Men's Health eBook by Nathan Bugden

MEN’S HEALTH UPDATE

Bring Your Mobile Device!

Wednesday June 17, 2015 0800 - 1200 hours St. Joseph’s Health Centre Education Centres A&B

MEN’S HEALTH UPDATE Supported By

MENâ&#x20AC;&#x2122;S HEALTH UPDATE Table of Contents Biographies

p.7

Case Study

p.9

David Greenberg

Questions to Consider

p.11

Metabolic Syndrome

p.13

Peter Mitoff

Nocturia

Jack Barkin

p.21

Sleep Apnea

p.31

Alcohol Use Disorders

p.41

Upcoming Continuing Medical Education Programs

p.47

Jennifer Hirsch Linda Weber

BIOGRAPHIES Jack Barkin Dr. Barkin is a Clinical Professor of Urology at the University of Toronto. He was the Chief of Urology at Humber River Hospital from 1997-2007 and the Chief of Staff there Humber River Hospital from 2007-2015. Currently, Dr. Barkin is a VP for the Canadian Society for the Study of the Aging Male (CSSAM) and the Executive Editor-inChief of Canadian Journal of Urology.

David Greenberg Dr. Greenberg is a graduate of the University of Western Ontario, the former Chief of Family & Community Medicine and Chief of Emergency Medicine at Doctors Hospital, and a regular on the television show “The Mom Show.” Dr. Greenberg played a leadership role in developing the Canadian Men’s Health Guidelines, an internationally peer reviewed document developed to ensure that GPs have the best resources to look after this segment of the population. Today, Dr. Greenberg is here to present to us on these guidelines. Welcome Dr. Greenberg!

Jennifer Hirsch Dr. Hirsch is a Psychiatrist with fellowship training in Sleep Medicine. At the Toronto Sleep Institute, she treats disorders ranging from insomnia and hypersomlenence to sleep-related breathing and movement disorders. In addition, she works as a Reproductive Psychiatrist, managing patients with mental illness both during pregnancy and post-partum. Dr. Hirsch runs the Perinatal Mindfulness Meditation program at Mount Sinai Hospital and practices Interpersonal Psychotherapy. Lastly, Dr. Hirsch works and supervises resident-trainees in the Emergency Department at the Centre for Addiction & Mental Health. Dr. Hirsch completed her Psychiatry residency at the University of Toronto.

Peter Mitoff Dr. Mitoff is a staff Cardiologist at St. Joseph’s Health Centre in Toronto. He completed medical school and Internal Medicine residency at the University of Toronto, Cardiology residency at the University of Ottawa Heart Institute and a fellowship in Advanced Heart Failure and Cardiac Transplantation at the University Health Network in Toronto. He has been at St. Joe’s for 2 years.

Linda Weber Dr. Weber joined the Family Medicine Centre Urban Family Health Team at St. Joseph’s Health Centre in 2010. She is a family physician with a special interest in addiction medicine. She provides inpatient and outpatient addictions care at SJHC and provides telehealth addictions support and periodic site visits for the Suboxone program in Wunnumin Lake, Northern Ontario. She is a lecturer at the University of Toronto and is very involved in teaching at all levels of training from clerkship to addictions fellowship. She sits on the Quality Program Committee at the DFCM and is the QI lead for the FMC/UFHT.

Case June 17, 2015

Case – Mr. J.B.

Presentation

 Recently divorced 55‐year‐old male

 Tried to re‐enter the dating scene

He has a number of concerns:  He’s frequently tired  Gets up to pee several times a night  Disruptive snoring, sometimes punctuated by very loud gasping sounds  Is not that interested in his newly single sex life, but is embarrassed to admit it

Past History

Physical Examination

 Hypertension  Dyslipidemia  Medications:

 Height: 5’8” (1.73 m)

 Living with his 18 year old son  Successful investment banker

 Enalapril 10 mg daily  Atorvastatin 20 mg qhs

    

No known drug allergies Smoker: 0.5 PPD X 25 years Drinks alcohol 5‐7 cups of coffee a day Family history: mother (MI), brother (depression)

 Weight: 203lbs (92.3 kg)  BMI: 30.9  Heart rate: 88 bpm  BP: 141/89 mmHg  Neck Circ ‐ 17.5”(44.45 cm)

Questions to Consider What parts of the medical and psychosocial history are important?

What are important parts of the physical exam to consider?

What laboratory tests should be considered?

At what age do you start to do PSA screening?

Is a PSA in a 55 year old man with s/s of BPH screening?

At â&#x20AC;&#x153;annual physicalâ&#x20AC;? what are the red flags that would indicate reasons for referral to the urologist?

Questions to Consider Continued What are this gentlemanâ&#x20AC;&#x2122;s risk factors for sleep apnea?

What symptoms does he already endorse?

If he is reluctant to attend a sleep study, what serious co-morbidities would you tell him are associated with untreated OSA?

What do you need to learn about Mr. JB's alcohol use to counsel him appropriately?

How might his alcohol use be impacting his health concerns - positively and negatively?

Metabolic Syndrome and Assessing Cardiometabolic Risk – A Cardiologist’s Perspective Peter Mitoff, MD FRCPC Cardiologist, St. Joseph’s Health Centre Men’s Health Update June 17, 2015

Faculty/Presenter Disclosure • • • •

• Faculty: Peter Mitoff • Relationships with commercial interests: – – – –

Outline

Grants/Research Support: None Speakers Bureau/Honoraria: None Consulting Fees: None Other: None

Metabolic Syndrome (MetS) defined MetS and cardiovascular risk assessment MetS and non‐atherosclerotic CV risk MetS and testosterone deficiency

Metabolic Syndrome

Metabolic Syndrome Definitions

• aka Syndrome X, Cardiometabolic syndrome, Insulin Resistance Syndrome • First described in ‘50s, but popularized in late ’80s • Is a syndrome, not a disease – Cluster of diabetogenic, atherogenic, prothrombotic and inflammatory metabolic abnormalities that impart increased risk of DM and CVD – No single unifying pathophysiology – Major underlying abnormality: abdominal obesity, insulin resistance and dyslipidemia • Estimated to affect 1 in 5 Canadians1 • Relevance debated

CJC 31 (2015) 601‐604.

1Circulation. 2009;120(16):1640‐5

MetS – Harmonized definition (2009) 3/5 of:

55M, recently admitted with anterior STEMI

1. Central Obesity ‐ Europids Men >94 cm ‐ South Asians Men >90 cm ‐ Chinese Men >90 cm ‐ Japanese Men >90 cm ‐ *ATP III uses Men>102cm

2. 3. 4. 5.

Case 1

Women >80 cm Women >80 cm Women >80 cm Women >80 cm Women >88cm

Cardiovascular risk assessment 6 years ago:

High Triglycerides (>1.7 mmol/L) Low HDL (Men <1.0, Women <1.3) Hypertension (> 130/85) Insulin Resistance (fasting glucose > 5.6mmol/L)

– – – – –

Age 49 Non‐smoker No diabetes Blood pressure 145/85 No family history of premature CVD

‐ Total cholesterol 4.2 mmol/L ‐ HDL 0.8 mmol/L ‐ TG 2.26mmol/L ‐ LDL 2.9mmol/L

CV Risk ?

Circulation 2009; 120:1640.

https://www.cvdriskchecksecure.com

… additional information available 6 years ago:

‐ Total cholesterol 4.2 mmol/L ‐ HDL 0.8 mmol/L Statin therapy not warranted ‐ TG 2.26mmol/L Advised to lose weight, and follow ‐ LDL 2.9mmol/L a more physically active lifestyle

– – – – – – –

Europid ethnicity Weight 87kg Body mass index 29.5 kg/m2 Abdominal girth 104cm Non‐HDL cholesterol 3.4mmol/L Fasting blood sugar 6.1mmol/L Hemoglobin A1C 5.9%

Cardiometabolic risk assessment now?

Visceral adiposity

Assessment of CV Risk 1. Framingham Risk Score (FRS) and modified FRS (which incorporates family history) are the most widely used method for assessment of CV risk and are used to approximate 10‐year CVD risk (mainly to determine if statin therapy is warranted)

• Measured by waist circumference • More powerful predictor than BMI • Metabolically active

2. FRS and mFRS fail to include cardiometabolic risk typified by dysglycemia and the Metabolic Syndrome (MetS)

• Independent predictor of MI

3. Interheart Study identified 9 factors that could predict >90% of MIs1, validated FRS factors, but identified additional factors including abdominal obesity, assessed by waist to hip ratio

• Population‐attributable risk similar smoking

– Leads to dysglycemia / insulin resistance, atherogenic dyslipidemia – Increased risk of insulin resistance and diabetes

1Lancet 2004 364 (9438) 937‐52

Not all Fat Is the Same…

Intra‐abdominal (visceral) adiposity

Subcutaneous fat

Not all Fat Is the Same… David Age: 58 years Weight: 92 kg BMI: 35.4 kg/m2

Michael Age: 58 years Weight: 92 kg BMI: 35.4 kg/m2

Intra‐abdominal (visceral) adiposity

Michael’s metabolic cardiovascular profile:  Cholesterol 4.87 mmol/l  LDL cholesterol 2.75 mmol/L  HDL cholesterol 1.45 mmol/l  Glucose 4.7 mmol/l  Blood pressure 125/78 mm Hg

Adapted from Van Gaal LF Eur Neuropsychopharmacol 2006;16:S142‐8

Subcutaneous fat

David’s metabolic cardiovascular profile:  Cholesterol 6.24 mmol/l  LDL cholesterol 4.79 mmol/l  HDL cholesterol 0.98 mmol/l  Glucose 7.3 mmol/l  Blood pressure 140/85 mm Hg

Adapted from Van Gaal LF Eur Neuropsychopharmacol 2006;16:S142‐8

Intra‐Abdominal (Visceral) Adiposity Promotes Insulin Resistance and β‐Cell Dysfunction  Hepatic insulin resistance

Lipolysis  TG‐rich VLDL cholesterol

 FFA

Portal circulation

Splanchnic & systemic circulation



Systemic circulation

dense LDL

glucose output

Glucose utilization

Long‐term damage to b‐cells by FFA

CETP, Lipolysis

Low HDL cholesterol

Insulin resistance



Intra‐abdominal adiposity

 Small,

 Hepatic

Insulin secretion

CETP: cholesteryl ester transfer protein FFA: free fatty acids TG: triglycerides Adapted from Lam TK et al. Am J Physiol Endocrinol Metab 2003;284:E281‐90: Carr MC et al. J Clin Endocrinol Metab 2004;89:2601‐7: Eckel RH et al. Lancet 2005;365:1415‐28.

Metabolic Syndrome and CV Risk 1. Presence of MetS is associated with increased relative risk of all cause mortality (RR 1.35), CV mortality (RR 1.74), CAD (RR 1.52) and stroke (RR 1.76) 2. MetS remains a significant risk for CVD after adjusting for traditional risk factors

Neck Circumference 1.

Predictor of MetS, OSA, CV risk

Easier to measure than WC –

Study of 168 obese pts, median age 52, BMI 35kg/m2 – –

3. CV risk with MetS is independent of its association with dysglycemia and diabetes

–

4. Global Cardiometabolic risk includes assessment of abdominal obesity, fasting glucose, and waist circumference

Measures subcutaneous adiposity rather than visceral adiposity

OR for MetS 1.35 for NC, 1.06 for WC OR for insulin resistance 1.24 for NC, 1.07 for WC OR for T2DM 1.3 for NC and 1.05 for WC

Recommended cut‐offs: NC >36cm in females, >39cm in males Kamenov, AACE 2015

CV Risk and Lipid Targets 1.

Most patients with MetS with have an intermediate (10‐19%) or high (>20%) 10‐year Framingham Risk Score

For patients with MetS, FRS should be increased by 1.8 fold

Patients with a high 10‐year FRS should receive statin therapy to reduce LDL according to guidelines (↓ by 50%, to a target <2mmol/L)

Patients with intermediate FRS with LDL > 3.5 or non‐HDL > 4.3 should be considered for statin therapy to reduced LDL < 2 and non‐HDL < 2.6

Patient with intermediate risk FRS and features of MetS but modified risk score <20% may be considered for additional testing to determine need for statin (ie. hsCRP, carotid doppler or CT for coronary Ca)

CJC 31 (2015) 601‐604.

MetS and Non‐atherosclerotic CVD 1. Several observational studies have shown a strong correlation between MetS and the risk of AF • •

Risk of AF 5.1% with 0 components and 22% if all 5 components are present Hypertension is the strongest RF (HR 1.95)

2. MetS is a strong risk factor for recurrent AF after catheter ablation 3. Obesity is a strong RF for AF • • •

Each 1 unit increase in BMI is associated with 7% greater risk of AF More LA dilation, diastolic dysfunciton, neurohormonal activation, ?OSA

Case 2 58M PMH: – Metabolic syndrome • Hypertension, Weight 107kg, WC 110cm, BMI 31, HDL 0.9, TG 2.1, FPG 6.5

‐ Complains of fatigue, low libido, poor concentration ‐ Normal blood counts, Fe levels, thyroid function ‐ am Testosterone level 8 ng/mL ‐ confirmed on repeat testing

Hypogonadism and MetS Questions: • How common is hypogonadism in men with MetS? • Can testosterone replacement impact MetS?

• Estimated prevalence of hypogonadism 10‐39%1 • Testosterone levels inversely related to BMI2 • Hypogonadism 2‐3X higher in men with diabetes3 – Men with higher testosterone levels had a 42% lower risk of type 2 diabetes (RR 0.58)3

• MetS is also 2‐3X more common in men with hypogonadism – association or causation? 1J Clin

Endocinol Metab 2004;89:5920‐26 2005;63:239‐50.

2Clin Endocrinol

3JAMA 2006; 295:1288‐99.

The hypogonadal–obesity–adipocytokine hypothesis

Testosterone Deficiency and MetS • Observational study • 255 men (age 33‐69) with testosterone deficiency (testosterone levels 5.9‐12.1 nmol/L, mean 9.9nmol/L) and at least mild symptoms of testosterone deficiency assessed by the Aging Males’ Symptoms Scale • Treated with parenteral testosterone undecanoate 1000mg at baseline, after 6 weeks then q12weeks for up to 60 months • Testosterone levels improved from 9.9nmol/L to 18nmol/L within 12m

Rao, P. M. et al. (2013) Testosterone and insulin resistance in the metabolic syndrome and T2DM in men Nat. Rev. Endocrinol. doi:10.1038/nrendo.2013.122

Int J Clin Pract, Mar 2014, 68, 3, 314‐29.

Testosterone Deficiency and MetS • Over course of 5 years, ↓ WC 8.5cm ↓ weight 15.4kg (p<0.0001 for both) Pre treatment

Post treatment

Total Cholesterol

7.3mmol/L

4.9mmol/L

LDL

4.2 mmol/L

2.8mmol/L

HDL

1.45mmol/L

1.52mmol/L

3.1mmol/L

2.2mmol/L

Fasting BG

5.7

5.4

HbA1C

7.1%

6.2%

154/93mmHg

138/80mmHg

CRP

6.29 U/L

1.03 U/L

* p<0.0001 for all

Testosterone Deficiency and MetS 1. Testosterone therapy is associated with reduced obesity, fat mass, waist circumference and also improves glycemic control 2. Several observational studies have shown incident CAD are inversely associated with serum T concentration 3. Mortality was reduced with T therapy in 2 retrospective studies. 4. Several RCTs in men with coronary artery disease or heart failure reported improved function in men who received T compared with placebo

Int J Clin Pract, Mar 2014, 68, 3, 314‐29.

Testosterone and CV Risk Testosterone in Older Men (TOM) trial, NEJM 2010 • 209 men, mean age 74, with limitations in mobility –

Total serum testosterone level of 100 to 350 ng per deciliter (3.5 to 12.1 nmol per liter) or a free serum testosterone level of less than 50 pg per milliliter (173 pmol per liter)

•

Randomly assigned to receive placebo gel or testosterone gel

•

Adverse CV events (MI, HF, syncope – not pre‐specified endpoints) in 23 vs. 5, testosterone vs. placebo

NEJM 2010; 363:109‐122

Testosterone and CV Risk JAMA 2013 • Retrospective analysis of 8709 men with a total testosterone level lower than 300 ng/dL who underwent coronary angiography –

•

1223 patients started testosterone therapy after coronary angiogram

Risk of all cause death, MI or stroke at 3 years –

–

19.9% in the no testosterone therapy group vs 25.7% in the testosterone therapy group, with an absolute risk difference of 5.8%(95%CI, ‐1.4%to 13.1%) Difference remained after correcting for presence of CAD

JAMA 2013 Nov 6;310(17):1829‐36

Testosterone and CV Risk • Meta‐analysis – 75 placebo‐controlled studies – No evidence of increased CV risk with testosterone therapy and clear evidence of improvement in metabolic profiles1

Bottom Line • There are no large, long‐term, placebo‐controlled randomized clinical trials in the field of testosterone therapy to provide definitive conclusions about CV risk 1

Expert Opin Drug Saf. 2014; 13(10):1327‐1351

Conclusions • Metabolic syndrome is common and is associated with increased adverse CV outcomes – Consideration of cardiometabolic risk may change risk stratification Combined hormone therapy was associated with a hazard ratio for CHD of 1.24

• Low testosterone is associated with the MetS, however it is not clear if testosterone deficiency is a cause or feature of MetS • Testosterone therapy improves metabolic parameters – Obesity, fat mass, glycemic control, lipids

• In patients with clinical evidence of hypogonadism and confirmed low testosterone, testosterone therapy is warranted to improve symptoms and metabolic profile

NEJM 2003; 349:523‐534

– In these patients, testosterone therapy is probably safe, and is unlikely to be associated with increased CV risk – Definitive evidence is lacking

QUESTIONS?

UPDATED APPROACH TO MEDICAL TREATMENTS OF SYMPTOMATIC LUTS/OAB/NOCTURIA PATIENTS Jack Barkin MD, FICS, FACS, CCPE, MHM, CCHL, DABU, FRCS(S)

Associate Professor: Department of Surgery, University of Toronto Urologic/Robotic Surgeon Humber River Hospital Director of Can‐Am HIFU Executive Editor‐in‐Chief of Canadian Journal of Urology

Faculty/Presenter Disclosure

Mitigating Potential Bias

Faculty: Dr. Jack Barkin No COI because Dr. Barkin speaks for all of the companies.

Relationships with commercial interests: Speakers Bureau/Honoraria: Medical Advisory Board and Speakers Bureau for: Astellas, Pfizer, Merus Labs, Allergan,Ferring

1. Adapted from Non‐Neurogenic Male Lower Urinary Tract Symptoms (LUTS), incl. Benign Prostatic Obstruction (BPO) (2014). Available at http://www.uroweb.org/; 2. Fusco F. et al J Sex Med 2013;10:2382–2393

BPH: Benign Prostatic Hyperplasia; histological diagnosis BPE: Benign Prostatic Enlargement; clinical condition BPO: Benign Prostatic Obstruction attributed to BPE; clinical BPH

Lower Urinary Tract Symptoms (LUTS) are common and have a multifactorial aetiology1 Lower urinary tract symptoms (LUTS) are a common age‐related condition in men characterized by a complex of symptoms that may belong to obstructive, irritative or postmicturition domains.2

BPH: Benign Prostatic Hyperplasia; histological diagnosis BPE: Benign Prostatic Enlargement; clinical condition BPO: Benign Prostatic Obstruction attributed to BPE; clinical BPH

OAB is One of the Many Causes of LUTS

By Age (United States)1

Overall (Canada)2,3

Prostate Conditions Enlargement (BPH) Neoplastic (prostate cancer) Inflammatory (prostatitis) Other Outlet Conditions Urethral or bladder neck stricture Neoplastic (urethral, vulvar or penile cancer) Inflammatory (urethritis) Dyssynergia of sphincter or bladder neck Urethral diverticulum, other masses, stenosis Pelvic organ prolapse Dr. K Carlson, used with permission

Men Women

35 Prevalence (%)

Bladder Conditions: Overactive Bladder Inflammatory • Bacterial cystitis • Interstitial cystitis • Radiation cystitis Neoplastic • Bladder cancer • Extrinsic mass Neurogenic • CNS (stroke, MS, SCI) • Peripheral (diabetes)

Prevalence of OAB in Men and Women

Polyuria

30 25

% OAB

20 15 10 5 0 18–24

Study

Men

Women

Herschorn et al 20071

13.1

14.7

Corcos et al 20042

14.8

21.2

25–34 35–44 45–54 55–64 65–74 75+ Age (years) 1. Stewart W, et al. Prevalence of OAB in the US: results from the NOBLE program. Poster presented at WHO/ICI; July, 2001; Paris, France 2. Herschorn S, et al. BJU Int 2008;101:52-8; 3. Corcos J, et al. Can J Urol 2004;11:2278-84

Screening for OAB • Question at‐risk patients using open‐ended questions, eg: “Are you having any trouble with your bladder?” • Basic evaluation – – – – –

Patient history Voiding diary Physical examination Urinalysis PVR if indicated (eg, prior incontinence surgery, pelvic organ prolapse, slow stream, feeling of incomplete emptying, palpable bladder)

Treatment options for patients CONSERVATIVE TREATMENT DRUG TREATMENT • 1‐adrenoceptor antagonists • 5‐reductase inhibitors • Muscarinic receptor antagonists • Combination therapies 1‐blockers + 5‐reductase inhibitors 1‐blockers + muscarinic receptor antagonists • Other drugs Phosphodiesterase (PDE) 5 Inhibitors (with or without 1‐ blockers) • Plant extracts ‐ Phytotherapy

Bettez M, et al. Can Urol Assoc J 2012;6:354-63

Anticholinergic Drugs Available in Canada for the Management of OAB

Nocturia is consistently reported as one of the most bothersome LUTS in OAB Understanding the elements of overactive bladder — EPIC study (N= 1434)

Agent

Dosage

Darifenacin

7.5 or 15 mg od

70%

Fesoterodine

4 or 8 mg od

60%

Oxybutynin ER

5–30 mg od

50%

Oxybutynin gel

100 mg gel daily

40%

Oxybutynin IR

2.5–5 mg 4x daily

30%

Oxybutynin TDS

36 mg patch 2x weekly

20%

Solifenacin

5 or 10 mg od

10%

Tolterodine ER

2 or 4 mg, od

Tolterodine IR

1 or 2 mg, bid

Trospium

20 mg bid on empty stomach

ER = Extended release, IR = Immediate release, LA = Long acting, TDS = Transdermal; XL = Extended release *An antispasmotic bladder drug with weak anticholinergic properties

Nocturia frequently occurs with OAB and BPH, however…

Bothered by nighttime urination* (%)

Bothered by waking at night because they had to urinate* (%) 59.4

55.8 52.6

50.2 45.2 41.9 38.4

36.6

Men Women

27.9 19 20.2

20.1

*Four women and one man did not answer the question

0% ≥1

1 ≥2 Nocturia Episodes

≥1

≥2

Among those with OAB, the most prevalent combination of symptoms was urgency and nocturia Irwin et al. BJU International 2008; 101, 1381‐87

Pharmacologic options Therapy

Examples

Indication

MOA

Efficacy in nocturia?

Therapies for BPH

• Usually daytime LUTS are effectively treated with BPH/OAB therapy, nocturia is often not resolved1

Alpha‐blockers

Tamsulosin Terazosin

Indicated for the treatment of LUTS associated with BPH

Blocks smooth muscle receptors of the bladder neck and the prostate called alpha‐ 1 adrenoceptors

Evidence supporting clinically relevant efficacy is low1

5‐alpha reductase inhibitors (5ARIs)

Finasteride

Indicated for treatment and control of BPH

Lowers dihydrotestosterone, leading to shrinkage of the enlarged prostate gland

Evidence supporting clinically relevant efficacy is low1

T h era p i es fo r OAB

Antimuscarinics

Solifenacin Trospium chloride Tolterodine Fesoterodine Darifenacin

Beta 3‐ adrenoceptor (AR) Mirabegron agonist

Indicated for the treatment of OAB

Helps to relax the smooth muscle of the bladder

May be effective for nocturnal voids due to urgency1 Evidence supporting clinically relevant efficacy is low2

T h era p i es fo r n o c t u r i a 1. Weiss et al. BJU Int 2011;108:6–21

1.Weiss et al. J Urol 2011;186:1358–1363; 2. Smith A and Wein A. Expert Opin Pharmacother 2013;14(7):885‐894.

Nocturia frequently occurs with OAB and BPH, however… • No studies have shown that alpha blockers, 5ARI’s, antimuscarinics, or the Beta 3 Agonists have a significant and consistent impact for the improvement of nocturnal polyuria. 1. Weiss et al. BJU Int 2011;108:6–21

What is nocturia? Although numerous definitions exist, Nocturia is defined by the International Continence Society (ICS) as:

The complaint that the individual has to wake at night one or more times to void…each void is preceded and followed by sleep

van Kerrebroeck et al. 2002

van Kerrebroeck et al. Neurourol Urodyn 2002;21:179–183

Nocturia is multifactorial… Estrogen

Primary

deficiency

polydipsia

Untreated diabetes mellitus or insipidus

Nocturia

Psychological / sleep problems

CAUSES OF NOCTURIA Urologic causes

Uncompensated heart disease Non‐urologic causes

Fonda. BJU Int 1999;84(suppl 1):13–15; Van Kerrebroeck et al. Neurourol Urodyn 2002;21:179–183; Wein et al. BJU Int 2002;90(suppl 3):28–31

…and is often only attributed to bladder storage problems

Underlying Conditions and Management Nocturnal Polyuria: NPi >33%

Causes of Nocturia Excessive PM fluid intake

Global Polyuria

Nocturnal Polyuria

Diabetes mellitus Congestive heart failure

Bladder Storage Problems

OAB

BPO/ BPH

Behavioral modification

Refer to cardiology

Aim for optimal glycemic control

Obstructive sleep apnea suspected (snoring, obesity, short neck)

Sleep studies

Peripheral edema due to venous disease

Impaired circadian rhythm of AVP secretion

Antidiuretic therapy Leg elevations/ stockings

MIXED ETIOLOGY OAB=overactive bladder; BPH=benign prostatic hyperplasia Van Kerrebroeck et al. Neurourol Urodyn 2002;21:179–183

Weiss et al. BJUI 2013;111:700-716.

Definition of Nocturnal Polyuria (NP)  NP is a common cause of nocturia (76–88% of patients in 2 large cohorts)1  Defined by the International Continence Society (ICS) as production of an abnormally large volume of urine during sleep:2 – Young: >20% of daily total output – Elderly: >33% of daily total output

Negative impact of Nocturia  Nocturia is a leading cause of sleep disturbance in patients > 50 years old and is an independent predictor of poor sleep1‐4  Nocturia may2,5‐17    

Be a sign of early disease Decrease health status and QoL Have a greater impact on people of younger age Impair work in the professionally active and increase sick leave  Cause falls and fractures in the elderly

Nocturnal Polyuria index (NPi) = nocturnal urine volume/24‐hr urine volume 1. Weiss et al. J Urol 2011;186:1358–1363; 2. Van Kerrebroeck et al. Neurourol Urodyn 2002;21:179–183

1. Middelkoop et al. J Gerontol A Biol Sci Med Sci 1996;51:M108–M115 2; 2. Bliwise et al. Sleep Med 2009;10:540–548 3. Ohayon. J Psychiatr Res 2009;43:48–54 ; 4. Paunio et al. Am J Epidemiol 2009;169:206–213 5. Yu et al. Urology 2006;67:713–718; 6. van Dijk et al. BJU Int 2002;90:644–648; 7. Asplund & Aberg. Maturitas 2000;35:143–148; 8. Fitzgerald et al. J Urol 2007;177:1385– 1389; 9. Lightner et al. BJU Int 2012; (epub ahead of print); 10. Tikkinen et al. Eur Urol 2010;57:488–496; 11. Zhang et al. Urol Int 2011; 86:173–178; 12. Kupelian et al. Eur Urol 2012;61:78– 84;13. Oztura et al. Sleep Med 2006;7:362–367; 14. Parsons et al. BJU Int 2009;104:63–68; 15. Temml et al. Neurourol Urodyn 2009;28:949–952; 16. Nakagawa et al. J Urol 2010;184:1413–1418; 17. Shvartzman et al. Fam Prac 2001;18:610–613;

Clinical evaluation of NP • Patients should be evaluated for underlying conditions1 • Urine analysis, culture, sensitivity, and cytology (if indicated) should be performed1 • Frequency–volume charts (FVCs) are a key tool for diagnosis of NP1

1. Weiss et al. BJU Int 2011;108:6–21; 2. Partinen & Gislason J Sleep Res 1995;4:150–155;

The value of FVCs • FVCs provide valuable information regarding voiding frequency and urinary volumes for 24–72 hours1–3 • Chart can also include record of volume and type of fluid ingested, time of retiring to bed and time of rising Night-time (including first void in morning)

Daytime Time

Voided volume (mL)

Comments

Time

Voided volume (mL)

Comments

1. Weiss. J Urol 2006;175:S16–18; 2. Van Kerrebroeck et al. Neurourol Urodyn 2002;21:179–183; 3. Van Kerrebroeck et al. Int J Clin Pract 2010;64:807–816

Management of nocturia • Non‐pharmacologic options1 – Lifestyle changes (fluid management, optimizing pedal edema) – Timed diuretic therapy – Sleep disturbance therapy – Surgical therapy for urological indications Despite lack of supporting evidence, the above non‐ pharmacologic interventions should be considered1

WHY DOES CURRENT TREATMENT OF OAB AND BPH SYMPTOMS OFTEN FAIL TO IMPROVE NOCTURIA?

1. Weiss et al. BJUI 2013;111:700‐716

Clinical treatment recommendations

Antidiuretic therapy and nocturia

Antidiuretic therapy (e.g. desmopressin) has proven well‐ tolerated and effective in several randomized, placebo‐ controlled trials and is recommended as a first‐line treatment (either as monotherapy or in combination with other agents) for patients who have been appropriately evaluated and whose nocturia is related to NP whether or not accompanied by BPH or OAB.

Antidiuretic Hormone / Arginine Vasopressin ( ADH / AVP )

Desmopressin

Secreted from pituitary gland

Synthetic analogue of ADH / AVP

V1 and V2 receptor agonist

Selective V2 agonist

Acts on V2 receptor in distal renal tubules and collecting ducts to promote water reabsorption

V1 mediated vasopressor and uterotonic effect

Weiss et al., The evaluation and treatment of nocturia: a consensus statement BJU Int, 2011

NO vasopressor or uterotonic effect

Desmopressin is the only antidiuretic therapy specifically indicated for nocturia1

Weiss et al BJU Int 2011;108: 6‐21;

1. Weiss et al. BJUI 2013;111:700‐716

Desmopressin for nocturia: Current Tablet Format

The role of AVP/desmopressin in the kidney Regulating water and electrolyte balance in the distal tubule and the collecting duct Distal tubule

PROS

Distal tubule

Cortex

Cortex H2O

H2O

• • •

Demonstrated efficacy Response observed within a week Prolongs initial sleep period

CONS • •

H2O H2O

H2O

•

0.1 mg (~60 μg ODT) at bedtime x 7days 0.2 mg (~120 μg ODT) at bedtime x 7 days

–

0.4 mg (~240 μg ODT) at bedtime

Serum sodium monitoring – – –

Solutes

–

Large volume of dilute urine Small volume of concentrated urine

No AVP: Collecting duct is NOT permeable to water and large volume of urine is produced

– –

Medulla

Medulla Solutes

Risk of hyponatremia associated with higher doses of desmopressin Dosing titration may be required

Baseline 3 days after initiation of therapy or increase in dosage At other times during treatment as deemed necessary by the treating physician > 65 years or at risk of hyponatremia, as above and either monthly or every 2‐3 months depending on patient’s risk of hyponatremia

AVP present: Collecting duct is permeable to water and a small volume of urine is produced

New desmopressin: Orally Disintegrating Tablet (ODT) • A freeze‐dried lyophilisate for sublingual administration • Dissolves in the mouth and does not require ingestion of water for swallowing • Shorter duration of action

Low dose desmopressin ODT studies in nocturia – CS29, CS31

HYPOTHESIS Will a lower exposure result in acceptable efficacy and at the same time minimize safety concerns for adults with Nocturia?

ODT has a higher bioavailability than the conventional tablet, allowing for lower dosing1 1. Weiss JP et al. Neurourol Urodyn 2012;31:441–447

Low dose desmopressin ODT Women

Men

25 μg daily at bedtime administered sublingually

50 μg daily at bedtime administered sublingually

CS29 trial of desmopressin ODT A multicentre, randomized trial in a broad population of adults with an average of ≥2 voids per night and baseline serum sodium ≥135 mmol/L

Dose Randomization

Monitoring and laboratory testing <65 years old ≥65 years old

• •

Prior to treatment, all patients should have serum sodium within the normal range No monitoring or laboratory tests required

•

No monitoring or laboratory tests required

•

Placebo 10 μg

10 μg

25 μg 50 μg 100 μg

25 μg 50 μg 100 μg Week 4

Week 0

Additional serum sodium monitoring is warranted within 4‐8 days of treatment, and repeated at one month of treatment

Part I 28-day placebo controlled

Notes •

Monitoring of serum sodium for men over 65 years old helps avoid clinically significant reductions

• •

CS 31 Rollover: open label extension Week 26

Part II Blinded, non-placebo controlled variable duration extension study

Primary endpoints Change in mean number of nocturnal voids from baseline Proportion of patients with >33% reduction in mean number of nocturnal voids from baseline

Secondary endpoints •

Change in diuresis (total and nocturnal volumes)

•

Change in duration of initial period of undisturbed sleep Change in NQoL

• Weiss et al. Neurourol Urodyn 2012;31:441‐447

Statistically significant reduction in mean number of voids with low dose desmopressin ODT in women

Proportion of women with >33% reduction in nocturnal voids from baseline to day 28

Lowest effective dose in women is 25 µg

Women

n=66

n=73

n=65

n=71

n=66

Placebo

10 μg

25 μg

50 μg

100 μg

* 62

-0.4 -0.6 -0.8 -0.88

-1 -1.2 -1.4

-1.22

-1.23

-1.6

*p=0.02 vs placebo -1.51

***

*p<0.0001 vs placebo

0 Placebo n=66

10 μg n=73

25 μg n=65

50 μg n=71

100 μg n=66

Weiss JP et al. Neurourol Urodyn 2012;31:441–447

Durable and improved response observed with long‐term desmopressin ODT treatment

Secondary end point – Increase in initial period of undisturbed sleep from baseline to Day 28 in women

** 98

100 80

*p=0.001 vs placebo

**p=0.0008 vs placebo

***p<0.0001 vs placebo

20 10 μg n=60

25 μg n=51

50 μg n=61

100 μg n=57

84% of women taking desmopressin ODT responded to treatment after 28 weeks Change from Baseline in Mean Number of Nocturnal Voids

*** 114

* 113

120

Mean change in duration of Initial period of undisturbed sleep (minutes)

*p<0.04 vs placebo

***p<0.0001 vs placebo

25 μg desmopressin ODT increases initial period of undisturbed sleep in women

Placebo n=49

*p<0.02 vs placebo

**p=0.009 vs placebo

Weiss JP et al. Neurourol Urodyn 2012;31:441–447

20 -1.15

-0.2

Patients (%)

Mean change in nocturnal void number

• After 1 year of treatment, the mean initial period of undisturbed sleep increased by approximately 2.5 hours

Females on 25 µg 0 -0.2 -0.4 -0.6 -0.8 -1 -1.2 -1.4

-1.22 N=65

-1.6 -1.8 -2

-1.75 N=31

-1.74 N=37

Day 28 28 Weeks 52 Weeks

Weiss JP et al. Neurourol Urodyn 2012;31:441–447

Juul et al. Neurourol Urodyn 2013;32(4):363‐70. Clinical Trial Report: FE992026 CS031

Dose related reductions in serum sodium concentration in women

Desmopressin ODT is well tolerated Treatment‐emergent adverse events considered possibly or probably related to study drug reported by at least 1.0% of subjects (CS 29 Part 1) Placebo

Females 25 µg

N=67

N=96

Any ADR

21 (31.3%)

40 (42.6%)

Dry mouth

17 (25.4%)

23 (24.0%)

Headache

2 (3.0%)

1 (1.0%)

Hyponatremia

3 (3.1%)

Dizziness

2 (2.1%)

Nausea

3 (3.1%)

Blood sodium decreased

1 (1.5%)

2 (2.1%)

Diarrhea

1 (1.0%)

Fatigue

Micturition urgency

2 (2.1%)

Muscle spasm

2 (2.1%)

Rates of serum sodium concentration <130mmol/L with desmopressin ODT (Part I and Part II) 10 µg

25 µg

50 µg

N=67

N=76

N=67

N=80

N=73

< 130 mmol/L (≥125 mmol/L)

1 (1%)

4 (6%)

6 (8%)

9 (12%)

<125 mmol/L

1 (1%)

4 (5%)

2 (3%)

•

Subjects were exposed for up to two years. Dry mouth with an incidence of 3% remained the most frequent reported adverse event. The other AEs had an incidence of <1%. The long‐term studies confirmed that desmopressin ODT is a safe and well tolerated drug. Weiss et al. Neurourol Urodyn 2012;31:441‐447; Juul et al. Neurourol Urodyn 2013;32(4):363‐70

•

100 µg

No cases of serum sodium <125 mmol/L were observed with the 25 µg dose in women, regardless of age No patients discontinued therapy because of hyponatremia

Ferring data on File CS29 Part I and Part II

Minimum post‐baseline serum sodium levels by age group in females

Desmopressin ODT safety in women

Females Treated with 25 µg Desmopressin ODT (Overall Safety population CS29+CS31) Serum Sodium (mmol/L)

Placebo

Serum Sodium

<65 years (N=59)

• No reported cases of hyponatremia <125 mmol/L were observed with desmopressin ODT in women at the 25 µg dose in the CS29 and CS40 trials

≥65 years (N=37)

Observed N*

100%

≥135

48 (81.4%)

27 (73.0%)

130‐134

10 (16.9%)

6 (16.2%)

125‐129

1 (1.7%)

4 (10.8%)

<125

• In the CS40 trial, patients whose serum sodium reached <130 mmol/L recovered to greater than 130 mmol/L within 2 to 4 days without discontinuing treatment

*Listed as ‘hyponatremia’ or ‘blood sodium decrease’ or ‘serum sodium <130 mmol/L’

With 25 μg desmopressin ODT, only baseline sodium measurement required to ensure normal range Weiss et al. Neurourol Urodyn 2012;31:441‐447; Juul et al. Neurourol Urodyn 2013;32(4):363‐70

Incidence of low serum sodium levels with 50 μg desmopressin ODT in men

Statistically significant reduction in mean number of voids with 50 μg desmopressin ODT in MEN Proportion of patients with a ≥33% reduction in mean number of nocturnal voids from baseline

Change in mean number of nocturnal voids from baseline n=119 50 µg

n=124 75 µg

Change from baseline in mean number of nocturnal voids

0 -0.2 -0.4 -0.6 -0.8

-0.88

-1 -1.25

-1.2

(-0.57, -0.17)

-1.4 -1.6

** **p=0.0003 vs placebo ***p<0.0001 vs placebo

Values within brackets represent 95% confidence intervals Weiss JP et al. J Urol 2013;190:965–972

-1.29 (-0.61, -0.22)

***

Summary of serum sodium levels Serum sodium

2.5 Odds of 33% Responder Status

n=142 Placebo

** (1.32, 2.96)

2.01

50 µg

75 µg

(n=143)

(n=119)

(n=122)

130–135, n (%)

2 (1%)

9 (8%)

12 (10%)

126–129, n (%)

0 (0%)

5 (4%)

≤125, n (%)

0 (0%)

2 (2%)

4 (3%)

mmol/L

2.08

1.5

1.02

•

0.5

Men Placebo

*** (0.38, 3.03)

9/11 and 5/6 male patients with serum sodium levels <130 mmol/L and ≤125 mmol/L, respectively were ≥65 years of age

With 50 μg Desmopressin ODT in men:

0 Placebo n=142

50 µg n=119

75 µg n=124

**p=0.0009 vs placebo ***p=0.0004 vs placebo

• ˂65 years of age, only baseline sodium measurement required to ensure normal range • ≥65 years of age, serum sodium monitoring within 4‐8 days after initiation and at one month of treatment Weiss JP et al. J Urol 2013;190:965–972

Desmopressin + LUTS agents in patients with BPH

Clinical treatment recommendations

• •

Patients with BPH >65 years with nocturia and NP All treated with α‐blocker; ~33% on anticholinergics

•

Clinical response (decrease ≥2 voids) was achieved by 61.4% patients (p<0.001 relative to placebo)

–

Most patients diagnosed with BPH or OAB have comorbid NP. It is important that clinicians take time to verify whether patients who have been prescribed traditional BPH and OAB therapies for daytime LUTS have an improvement in their nocturia. If not, combined therapy using α1‐adrenergic blockers and/or anticholinergics in conjunction with desmopressin should be considered.

In combination with placebo or desmopressin

Increase in duration of first sleep period over time

Mean number of nocturnal voids

Weiss et al., The evaluation and treatment of nocturia: a consensus statement BJU Int, 2011

Placebo n=58 Desmopressin n=57

8 6 4 2 0 Baseline

3 6 Time (month)

Mean duration of first sleep period (min)

Reduction in number of nocturnal voids over time

Placebo n=58 Desmopressin n=57

150 100 50 0 Baseline

3 6 Time (month)

Reprinted from J Urol, 185, Wang et al, Low dose oral desmopressin for nocturnal polyuria in patients with benign prostatic hyperplasia: a double‐blind, placebo controlled, randomized study, 219–223., Copyright 2011, with permission from Elsevier

Weiss et al BJU Int 2011;108: 6‐21;

LUTS/NOCTURIA

Summary — Low dose desmopressin

RULE OUT NON‐ UROLOGICAL CAUSES Daytime LUTS

Mixed LUTS

Nighttime LUTS

(predominantly daytime symptoms)

(mixed daytime & nighttime symptoms)

(predominantly nighttime symptoms)

Incorporate lifestyle changes

OAB and BPH

OAB

Antimuscarinic, B3‐agonist

Mixed causality

BPH

1‐blocker; 5‐ RI; combination

Address daytime symptoms

1st line

Nocturia

Address nighttime symptoms

Nocturnal Polyuria

Polyuria

Anti‐diuretic desmopressin

Further investigation required

2nd line (add‐on)

1st line 5‐ARI=5‐alpha reductase inhibitor Adapted from Weiss et al. Curr Urol Rep 2008;9:362–367; Van Kerrebroeck et al. Neurourol Urodyn 2002;21:179–183; Weiss et al. Neurourol Urodyn 2012;31:441‐447

• Desmopressin specifically treats nocturnal polyuria • Desmopressin ODT demonstrated efficacy against Nocturia due to nighttime urine overproduction – Convenient gender based dosing with 25 ug for women and 50 ug for men helps reduce the risk of hyponatremia • Desmopressin is well tolerated over short‐ and long‐term • Patients with nocturia treated with desmopressin experience significant reduction in nighttime voiding and prolongation of initial sleep period with short‐ and long‐term treatment • Desmopressin can be used in combination with other therapies for nocturia of mixed aetiology • Patient sleep, QoL and work productivity improve with desmopressin treatment

Thank you

Sleep Apnea: overview Jennifer Hirsch MD FRCP(C) Lecturer, Faculty of Medicine University of Toronto June 17, 2015

Faculty/Presenter Disclosure

Mitigating Potential Bias

Faculty: Dr Jennifer Hirsch

The presentation does not discuss the use of sedative/hypnotic medications.

Relationships with commercial interests: Speakers Bureau/Honoraria: Paladin Labs Inc.

Everybody was excited, except the fat boy, and he slept as soundly as if the roaring of cannon were his ordinary lullaby… “Sleep!” said the old gentleman. “He’s always asleep. Goes on errands fast asleep, and snores as he waits at table.”

Objectives 1. 2. 3. 4.

Define Obstructive Sleep Apnea Learn history taking for OSA Discuss Comorbidities Review OSA management options

Charles Dickens The Posthumous Papers of the Pickwick Club 1884

Obstructive Sleep Apnea: criteria

(A and B) or C A.one or more: 1. insomnia, sleepiness, fatigue or non-restorative sleep 2. waking from breath holding/gasping 3. observed snoring or breath holding 4. comorbid HTN, mood d/o, cog imp, CAD, stroke,heart failure, atrial fibrillation or DM

PSG demonstrates: B. 5 or more predominantly obstructive events per hour of sleep. Or

1The

International Classification of Sleep Disorders, 3rd ed. Darien, IL: American Academy of Sleep Medicine, 2014.

1The

15 or more predominantly obstructive events per hour of sleep. International Classification of Sleep Disorders, 3rd ed. Darien, IL: American Academy of Sleep Medicine, 2014.

Obstructive Sleep Apnea

Demographics

• Repetitive episodes of complete (apnea) or partial (hypopnea) upper airway obstruction during sleep1 • Airflow cessations or reductions produce – Arousals1,2 – Fragmented sleep2 – Reductions in blood oxygen saturation1,2 – Fluctuations in blood pressure and heart rate2

OSA with Daytime Sleepiness: Males 4% Females 2%

1The 2

International Classification of Sleep Disorders, 3rd ed. Darien, IL: American Academy of Sleep Medicine, 2014. Young T, et al. JAMA. 2004;291:2013-2016.

Where is Obstructive Sleep Apnea?

OSA without Daytime Sleepiness: Males 24% Females 9% • Prevalence increases with age. • Rates in women increase after menopause. • 60% of OSA is attributable to obesity Young T. et al. N Engl J Med. 1993:328:1230-1235

Overnight PSG Study

Narrowing at the nose, retropalatal, retroglossal or hypoglossal region. Abnormal activity of the dilatory pharyngeal muscles (genioglossus and tensor palantine).

Obstructive Sleep Apnea (OSA)

Objectives

Obstructive Sleep Apnea

1. 2. 3. 4.

• Snoring, gasping, witnessed breath holding

Define Obstructive Sleep Apnea Learn history taking for OSA Discuss Comorbidities Review OSA management options

• Excessive daytime sleepiness • Fragmented, non-refreshing sleep • Poor memory, irritability, personality changes • Morning headaches, migraines • Decreased sex drive, impotence • Depression, anxiety • Fatigue, non-specific pain

Risk Factors

OSA: History Taking Nighttime:

Ohayon, 2003

• • • • • • • • •

difficulty maintaining sleep Snoring waking gasping nightmares of being choked leg kicking/body movements in sleep night sweats GERD Nocturia bed partner complaints

OSA: History Taking

Daytime:

Lifestyle:

• • • • • • •

non-refreshing sleep waking with dry throat and/or headache cognitive complaints daytime fatigue sleepiness (driving) caffeine intake naps

OSA: History Taking

• • • • •

obesity/recent weight gain alcohol/sedative intake smoking decreased libido sleep position (injury?)

OSA: History Taking

Other History: • • • • • • • •

HTN, CAD, CHF Stroke Atrial fibrillation Metabolic syndrome DM Gout, Glaucoma, GERD Depression family history

Physical Exam:

Pagel JF. JABFM. 2007;20:392-398. Abrams B. Med Hypotheses 2005;65:1024-1027. Waller AE, et al. Mayo Clin Proc. 2008;83:1251-1261.

Physical Examination Normal

neck (circumference, thyroid) nose (septum, polyps) throat (tonsil size, palate height) mandible size and position (micrognathia or retrognathia) • peripheral edema • BMI • BP and pulse • • • •

Objectives Patient

1. 2. 3. 4.

Define Obstructive Sleep Apnea Learn history taking for OSA Discuss Comorbidities Review OSA management options

Sleep and your Heart

OSA Associations Heart Failure, Arrhythmias, MI, Stroke HTN, DMII Pulmonary Hypertension Mood Disorder GERD Nocturia Erectile Dysfunction Worsening Disorders of Arousal

“In the old country, no one died of heart disease or cancer. They just died in their sleep.” → My Grandmother

• • • • • • • •

Hypertension

Diabetes

In the Sleep Heart Health Study of over 6000 patients showed an independent association between OSA and HTN.

OSA is independently associated with alterations in glucose metabolism placing patients at an increased risk of the development of type 2 diabetes.

In the Wisconsin Cohort following over 700 government employees, those with AHI>15 were 2.89x more likely to develop HTN 4 years after baseline assessment.

Experimental studies in humans and animals have demonstrated that intermittent hypoxia and reduced sleep duration due to sleep fragmentation, as occur in OSA, exert adverse effects on glucose metabolism.

Sleep Disorders Medicine:basic science, technical considerations, and clinical aspects/Sudhansu Chokroverty. 3rd Ed

Tasali E et al. Obstructive sleep apnea and type 2 diabetes: interacting epidemics.Chest. 2008 Feb;133(2):496-506.

Cardiovascular Impact

Sleep Heart Health Study

Severe untreated OSA (AHI >30) is associated with an increased risk of cardiovascular mortality, defined by fatal myocardial infarction (MI) or stroke. Patients with mild OSA or those undergoing treatment with CPAP did not have a significantly increased odds ratio compared with a group of subjects without OSA.

6441 men and women were followed for a mean of 8.2 years.

Untreated severe OSA is a significant risk factor for the development of cardiovascular morbidity, which included nonfatal MI and stroke.

The increased mortality was seen primarily in patients with the most oxygen desaturation during their sleep.

Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoeahypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet. Mar 19-25 2005;365(9464):1046-53.

Punjabi NM, Caffo BS, Goodwin JL, Gottlieb DJ, Newman AB, O'Connor GT, et al. Sleep-disordered breathing and mortality: a prospective cohort study. PLoS Med. Aug 2009;6(8):e1000132

Increased mortality was observed in patients with OSA, but the effect was primarily observed in men younger than 70 years. Women and men older than 70 years did not have increased mortality.

Sudden Death • Patients with untreated OSA are 2.5 times more likely to die from a cardiac cause (MI, heart failure, arrhythmia) between midnight and 6 am • Risk of stroke doubles in untreated OSA

OSA was associated with an increased risk of sudden death between the hours of midnight and 6 AM, as compared with the general population (in whom sudden death is more common between 6 AM and noon).

Gami AS, Howard DE, Olson EJ, Somers VK. Day-night pattern of sudden death in obstructive sleep apnea. N Engl J Med. Mar 24 2005;352(12):1206-14 Yaggi et al. Obstructive Sleep Apnea as a risk factor for stroke and death. N Engl J Med. 2005;353:2034.

Accidents Patients with OSA are 2-7 times as likely as control individuals to have a motor vehicle crash; the overall estimated risk was 2.5 in a meta-analysis of 6 studies.

Objectives 1. 2. 3. 4.

Define Obstructive Sleep Apnea Learn history taking for OSA Discuss Comorbidities Review OSA management options

Sassani A, Findley LJ, Kryger M, Goldlust E, George C, Davidson TM. Reducing motor-vehicle collisions, costs, and fatalities by treating obstructive sleep apnea syndrome. Sleep. May 1 2004;27(3):453-8.

Therapeutic Approach • • • •

Education Accident and injury counselling Treatment of OSA Treatment of contributing factors (obestity, ENT consult)

Conservative Management • • • • • • •

Weight control Avoidance of alcohol at night Avoidance of sedatives/opioid analgesics at night Smoking cessation Position therapy (i.e. sleep on your side) Safety awareness Address chronic nasal or sinus problems

Treatment Options

Definitive Treatments Positive Airway Pressure (CPAP/APAP, BiPAP, ASV) Oral appliance Provent Surgery Augmentation: stimulants (ie modafinil)

Nasal C.P.A.P.

CPAP and Mortality Cohort of 871 patients Patients who used CPAP more than 6 hours per night had an increased survival rate (96.4%) at 5 years compared with those who used CPAP 1-6 hours per night (91.3%) and less than 1 hour per night (85.5%)

Campos-Rodriguez F, Pe単a-Gri単an N, Reyes-Nu単ez N, De la Cruz-Moron I, Perez-Ronchel J, De la Vega-Gallardo F, et al. Mortality in obstructive sleep apnea-hypopnea patients treated with positive airway pressure. Chest. Aug 2005;128(2):624-33.

Oral Appliances

Oral Appliance

Indications Mild-to-moderate OSA Patient preference over CPAP Lack of success with CPAP and/or behavioral measures Not appropriate candidates for CPAP Efficacy Variable (eliminates apnea in ~50% of patients) Side effects TMJ discomfort, dental misalignment, and salivation Kushida CA, et al. Sleep. 2006;29:240-243.

The Case Questionnaires? Berlin Questionnaire for Sleep Apnea (3 categories relating to snoring, daytime impairment and HTN)

Epworth Sleepiness Scale

Q: What parts of the medical and psychosocial history are important?

Q: What are important parts of the physical exam to consider?

nighttime sleep disruption witnessed events daytime fatigue/sleepiness alcohol intake weight gain increase need for caffeine

BMI neck circumference mandibular position palate height tonsil size peripheral edema

Q: What laboratory tests should be considered? Level one polysomnogram

FACULTY/PRESENTER DISCLOSURE

OBJECTIVES

• Faculty: Linda Weber

• Review how to screen for alcohol use disorders • Review the new terminology and diagnostic criteria for alcohol use disorders

• Relationships with commercial interests:

• Discuss health consequences of alcohol use in the context of this case • Review options for therapy for alcohol use disorder • Provide referral resources

• Grants/Research Support: None • Speakers Bureau/Honoraria: None • Consulting Fees: None • Other: None

INITIAL SCREENING FOR ALCOHOL USE

THE CASE – MR. J.B. Current symptoms Fatigue, nocturia low libido, snoring

• Do you drink alcohol (wine, liquor, beer)? Yes • On average how many days/week do you have an alcoholic beverage? • On a typical drinking day how many drinks do you consume? • “On any single occasion during the past 3 months, have you had more than 5 drinks

Past history

Hypertension Dyslipidemia Medications: Enalapril 10 mg daily Atorvastatin 20 mg qhs No known drug allergies Smoker: 0.5 PPD X 25 years Drinks alcohol – a couple drinks of wine with dinner every night, occasional scotch before bed 5-7 cups of coffee a day Family history: mother (MI), brother (depression)

Physical Exam

¨ Height: 5’8” (1.73 m) Weight: 203lbs (92.3 kg) ¨ BMI: 30.9 Heart rate: 88 bpm BP: 141/89 mmHg ¨ Neck Circ- 17.5”(44.45 cm)

containing alcohol?” Alcohol Screening, Brief Intervention and Referral: A clinical Guide www.sbir-diba.ca

HOW MUCH IS TOO MUCH?

MR JB

Canada’s Low Risk Drinking Guidelines:

•On further inquiry, Mr. JB drinks: • 4 bottles of wine/week = 20 SD a week. • scotch 3-4 nights a week – not measured = ? 7-8 SD

•Total = approx 28 standard drinks weekly •He also drinks more than 5 SD about once a month Developed on behalf of the National Alcohol Strategy Advisory Committee Canadian Centre on Substance Abuse 2013 www.ccsa.ca

SCREENING TOOLS

•CAGE questionnaire

•C Have you ever felt you should cut down on your drinking? •A Have people annoyed you by criticizing your drinking? •G Have you ever felt bad or guilty about your drinking? •E Eye opener: Have you ever had a drink first thing in the morning to steady your nerves or to get rid of a hangover?

•AUDIT: developed by WHO – may be self-administered

ALCOHOL USE DISORDER – DSM V

From: DSM-5 Criteria for Substance Use Disorders: Recommendations and Rationale

Am J Psychiatry. 2013;170(8):834-851. doi:10.1176/appi.ajp.2013.12060782

DSM-IV

•Abuse •Dependence •Intoxication •Withdrawal

DSM-V

•Substance use disorder mild/moderate/severe

•Intoxication •Withdrawal Figure Legend:

DSM-IV and DSM-5 Criteria for Substance Use Disordersa One or more abuse criteria within a 12-month period and no dependence diagnosis; applicable to all substances except nicotine, for which DSM-IV abuse criteria were not given. b Three or more dependence criteria within a 12-month period. c Two or more substance use disorder criteria within a 12-month period. d Withdrawal not included for cannabis, inhalant, and hallucinogen disorders in DSM-IV. Cannabis withdrawal added in DSM-5.

Date of download: 2/17/2014

ALCOHOL USE DISORDER CRITERIA

IMPLICATIONS ON CLINICAL PRACTICE

• 11 criteria (abuse + dependence) • Removed trouble with the law and added cravings • Classified as mild, moderate or severe • Mild: 2-3 • Moderate: 4-5 • Severe: 6-11

• Easier diagnosis

• Do not diagnose substance use disorder based solely on tolerance and withdrawal (only exception to the ≥ 2 criteria threshold)

• Use of one checklist • Easy severity assessment through criteria count

• Development of new treatments tailored to severity

• but currently no studies to direct use of severity index for treatment assignment

• Mild substance use disorder target for early interventions – eg. Recommending they cut down on their drinking

• Pharmacotherapeutic maintenance therapy should be offered to moderate and severe alcohol users Charles O’Brien, MD/APA

IMPLICATIONS ON CLINICAL PRACTICE

ALCOHOL AND MR. J.B.

• Goal of new criteria was to preserve prevalence

•Hypertension

• NESARC study (43 000 random USA people surveyed) • 29 993 lifetime alcohol use • 9.7% alcohol abuse/dependence (DSM-IV) • 10.8% alcohol use disorder (DSM-V) • No significant change in prevalence NIH/NIAA - NESARC study. Grant, B. 2003 New York Times - APA. O’Brien, Charles. 2013

HYPERTENSION •A strong association between drinking

- Sleep disordered breathing (DSB)

• Decreased Libido

SLEEP •“normal” individuals - induces sleep but poor sleep 17-28 SD and the diagnosis of HTN. Binge

drinking results in greater increase in BP

•Intersalt study (controlling for age, BMI and urinary excretion of salt and potassium).

•Reducing alcohol intake reduces blood pressure

•Metaanalysis of 15 studies showed decreasing alcohol intake by 76 % on average results in reduction of systolic and diastolic BP of 3.3mmHg and 2mmHg respectively

•Abstention from alcohol results in clinically significant reduction in BP in heavy drinkers.

LIBIDO AND SEXUAL DYSFUNCTION •Studies of

•Sleep Apnea

alcohol dependent men (with moderate or severe alcohol use disorder)

•sexual dysfunction ranging from 60-85%. •Complaints include decreased libido, premature or delayed ejaculation, anorgasmia, and impotence

•Could it be protective against ED? •one meta-analysis found a significant protective association of regular (chronic) alcohol consumption on ED in cross-sectional studies, in particular for the consumption of 8 or more drinks/week.

• Evidence from large cohort studies suggests that regular alcohol consumption is not significantly associated with ED development. (Health Professionals Follow-up Study)

•multiple awakenings, REM rebound, nightmares, sweating, general activation, reduced overall sleep •Individuals with severe alcohol use disorder - delayed sleep and poor sleep. •Can persist for weeks or months after abstinence •Induces apnea in those without a history of sleep apnea or of alcohol use disorder •70kg male – 8 SD drink binge Increased apneic episodes from 20 to 110, sleep events 207 to 383 – these effects persisted to one night after drinking.

• alcohol increases likelihood and severity of OSA •For men, each increment of one drink /day increased the odds of SDB by 25% •LSAT decreased from 85.1 to 79.3. Number of desats /hour increased from 13.9 to 18.5

MANAGEMENT PEARLS

•Drinking in excess of safe drinking guidelines and/or mild alcohol use disorder

• Express concerns, educate, assess motivation to change, goal set, arrange follow-up, correlate alcohol use with physical consequences eg: sleep difficulties, hypertension. • Consider lab tests to evaluate for physical consequences of drinking (CBC, MCV, GGT, Enzymes, LFT’s)

MANAGEMENT PEARLS – MODERATE OR SEVERE ALCOHOL USE DISORDER

MODERATE/SEVERE ALCOHOL USE DISORDER

• Patient experiences withdrawal when stops drinking:

• History of seizure – loaded with Diazepam 20mg q1-2 hours x 3 • Consider outpatient nonmedical detox – Central Access 1 (866) 366-9513 • Outpatient medical detox – in your office or refer • SJHC – Shared care addiction medicine fax 416-530-6160

• Diazepam medication of choice to control withdrawal. • Do not give large prescriptions or repeat prescriptions. (3-5 tabs – 10mg

•Inpatient Medical Detox: •CAMH 416-535-8501, ext. 36071 •Humber Regional Hospital 416-658-2029

tabs) and close follow-up with plans to ensure sobriety post detox.

MANAGEMENT PEARLS – MAINTAINING ABSTINENCE

•Manage insomnia – gabapentin, trazodone or remeron •Reduce cravings •Naltrexone, acamprosate, off label – gabapentin, topiramate, baclofen

•Aversion therapy - antabuse

MANAGEMENT PEARLS – MAINTAINING ABSTINENCE

•Alcoholics Anonymous •http://www.drugandalcoholhelpline.ca •Glendale house – 416-530-6400

•outpatient counselors, referral to treatment programs, day program

•Inpatient treatment programs private and public

REFERENCES • • • • • •

Alcohol Screening, Brief Intervention and Referral: A clinical Guide www.sbir-diba.ca

• • • • • •

Alcohol Consumption and Erectile Dysfunction: Meta-Analysis of Population-Based Studies J Y W Cheng; E M L Ng; R Y L Chen; J S N Ko Int J Impot Res. 2007;19(4):343-352.

Questions/Consults?

DSM 5th edition. APA. 2013. http://dsm.psychiatryonline.org.myaccess.library.utoronto.ca/content.aspx?bookid=556&sectionid=41101782#103441455 DSM 4th edition revised. APA. 2000. http://justines2010blog.files.wordpress.com/2011/03/dsm-iv.pdf DSM 5th edition fact sheet. APA. 2013. http://www.dsm5.org/Documents/Substance%20Use%20Disorder%20Fact%20Sheet.pdf

Addictions Shared Care:

DSM-5 Criteria for Substance Use Disorders: Recommendations and Rationale. Hasin, Deborah S. et al. American Journal of Psychiatry. 2013. http://ajp.psychiatryonline.org/article.aspx?articleID=1722068 DSM-5 Changes: Addiction, Substance-Related Disorders & Alcoholism. Psych Central Professional. Grohol, John M. 2014. http://pro.psychcentral.com/2013/dsm-5-changes-addiction-substance-related-disordersalcoholism/004370.html

Alcohol increases sleep apnea and oxygen desaturation in asymptomatic men White, Carole et al the American Journal of medicine August 1981 240-245 Association of Alcohol Consumption and Sleep Disordered Breathing In Men And Women, Peppard etal Journal of Clinical Sleep Medicine 2007 Gabapentin Treatment for Alcohol Dependence :A Randomized Clinical Trial JAMA Intern Med. 2014;174(1):70-77 A brief alternative for identifying alcohol use disorders. Proctor SL and Hoffmann NG. Substance Use Misuse. 2012. http://www.ncbi.nlm.nih.gov/pubmed/22497880

Fax: 416-530-6106 Phone: 416-530-6000 ext 3969 Linda Weber (weberl@stjoe.on.ca)

AUDIT : http://www.talkingalcohol.com/files/pdfs/WHO_audit.pdf

2015 CONTINUING MEDICAL EDUCATION ANNUAL CURRICULUM 4th Annual Academic Achievement Day June 12, 2015 | 1200-1300

2 Annual Men’s Health Update June 17, 2015 | 0800-1200 hours

Senior’s Health Update

September 16, 2015 | 0800-1200 hours

Art & Science of Cardiac Physical Exam Workshop September 25-26, 2015 | 0800-1630 hours

2nd Annual Bugs & Drugs Day October 14, 2015 | 0800-1200 hours

60th Annual Clinical Day

November 6, 2015 | 0800-1600 hours

sjhcdmes.eventbrite.ca 49