HSE; Ms Anne Maher, Chairperson of the RCSI Hospitals Group, Professor Cathal Kelly, CEO of November 2016 • HPN

the RCSI, Ms Sheila McGuinness, COO & RCSI Hospitals Group Healthy Ireland Executive Lead and Brian Fenton, Dublin GAA Player and Physiotherapist. The plan includes 74 actions setting ambitious targets to better meet the needs of its growing population and healthcare workforce. The three priority areas to be progressed under this plan are: 1) Reducing the burden of chronic disease

2) Improving breastfeeding rates in the Group's three maternity services 3) Improving staff health and wellbeing Having a large maternity hospital and Maternity Units in the Group, this plan has prioritised breast feeding. The RCSI Hospitals Group will continue to provide specific patient-centred breast feeding supports to pregnant women. It focuses on reaching the Baby Friendly Hospital Programme

breastfeeding target of an annual 2 % increase in initiation rates in all Maternity Units. The RCSI Hospitals Group is experiencing increasing patient presentations due to the rising levels of chronic diseases due to smoking, alcohol, obesity and inactivity. Ms Anne Maher, Chair of the RCSI Hospitals Group, welcomed the Plan. “Hospitals are busy and stressful environments which present patients and staff with challenges to achieve high quality care at all times. I believe the implementation of this plan will improve the health of our communities which in turn will enable us to change the hospital environment to become more accessible and provide a healthier environment in which patients can recover and staff can flourish. This plan also includes 10 specific actions prioritising the health & wellbeing of our 8,000 staff." Dr Stephanie O’Keeffe, HSE National Director of Health and Wellbeing said that over time, it is envisaged that all remaining Hospital Groups and the 9 Community Healthcare Organisations will develop similar plans.


Epilepsy Ireland celebrates 50 years with largest ever National Conference Epilepsy Ireland, the national epilepsy organisation, recently held a two-day national epilepsy conference with 12 nationally and internationally renowned speakers in the Alexander Hotel, Dublin. Affecting almost 40,000 people in Ireland, epilepsy is one of the most common neurological conditions. The extended event marks 50 years of Epilepsy Ireland focusing on the latest developments for adults and children with the condition. The conference also included a number of world class academics and medical experts, including Dr Colin Doherty, Director of Epilepsy Services at St James's and national clinical lead for the National Epilepsy Care Programme in Ireland. He is involved in a number of large collaborate research projects covering the genetics and imaging of epilepsy and cognition. Speaking ahead of event, CEO, Peter Murphy, said, “Over the years this event has proved extremely beneficial for people with epilepsy, their families and carers. The conference always provides useful information in the advances of treating the condition as well as Q&A sessions with medical professionals. There is a strong focus on children this year, which will also be extremely beneficial for parents.” Epilepsy Ireland Patron and Broadcaster Rick O’Shea pictured with Epilepsy Ireland CEO, Peter Murphy

Arsenal of new antimicrobials identified

Orla O'Sullivan, Paula O'Connor, Fergus Collins and Mary Read The latest antimicrobial, called formicin, is a bacteriocin which is a small bacterially produced antimicrobial protein. “Formicin was picked up in our most recent screening for new antimicrobials. We have identified 20 new small proteins to date including Thuricin and Lacticin

3147” said Professor Paul Ross, who leads the research with Professor Colin Hill at the APC Microbiome Institute in University College Cork and Teagasc. “We plan to further develop these compounds which have important implications for human and animal health.”

Antimicrobial resistance poses one of the biggest threats to global health today. According to the WHO (2015) antibiotic resistance in the European Union alone, is estimated to cause 25,000 deaths and cost more than US$1.5 billion every year in healthcare expenses and productivity losses. Without effective antibiotics for the prevention and treatment of infections, many of the achievements of modern medicine such as organ transplantations, chemotherapy and surgeries such as caesarean sections become much more dangerous. “The new antimicrobial, Formicin, was isolated from Bacillus paralichenformis APC1576, a bacteria which was originally isolated from the intestine of a mackerel” said Fergus Collins, the PhD student at Teagasc, Moorepark who discovered Formicin. “Formicin can kill a wide

range of harmful bacteria including the Gram positive pathogens Staphyloccous aureus, Clostridium difficile, Listeria monocytogenes and Steptococcus mutans, a causative agent of tooth decay.” Formicin is a member of a subclass of bacteriocins called lantibiotics which contain certain modified amino acids. Formicin is made up of 2 lantibiotic peptides. The first peptide likely binds to the cell membrane of the bacterial target and subsequently recruits the second formicin peptide which then inserts into the membrane; the resulting pore formed then causes cell death. Formicin is unique among lantibiotics due to differences in the peptide’s charge and composition. This research was supported by Science Foundation Ireland through a Research Centre grant to the APC Microbiome Institute.

Best Paper Award for TCD Researcher An open access research paper on vitamin D has won Best Published Paper Award from United European Gastroenterology (UEG). The winning paper entitled, ‘Effects of vitamin D supplementation on intestinal permeability, cathelicidin and disease markers in Crohn’s disease: Results from a randomised double-blind placebo-controlled study’ emerged from Dr Tara Raftery’s Irish Research Council funded PhD research in Trinity’s Department of Clinical Medicine, with principal investigator Associate Professor in Human Nutrition, Maria O’Sullivan, and colleagues. Dr Raftery, as first author, will receive the prize at the opening ceremony at UEG Week in Vienna. The paper represents collaboration with researchers from Queen Mary University of London and the University of Calgary Canada. This pilot study increases the understanding of how vitamin D, in addition to standard medications, might help maintain remission in chronic inflammatory diseases, such as Crohn’s disease. The full paper may be accessed here:

HPN • November 2016

50 Clinical R&D ABLYNX ANNOUNCES SECOND EXTENSION OF ION CHANNEL RESEARCH COLLABORATION Ablynx [Euronext Brussels: ABLX; OTC: ABYLY] have announced a second extension of its research collaboration with a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, known as MSD outside the United States and Canada, to develop and commercialise Nanobody® candidates directed towards an undisclosed voltage gated ion channel. The extension agreement will trigger a ¤1 million milestone payment to Ablynx, and Merck will extend their funding of the research collaboration at Ablynx to September 2018. The ion channel collaboration was announced in October 2012 and included a ¤6.5 million upfront payment and ¤2 million in initial research funding. In March 2015, the Company announced a first extension of the research term to September 2016. Dr Edwin Moses, CEO of Ablynx, commented, "We are pleased that Merck will, for the second time, extend the research term of our current ion channel collaboration. This decision is based on the very encouraging progress we made in the discovery of Nanobodies against this challenging target and builds on the competitive advantage of our proprietary Nanobody platform in the generation of innovative therapeutic candidates against target classes that have proven difficult to address with conventional antibody technologies."

MCCI AND BOSTON SCIENTIFIC DEVELOP MULTI-FUNCTION CHIP TO ENABLE NEXT GENERATION IMPLANTABLE DEVICE INNOVATIONS In collaboration with Boston Scientific, the Microelectronic Circuits Centre Ireland (MCCI) an EI/IDA funded Technology Centre hosted at Tyndall National Institute, has developed an innovative multi-function programmable electronic chip designed to enable heart pacemakers that can be November 2016 • HPN

smaller, more efficient and more convenient for patients. The nano-watt power biomedical Integrated Circuit (IC) includes power management, a flexible microprocessor interface and therapy monitoring, that supports pacemaker and neuro-stimulation therapy applications. The prototype chip also incorporates a novel instrumentation amplifier to allow pacemaker devices to more effectively sense bio-potential signals. "We have combined the pacemaker and other novel circuits into a single chip in order to make them smarter, more sensitive and more powerefficient, in addition to reducing form factor” explains Donnacha O’Riordan, MCCI Executive Director. “The programmable Integrated Circuit uses separate channels on a single chip for sensing the activity of the heart and for setting the pace of beating. This research will enable smaller implantable pacemakers in the future, which would result in less invasive procedures to implant them and the devices would need to be replaced less frequently, firmly establishing MCCI as a center of excellence for bio-medical microelectronics research.” MCCI and Boston Scientific collaborated on the research program through a twoyear Innovation Partnership supported by Enterprise Ireland and led by Gerry McGlinchey and Dr Ivan O’Connell at MCCI. “The project has brought together the engineering and circuit-design expertise at MCCI and the medical and scientific expertise of researchers at Boston Scientific,” said Mr O’Riordan. “We look forward to building on this relationship in the next phase of our collaboration with Boston Scientific.”

LEO PHARMA LAUNCHES ENSTILAR® IN IRELAND, THE FIRST FIXED-COMBINATION FOAM SPRAY FOR THE TREATMENT OF PLAQUE PSORIASIS LEO Pharma has officially launched Enstilar®, the first fixed-combination, cutaneous foam spray for the once-daily

topical treatment of all severities of plaque psoriasis for patients 18 years or older. Data shows that Enstilar® is a more effective topical combination treatment than those currently available, is generally well-tolerated with more than half of patients in clinical trials experiencing significant visible signs of improvement within four weeks and with some patients seeing improvements at one week. This innovative treatment can also improve patients’ quality of life (QoL). 75% of patients feel that their quality of life is significantly impacted by psoriasis, both emotionally and physically. 81% of psoriasis patients using Enstilar® foam spray in trials reported QoL improvements after four weeks, with more than 70% seeing a reduction in itch-related sleep loss. The symptomatic relief experienced by the majority of patients may be attributed to the cooling effect of the new foam spray. “Enstilar® foam spray represents a welcome new choice of topical therapy for people living with plaque psoriasis, particularly those who are looking at new options with their GP or dermatologist,” said Dr Niki Ralph, Consultant Dermatologist at the Mater Hospital, Dublin. “In my experience, patients using Enstilar® report that they find the foam spray easy to use and pleasant to apply to their skin. Further, because some patients experience difficulties in adhering to their psoriasis treatment, I feel that Enstilar® offers a simpler, convenient option thereby potentially improving adherence," she concluded. The launch of Enstilar® foam spray in Ireland follows findings in the positive regulatory review of the results of the pivotal Phase 3a PSO-FAST study, which evaluated its efficacy and safety profile across a four-week period, and the Phase 2 MUSE safety profile study. In the PSO-FAST clinical trial, over half of patients treated with calcipotriol/betamethasone dipropionate foam spray were “Clear” or “Almost Clear” by week 4, as measured by the

Physician Global Assessment (PGA) improvement score. Additionally, more than half of patients treated with calcipotriol/ betamethasone dipropionate foam spray achieved a 75% improvement in modified (excluding head) Psoriasis Area and Severity Index (mPASI) score from baseline after 4 weeks of treatment. “The launch of Enstilar® is an exciting landmark for LEO Pharma, as it’s the first combination treatment of its kind,” said Geraldine Murphy, Managing Director of LEO Pharma UK & Ireland. “At LEO Pharma we are commited to improving outcomes and quality of life for people living with skin conditions such as psoriasis. This new foam spray delivery is easy-to-apply and will hopefully encourage patients to adhere to their treatment plan,” she added. Adherence in Psoriasis Management – LEO Pharma’s Solutions for Patients Adherence is still a significant challenge for patients living with psoriasis (studies consistently suggest that up to 40% of people with psoriasis do not use their medication as directed). In recognition of this challenge and to help patients achieve optimal outcomes, LEO Pharma has developed the below suite of new resources: • QualityCareTM website - For more information about psoriasis visit • MyPso app - For practical advice to make small changes that can have a big impact on psoriasis, download the MyPso app at the Apple App Store or Google Play • Nurse support line - To speak in confidence to a nurse before, during and after treatment call our dedicated nurse support line on 1800 77 33 88. Lines are open Monday to Friday from 08:30-17:00

51 CANCER IMMUNOTHERAPY ATEZOLIZUMAB HELPS SPECIFIC TYPE OF LUNG CANCER SUFFERERS LIVE LONGER Roche has announced positive results for atezolizumab from the Phase III study, OAK [NCT02008227]. The study met its co-primary endpoints and showed a statistically significant and clinically meaningful improvement in overall survival (OS) compared with docetaxel chemotherapy, in people with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease progressed on or after treatment with platinum-based chemotherapy. Adverse events were consistent with what has been previously observed for atezolizumab. Roche looks forward to presenting the full results at the upcoming European Society of Medical Oncology (ESMO) meeting, 7-11th October 2016.1 “These results add to the growing body of evidence that supports the role of atezolizumab as a potential new treatment for specific types of advanced NSCLC,” said Dr Michal Starnawski, MD, PhD, Medical Director of Roche Products (Ireland) Ltd. “This is very encouraging news for people living with this disease because lung cancer is one of the leading causes of cancer deaths in Ireland. We hope to bring this treatment option to patients as soon as possible”. Lung cancer is the fourth most common cancer in Ireland, with an estimated 2,200 new cases diagnosed every year. NSCLC is the most common type of lung cancer, accounting for around 85% of all cases2. A total of 1,225 patients were enrolled and randomised 1:1 to receive either docetaxel (75 mg/m2 Intravenous infusion) or atezolizumab (1,200 mg intravenous infusion) every three weeks. Treatment on atezolizumab continued as long as patients experienced clinical benefit, as assessed by the investigator, or until unacceptable toxicity. The primary efficacy analysis was based on the first 850 randomised patients, and the secondary efficacy analysis will include all 1,225 randomised patients3. The FDA granted Breakthrough Therapy Designation (BTD) for atezolizumab for the treatment of people with PD-L1 (programmed death-ligand 1) positive nonsmall cell lung cancer (NSCLC) whose disease has progressed during or after platinum-based

chemotherapy (and appropriate targeted therapy for those with an EGFR mutation-positive or ALKpositive tumour).

We will work with all stakeholders to ensure that Gazyvaro is made available to all eligible patients as soon as possible.”

Atezolizumab does not currently have a European Medicines Agency (EMA) licence in Europe. “We anticipate license approval from June 2017 for this medicine in lung cancer and will be engaging with the relevant authorities to ensure that Irish patients have timely access to this treatment. ” said Ms. Clare Blaney, Market Access Director at Roche Products (Ireland) Ltd.

During initial therapy, response rates to MabThera- based treatment, the current standard of care, are greater than 90%, but there is no cure and people will eventually relapse. The disease becomes more difficult to treat at each relapse, and if a patient does not respond or relapses during or within six months of MabTheracontaining treatment, they will likely need a different treatment. These people often have a poor prognosis and few treatment options.

ROCHE’S GAZYVARO®  (OBINUTUZUMAB) APPROVED IN EUROPE IN COMBINATION WITH BENDAMUSTINE Roche recently announced that the European Commission has approved Gazyvaro® (obinutuzumab) in combination with bendamustine chemotherapy followed by Gazyvaro maintenance in people with follicular lymphoma who did not respond or who progressed during or up to six months after treatment with MabThera® (rituximab) or a MabThera-containing regimen. The approval is based on results from the pivotal phase III GADOLIN study which showed that Gazyvaro plus bendamustine, followed by Gazyvaro alone resulted in a 52% reduction (HR=0.48, 95% CI 0.34-0.68, p<0.0001) in the risk of disease worsening or death (progression-free survival, PFS), compared to bendamustine alone, as evaluated by an independent review committee (IRC). As assessed by investigator review, median PFS with the Gazyvaro regimen was more than double that with bendamustine alone (29.2 months vs. 13.7 months; HR=0.48, 95% CI 0.35-0.67, p<0.0001). “The latest approval indicates a significant development in the treatment of follicular lymphoma,” said Dr Mike Starnawski, Medical Director of Roche in Ireland. “The reductions in the risk of disease progression or death, as evidenced by the GADOLIN Phase III results, illustrate the important role this combination will play in the management of patients in Ireland who did not respond or progressed under MabThera treatment.” Clare Blaney, Market Access and Strategic Partnerships Director at Roche in Ireland, said, “We submitted a Health Technology Assessment (HTA) dossier for Gazyvaro in this indication to the NCPE earlier this year and expect a reimbursement decision from them by the end of October 2016.

With this approval, Gazyvaro is now permitted in Europe to treat two common types of blood cancer. Gazyvaro was previously approved in combination with chlorambucil for people with previously untreated chronic lymphocytic leukaemia (CLL) and comorbidities that make them unsuitable for full-dose fludarabine based therapy. That approval was based on data from the pivotal CLL11 study, where the combination of Gazyvaro plus chlorambucil showed superior efficacy when compared headto-head with MabThera plus chlorambucil and chlorambucil alone.

VITAROS® THE FIRST TOPICAL TREATMENT INDICATED IN ERECTILE DYSFUNCTION Recordati Ireland has announced the launch of Vitaros® (alprostadil cream). VITAROS® is the first topical cream treatment indicated in erectile dysfunction and is effective in a broad range of patients with erectile dysfunction1-7. Please see enclosed our Patient Information Brochure with details of our website www.reactivatingpassion. ie which contains general information for patients and a reserved area with product information and mode of action videos for Medical Practitioners. VITAROS® can be used in treatment-naïve patients as well as patients with mild to severe erectile dysfunction, it has reliable short- and long-term improvement in erectile dysfunction and a fast onset of action when and where it is needed. VITAROS® also has no interference with drugs, food, or alcohol and has reduced concerns over systemic adverse events compared to oral medications. 2 Erectile dysfunction (ED) is a very common disorder with a deep impact on patients and their partners. Several options

are now available for treating ED; oral pharmacotherapy with phosphodiesterase-5 (PDE5) inhibitors currently represents the first-line option for many ED patients. Vitaros® is a new topical, non-invasive treatment for ED that offers the combination of an active drug (alprostadil, a synthetic PGE1) with a skin enhancer that improves its local absorption directly at the site of action. 2 Vitaros® has a favourable Pharmacodynamic profile and is poorly absorbed in systemic circulation. This makes it suitable in any circumstances and results in a reduced risk of adverse events (AEs), systemic AEs being reported in only 3% of the treated population. Its clinical efficacy has been demonstrated in both phase II and III trials, showing a global efficacy up to 83% with the 300 mcg dose in patients with severe ED significantly better than placebo. Its fast onset of action together with its favourable toxicity profile and lack of interactions with other drugs makes Vitaros® a firstline therapeutic option for patients with ED, particularly for individuals who are reluctant to take systemic treatments or with AEs. It may also have an important role in patients not responding to PDE5 inhibitors, particularly those with ED after radical prostatectomy.2 Vitaros® 300 μg is indicated for the treatment of men ≥18 years of age affected by Erectile Dysfunction and is applied topically onto the urethral meatus 5-30 minutes prior to attempting intercourse. Vitaros® is effective within 5 to 30 minutes of administration and its effect lasts approximately 1 to 2 hours depending on the individual patient. It should be used with a maximum frequency of once every 24 hours and no more than 3 times per week.6 Vitaros® is available in packs of 4 single use Accu-Dose containers, and each Accu-dose contains 3mg/g alprostadil cream. Full prescribing information is available from Recordati Ireland, Raheens East, Ringaskiddy, Co. Cork (021) 4379400. For Medical information Tel (1800) 303351 or email References: 1. Padma-Nathan H, Steidle C, Salem S, et al. Int J Impot Res 2003;15(1):10-7 2. Moncada I, et al. Urologia 2015; 3. Padma-Nathan H, Yeager JL. Urology. 2006;68(2):386-91 4. Rooney M, Pfister W. Mahoney M, et al. J Sex Med. 2009;6(2):520-34 5. Becher E. Expert Opin Pharmacother 2004;5(3):623-32 6. Vitaros. Summary of Product Characteristics 7. Yeager J. Beihn RM. Int J Impot Res 2005;17(1):91-5

HPN • November 2016

For Pulmonary Arterial Hypertension For Chronic thromboembolic Pulmonary Hypertension For patients like yours Adempas® is the first and only therapy that stimulates soluble guanylate cyclase (sGC) independently of nitric oxide1 Adempas® is the first treatment to demonstrate significant and sustained clinical efficacy alone or in combination with an ERA or non-IV PCA in PAH patients across multiple endpoints2 Adempas® is the first and only pharmacologic treatment to significantly improve exercise capacity and haemodynamic parameters in patients with CTEPH3 Riociguat significantly improved 6MWD and WHO FC in two independent, randomised, double-blind, placebo controlled trials (PATENT-1, CHEST-1).2,3

Adempas®t (Riociguat) This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 of the SPC for how to report adverse reactions.


Refer to Summary of Product Characteristics before prescribing. Presentation: Film-coated tablet containing 0.5mg, 1mg, 1.5mg, 2mg and 2.5mg riociguat. Indications: Chronic thromboembolic pulmonary hypertension (CTEPH): treatment of adult patients with WHO functional class II to III with inoperable CTEPH, persistent or recurrent CTEPH after surgical treatment to improve exercise capacity. Pulmonary arterial hypertension (PAH): In monotherapy or in combination with endothelin receptor antagonists, is indicated for the treatment of adult patients with pulmonary arterial hypertension (PAH) with WHO functional class II to III to improve exercise capacity. Efficacy has been shown in a PAH population including aetiologies of idiopathic or heritable PAH or PAH associated with connective tissue disease. Dosage and Administration: Adults: Treatment should only be initiated and monitored by a physician experienced in the treatment of CTEPH or PAH. Recommended starting dose: 1mg taken orally, approximately 6-8 hours apart, three times daily for 2 weeks. Increase dose by 0.5mg three times daily every 2 weeks, to maximum of 2.5mg three times daily if systolic blood pressure ≥ 95mmHg. 1.5mg is adequate for some PAH patients. If systolic blood pressure falls below 95mmHg, the dose should be maintained provided the patient does not show any signs or symptoms of hypotension. If at any time during the up-titration phase systolic blood pressure decreases below 95mmHg and the patient shows signs and symptoms of hypotension the current dose should be decreased by 0.5mg three times daily. Individual dose titration at treatment initiation allows adjustment of the dose to the patients needs. The established individual dose should be maintained unless signs and symptoms of hypotension occur. Tablets can generally be taken with or without food. Paediatric: Use of riocguat in children and adolescents should be avoided. Elderly: Exercise particular care during dose titration. Renal Impairment: Severe- Not recommended, Moderate- Exercise particular care during individual dose titration due to risk of hypotension. Hepatic Impairment: Severe-contraindicated, Moderate- Exercise particular care during

individual dose titration due to risk of hypotension. Smokers: Smokers are advised to stop smoking as concentrations of riociguat in smokers are reduced compared to non-smokers. A max dose of 2.5mg three times daily may be required in patients who are smoking or start smoking during treatment. Contraindications: Co-administration with PDE 5 inhibitors (such as sildenafil, tadalfil, vardenafil); severe hepatic impairment (Child Pugh C); hypersensitivity to the active substance or to any of the excipients; pregnancy; co-administration with nitrates or nitric oxide donors (such as amyl nitrite) in any form including recreational drugs called “poppers”; patients with systolic blood pressure below 95 mm Hg at treatment initiation; patients with pulmonary hypertension associated with idiopathic interstitial pneumonias (PH-IIP). Precautions and Warnings: In PAH, studies with Adempas have been mainly performed in forms related to idiopathic or heritable PAH and PAH associated with connective tissue disease. The use of Adempas in other forms of PAH not studied is not recommended. In CEPTH, pulmonary endarterectomy is the treatment of choice as it is potentially curative. Therefore, an expert assessment of operability should be done prior to treatment with Ademapas. Pulmonary veno-occlusive disease (PVOD): Administration of Adempas to PVOD patients is not recommended. Respiratory tract bleeding: Careful monitoring of patients taking anticoagulants is recommended. The risk of serious and fatal respiratory tract bleeding may be further increased under treatment with Adempas, the use should be avoided in patients with a history of serious haemoptysis or who have previously undergone bronchial arterial embolization. Hypotension: Adempas has vasodilatory properties which may result in lowering of the blood pressure. Adempas must not be used in patients with a systolic blood pressure below 95 mmHg. Patients older than 65 years are at increased risk of hypotension. Therefore, caution should be exercised when administering Adempas in these patients. Renal impairment: Data in patients with severe renal impairment (creatinine clearance <30ml/min) are limited and there are no data for patients on dialysis, therefore Adempas is not recommended in these patients. There is increased Adempas exposure in patients with mild and moderate renal impairment. There is a higher risk of hypotension in these patients, particular care should be exercised during individual dose titration. Hepatic impairment: There is no experience in patients with severe hepatic impairment (Child Pugh C); Adempas is contraindicated in these patients. PK data show that higher Adempas exposure was observed in patients with moderate hepatic impairment (Child Pugh B). Particular care should be exercised during individual dose titration.

References: 1. Grimminger F. et al. Eur Respir J 2009; 33: 785-92. 2. Ghofrani H-A et al. New Engl J Med 2013; 369: 330-40 (PATENT-1) and Supplementary Appendix. 3. Ghofrani H-A et al. New Engl J Med 2013; 369: 319-29 (CHEST-1) and Supplementary Appendix. WHO FC = World Health Organization functional class. sGC = soluble guanylate cyclase. 6MWD = 6 minute walking distance

There is no clinical experience with Adempas in patients with elevated liver aminotransferases (>3 x Upper Limit of Normal (ULN)) or with elevated direct bilirubin (>2 x ULN) prior to initiation of treatment; Adempas is not recommended in these patients. Smokers: Plasma concentrations of Adempas in smokers are reduced compared to non-smokers. Dose adjustment may be necessary in patients who start or stop smoking during treatment with Adempas. Paediatric Population: The safety and efficacy in children and adolescents below 18 years have not been established. The use in children and in growing adolescents should be avoided. Adempas contains lactose. Interactions: The concomitant use of Adempas with strong multi pathway cytochrome P450 (CYP) and P-glycoprotein (P-gp) / breast cancer resistance protein (BCRP)inhibitors such as azole antimycotics (e.g. ketoconazole, itraconazole) or HIV protease inhibitors (e.g. ritonavir) is not recommended, due to the pronounced increase in Adempas exposure. The concomitant use of Adempas with strong CYP1A1 inhibitors, such as the tyrosine kinase inhibitor erlotinib and the immuno-suppressive agent cyclosporine A, may increase Adempas exposure. Blood pressure should be monitored and dose reduction of Adempas be considered. Pregnancy and Lactation: Contraindicated during pregnancy and breast-feeding. Side Effects: Very common: headache, dizziness, dyspepsia, peripheral oedema, nausea, diarrhea and vomiting. Common: Gastroenteritis, anaemia, palpitation, hypotension, haemoptysis, epistaxis, nasal congestion, gastritis, gastro-oesophagus reflux disease, dysphagia, gastrointestinal and abdominal pain, constipation, abdominal distension. Uncommon: Pulmonary haemorrhage (fatal pulmonary haemorrhage was reported in uncontrolled long term extension studies. Package Quantities: 42 or 84 film-coated tablets. Legal Category: POM. Marketing Authorisation numbers: EU/1/13/907/001,004,007,010,011,014. Marketing Authorisation Holder: Bayer Pharma AG, 13342 Berlin, Germany. Date of revision: July 2016. © Merck Sharp & Dohme Ireland (Human Health) Limited 2016. All rights reserved. Further information is available on request from: MSD, Red Oak North, South County Business Park, Leopardstown, Dublin 18 or from Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to MSD (Tel: 01-2998700)

Date of preparation: August 2016 CARD-1180850-0001

HPN November 2016  
HPN November 2016