Resident Editors: Anusha MacNamara, Pharm.D., Mark Nickell, Pharm.D. Faculty Editor: Todd Sorensen, Pharm.D.
Volume 10, Issue 2 Second Quarter 2012 In this Issue: Updates in Research Donepezil and Memantine for Alzheimer’s Disease Lifetime Risks of Cardiovascular Disease Adiposity – A Key Determinant in the Differential Pharmacodynamic Effects of Basal Insulins New Drug Updates Daliresp™ Therapeutic Thoughts Type 2 Diabetes; Emphasizing the Patient-Centered Care Model 2012 American Geriatric Society Beers Criteria Update Statin Treatment in Patients with History of Myalgia Episodic Migraine Prevention in Adults Patient-Centered Care:Turning the Rhetoric into Reality Revisiting Aspirin Primary Prophylaxis From the Pharmacy Press Evaluation of Multiple Methods of Billing for Reimbursement The Pharmacists’ Role in the Patient-Centered Medical Home (PCMH) Miscellaneous News Logistics Trump Desire in Collaborative Care
Donepezil and Memantine for Moderate-to-Severe Alzheimer’s Disease Michael F. Akers, PharmD Essentia Health Clinics Background: Cholinesterase inhibitors are FDA-approved for use in Alzheimer’s disease, and are recommended in guidelines. However, studies have mainly focused on mild-tomoderate disease severity, leaving the decision to initiate, continue, or discontinue use in the later stages of disease more anecdotal than evidence-based. Moreover, memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has shown benefit more so in moderate or severe Alzheimer’s disease. Purpose: To ascertain whether patients living in the community with moderate-to-severe Alzheimer’s disease who are currently taking donepezil benefit from continuation versus discontinuation of treatment, and whether the addition of memantine in the later stages of disease progression adds further benefit. Study Design: In this 52-week, multicenter, double-blind, placebo-controlled trial, 295 patients who had been on donepezil continuously for at least three months were randomly assigned to one of four groups: continuation of donepezil (10 mg per day) plus placebo memantine, discontinuation of donepezil plus placebo memantine, discontinuation of donepezil plus initiation of memantine, continuation of donepezil and initiation of memantine. Doses were titrated and tapered appropriately and patients were required to have been on the 10 mg per day dose of donepezil for at least six weeks prior to trial entry. The primary outcomes were changes in the Standardized Mini-Mental Status Examination (SMMSE) and the caregiver-rated Bristol Activities of Daily Living Scale (BALDS). Predefined minimum clinically important differences in SMMSE and BALDS were 1.4 points and -3.5 points, respectively. A sample size of 430 was estimated in order to meet power requirements; 95% power to detect a 1.0-point difference in SMMSE scores and 90% power to detect a 2.0-point difference in BALDS scores. Results: Continuation of donepezil versus discontinuation showed higher SMMSE scores (better cognitive function) and lower BALDS scores (less functional impairment). SMMSE scores increased by 1.9 points (95% CI, 1.3-2.5; P<0.001) and the BALDS scores decreased by 3.0 points (95% CI, 1.8 to 4.3; P<0.001). Memantine versus placebo showed similar results, but did not reach predefined clinical significance for either primary outcome; SMMSE increased by 1.2 points (95% CI, 0.6 to 1.8; P<0.001) and BALDS decreased by 1.5 points (95% CI, 0.3 to 2.8; P<0.02). No significant benefit from the addition of memantine to donepezil was realized; SMMSE increased 0.8 points (95% CI, -0.1 to 1.6; P=0.07) and BALDS decreased 0.5 points (95% CI, -2.2 to 1.2; P=0.57). Severity of disease at entry did affect the SMMSE score with moderate disease showing greater benefit when compared to those with severe disease. Conclusion: Continued treatment with donepezil in patients with moderate-to-severe Alzheimer’s disease reached minimum clinically important differences in cognition and had significant functional status improvement at 12 months. The combination of donepezil and memantine did not show significant benefit at 12 months with regard to cognitive or functional status.
Key Point: This study contributes important evidence that will aid in the treatment of moderate-to-severe Alzheimerâ&#x20AC;&#x2122;s disease patients given limited literature in this area. It is important to note, however, that the study did not meet the power criteria leading to the potential for a Type II error. Despite this downfall, clinicians should be aware of these results, in particular when electing to initiate combination therapy given limited benefit, higher pill burden, and increased cost. 1
Lifetime Risks of Cardiovascular Disease Maria Amaro, PharmD, Essentia Health Clinics Background: Efforts to reduce the burden of cardiovascular disease have emphasized the importance of calculating global, short-term (generally 10 year) risk estimates. However, the majority of adults in the United States who are considered to be at low risk for cardiovascular disease in the short term are actually at high risk across the remaining lifespan. Most of the estimates of the lifetime risk of cardiovascular disease have been derived from analyses restricted to risk factors measured at a single age in a predominantly white population. These estimates do not account for the potential effects of birth cohort that may rise from secular changes in risk-factor levels or the wide spread use of medical treatment, which has translated into reductions in rates of cardiovascular events in the U.S. Unlike previous studies, the authors pooled data from numerous longitudinal epidemiologic cohort studies conducted in the United States over the past 50 years, providing an opportunity to calculate estimates of the lifetime risk of cardiovascular events according to age, sex, race, and other risk factors. Objective: To determine the lifetime risks of cardiovascular disease across the age spectrum in black and white adults based on a risk-factor profile. Study Design: The study was a meta-analysis at the individual level using data from 18 cohort studies involving a total of 257,384 black and white men and women whose risk factors for cardiovascular disease were measured at the ages of 45, 55, 65, and 75 years. Participant data were stratified according to risk-factor levels or status as assessed within 5 years of each age index. Blood pressure, cholesterol, smoking status, and diabetes status were used to stratify participants according to risk factors into five mutually exclusive categories; all factors optimal, at least one risk factor not optimal, at least one risk factor elevated, one major risk factor present, and two or more major risk factors present. The remaining lifetime risks of cardiovascular events were estimated for participants in each category at each age, with death free of cardiovascular disease treated as a competing event.
Results: Marked differences in the lifetime risks of cardiovascular disease across risk-factor strata were observed. Among participants who were 55 years of age, those with an optimal risk-factor profile (total cholesterol level <180 mg/dL; blood pressure <120 mmHg systolic and <80 mmHg diastolic; non-smoking status; and non-diabetic status) had substantially lower risks of death from cardiovascular disease through the age of 80 years than participants with two or more major risk factors (4.7% vs 29.6% among men, 6.4% vs 20.5% among women). Those with an optimal risk-factor profile also had lower lifetime risks of fatal coronary heart disease or nonfatal myocardial infarction (3.6% vs 37.5% among men, <1% vs 18.3% among women) and fatal or nonfatal stroke (2.3% vs 8.3% among men, 5.3% vs 10.7% among women). Similar trends within risk-factor strata were observed among blacks and whites across diverse birth cohorts. Conclusion: Differences in risk-factor burden translate into marked differences in the lifetime risk of cardiovascular disease, and these differences are consistent across race and birth cohorts. Key Points: The presence of elevated risk factors was a consistent determinant at all ages of markedly higher lifetime risks of cardiovascular disease across the lifespan, regardless of race or birth cohort. Efforts to lower the burden of cardiovascular disease will require the prevention of the development risk factors rather than the sole reliance on the treatment of existing risk factors. Adiposity â&#x20AC;&#x201C; A Key Determinant in the Differential 1 Pharmacodynamic Effects of Basal Insulins Jessica Hammes, PharmD, FirstLight Health System Background: A previous study suggested that pharmacokinetics and pharmacodynamics of basal insulins vary in patients with type 2 diabetes mellitus. In that study, the glucose infusion rate (GIR) was used as the primary endpoint and was found to be greater for glargine versus NPH and detemir using a 32-hour euglycemic clamp method. Other studies have been limited by shorter observation periods. Euglycemic clamp refers to a method of measuring insulin secretion and resistance in an individual [3]. Purpose: To determine independent variables that may predict the pharmacodynamic differences observed between insulin NPH, glargine, and detemir. Study Design: Eighteen type 2 diabetes patients on insulin, with or without any oral hypoglycemic agents, were recruited and randomized in a single-dose, singleblind, three-way, cross-over study. Patients received treatment by a Latin square design (ABC/BCA/CAB).
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After a two-week run in period in which previous treatments were continued, patients received a oncedaily dose of either NPH, glargine, or detemir at the time 2200 [2]. A euglycemic clamp protocol was then followed [3]. Regression analyses were used to identify independent variables that may best predict GIR response. Age of patients, duration of diabetes, plasma C-peptide, and body mass index (BMI) were included as independent variables in the analyses. The GIR represented the dependent variable. Pearson product moment correlation was used to assess association between changes in GIR and other parameters. Mixed-model analysis was used to analyze data. Bonferroni adjustments were made for multiple comparisons; tests were two-sided with significance level of 0.05 [2]. Results: BMI was determined to be a significant model of pharmacodynamic differences through the multiple 2 regression analysis (p = 0.017; adjusted R = 0.45). BMI accounted for 39% of variation in GIR (p = 0.013). On the basis of BMI for the three basal insulins, GIR was 2 lower in people with a higher BMI (>29 kg/m ) compared 2 to those with a lower BMI (<29 kg/m ). Statistical significance was found with insulin detemir only (598 604 and 1564 649 mg/kg, respectively; p = 0.03) and not with NPH (1058 859 and 1282 532 mg/kg) or glargine (1408 563 and 1668 807 mg/kg) (both p > 0.2). Also observed was that residual endogenous glucose production (EGP) was greater in people with 2 2 BMI > 29 kg/m versus < 29 kg/m . This was significant for detemir (7.8 1.8 vs 4.1 2.1 mol/kg/min, p = 0.001) but not for glargine (5.3 1.3 vs 3.8 2.7 mol/kg/min, p = 0.231) or NPH (6.6 2.2 vs 4 2.1 mol/kg/min, p = 0.068). Conclusions: There is an inverse correlation between BMI and GIR in type 2 diabetes mellitus when insulin is given by a euglycemic clamp method. The relationship indicates that with greater adiposity, there is lower insulin sensitivity. It may be possible to use this information when considering subcutaneous injections of long-acting insulins, however, no present studies exist. The pharmacodynamics of detemir, glargine, and NPH are affected by BMI; the pharmacodynamic effect was lower for detemir than for NPH and glargine. All three insulins showed lower suppression of endogenous glucose production with an increasing BMI. This correlation was only significant with NPH and detemir, and potentially suggests that glargine has a greater effect in lowering EGP with increasing adiposity. Key Point: Body mass index largely explains the pharmacodynamic effects of insulins NPH, detemir, and glargine in type 2 diabetes mellitus as previously reported [2]. As BMI increases, the effect of detemir is lower versus NPH and glargine (lower GIR and greater
EGP). Obesity is the primary driver of larger detemir doses versus NPH and glargine needed in type 2 diabetes mellitus. 5
Hypnoticsâ&#x20AC;&#x2122; Association with Mortality Lindsay A Sorge, PharmD, Smileyâ&#x20AC;&#x2122;s Clinic Background: Six to ten percent of American adults used a hypnotic for sleep in 2010. The authors reviewed 24 studies which examined hypnotic use and mortality. Eighteen of those studies reported statistically significant increased mortality in those who used hypnotics. Due to variability of study design and the lack of data on newer hypnotics such as, zolpidem, zaleplon, and eszopiclone, the authors wished to expand this area of research rather than complete a meta-analysis. Objective: The study objective was to contrast mortality associations of zolpidem and newer short acting hypnotics with controls. Study Design: The study was a one-to-two matched cohort survival analysis where the data was extracted retrospectively from the electronic medical records of a large health system in rural Pennsylvania. There were 10,529 people who received hypnotics matched to 23,676 controls who did not have hypnotic prescriptions. These people were followed for an average of 2.5 years between January 2002 and January 2007. The data analysis controlled for age, sex, ethnicity, marital status, body mass index, self-reported alcohol use and smoking status, and comorbid conditions. However, they did not control for depression, anxiety, and other emotional factors due to Pennsylvanian law requiring the confidentiality of these diagnoses. Results: The overall hazard ratio for was 4.56 (95% CI 3.95 to 5.26) for the hypnotic user cohort to non-user controls when adjusted for covariates (i.e., age, gender, BMI, smoking). Patients prescribed 1-18 doses per year of any hypnotic had a HR for death of 3.6 (95% CI 2.92 to 4.44). This increased for 18-132 doses per year and >132 doses per year to 4.43 (95% CI 3.67 to 5.36) and 5.32 (95% CI 4.5 to 6.3), respectively. Conclusions: There is a trend of increased risk of death for patients prescribed hypnotics compared to nonusers. This risk increases with the number of doses prescribed each year. These findings are consistent when adjusted for confounders and health status. It is important to note the results do not take into account diagnoses of depression, anxiety, or other mental health conditions nor are there baseline characteristics describing the prevalence of these conditions in either arm of the trial.
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Proposed pathways for mortality associated with hypnotic use include: mixed drug overdoses, falls, automobile crashes due to hangover effects, sleep apnea, or somnambulistic night-eating syndromes leading to poor diet and obesity. Key Point: There was an association of mortality for patients prescribed hypnotics, even for those prescribed fewer than 18 doses of per year. There was greater mortality associated with greater dosages of hypnotics prescribed. Since the trial was retrospective and did not adjust the results for mental health conditions (i.e., anxiety and depression) it is important to recognize a trend rather than causation. Applying these results in clinical practice would be to become more aware of hypnotic use of patients, evaluate potential adverse reactions, and how the medication is interacting with comorbid conditions.
Nicotine Therapy Sampling to Induce Quit Attempts 6 Among Smokers Unmotivated to Quit Stephanie Smith, PharmD, Fairview Pharmacy Services Background: The most common method for increasing motivation to quit smoking is physician advice and motivational interviewing. Many smokers are apprehensive to commit to stopping smoking due to fear of embarrassment if they are unsuccessful. Practice-Quit Attempts (PQAs) may be a less intimidating option which can increase confidence and introduce coping skills for when a patient is ready to quit. An example of a PQA would be having a patient attempt to not smoke for a few hours or days without pressure to permanently quit. Offering Nicotine Therapy (NT) to motivated smokers has been shown to increase quit attempts and abstinence. Therapeutic benefits of NT could empower patients to make a quit attempt, even if they are unmotivated, but this has not been tested. Objective: To determine if NT sampling during PQAs would increase subsequent attempts to permanently quit smoking in patients unmotivated to quit. Study Design: In a randomized, non-blinded, two group study design, smokers unmotivated to quit were assigned to (1) a PQA alone or (2) PQA + NT. Patients were recruited via email using a database provided by a marketing research firm. To be included, patients must have been 18 years or older, smoked ≥ 10 cigarettes per day, not using non-cigarette tobacco, accessible by phone for the 6 month study period, have no FDA contraindications for nicotine lozenge use, no previous NT use, and have no quit attempt longer than 1 week in the last year. To identify that a patient was unmotivated to quit, patients were offered 2 study options: an option to quit within the next 30 days or an option to quit at a
later time after 30 days – only those who chose the latter study option were included. The intervention included 3 telephone calls over 6 weeks during which both groups of participants worked with a telephone counselor to establish an individual PQA plan (smoking cessation ranging from a few hours to days) with support materials mailed to them. Two samples of nicotine lozenges were mailed to the second group of participants only and the telephone counselors queried on the efficacy of these products. After the 6 week period, there were 3 subsequent follow-up phone calls made at 4, 12, and 26 weeks to assess outcomes. The primary outcome was an attempt to permanently quit smoking. The secondary outcome was abstinence from smoking for 7 days. Results: There were 423 participants assigned to the PQA only group and 426 participants assigned to the PQA + NT group. Eighty-eight percent of participants categorized themselves as non-Hispanic white. Within the PQA + NT group, 73% reported using the Nicotine lozenges. The mean number of days of nicotine lozenge st use was 6.8 days for the 1 sampling period and 9.3 nd days for the 2 sampling period. A summary of the results for 24 hour quit attempts and 7-day abstinence is provided in Table 1. Table 1 – Smoking Cessation Results
4-week follow-up 12-week follow-up 26-week follow-up
24-hour quit attempt PQA + PQA p-value NT only 22% 13% <0.001 32% 23% 0.003 43% 34% 0.004
7-day abstinence PQA + PQA pNT only value 7% 3% 0.004 13% 8% 0.03 16% 14% 0.3
Although patients in the PQA + NT group had statistically significant higher measures of cessation readiness at the end of treatment, this did not carry through to the final follow-up assessment where no statistically significant changes were seen between the groups in regards to intent to quit in the next month and confidence in quitting. Conclusions: The intervention with NT during a PQA increased the likelihood of quit attempts but did not increase abstinence at the 6 month follow-up. Measures of readiness to quit favored the PQA + NT group, but were not significant. Rates of quit attempts and 7-day abstinence with the PQA + NT approach seen in this study are higher than what is generally seen with other options for initiating cessation such as motivational interviewing, physician advice, and smoking reduction. NT sampling during a PQA is an effective intervention to motivate unmotivated smokers to attempt quitting. Key Points: It is unclear how increasing quit attempts relates to permanent abstinence from smoking. It is possible that introduction of the PQA + NT approach, in the clinic setting with a healthcare provider that the patient has a
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therapeutic relationship with (rather than by phone), would further enhance outcomes. Limitations of the study include the absence of a control group without treatment and the lack of diversity with regards to ethnicity. The rates of quit attempts and cessation in
PQA groups, whether or not NT was used, were considerably higher than the standard norms and the theory of PQA is a novel treatment approach that may be helpful for unmotivated patients resistant to other therapies.
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Daliresp™ (roflumilast, Forest Laboratories, Inc.) Alison Knutson, PhamD, Park Nicollet Creekside Clinic Indication: FDA approved to reduce the risk of exacerbation in patients with severe COPD associated with chronic bronchitis and a history of exacerbation Mechanism of Action: Roflumilast is a phosphodiesterase- 4 (PDE4) inhibitor. Inhibition of this cyclic AMP-metabolizing enzyme leads to accumulation of intracellular cyclic AMP in the lung tissue and down regulation of inflammatory cell activity. The antiinflammatory properties are thought to lead to the benefit in COPD and potentially asthma. Dosage and Administration: The dose is one 500mcg tablet once daily, with or without food. Effectiveness: In 2 double-blind, placebo-controlled trials, 3091 patients with severe COPD associated with chronic bronchitis and at least one COPD exacerbation within the past year (requiring systemic glucocorticosteroids or hospitalization) were randomized to receive roflumilast or placebo for one year. Prebronchodilator FEV1 increased by 48 mL compared to placebo, and the annual rate per patient of moderate to severe exacerbations was significantly lower in patients treated with roflumilast (1.14 vs. 1.37). Roflumilast also significantly improved post-bronchodilator FEV1 compared to placebo, but did not lower overall mortality. In studies in patients with less severe disease,
Updates in the Management of Type 2 Diabetes; 9-11 Emphasizing the Patient-Centered Care Model Alan Bartolucci, PharmD, Cub Pharmacies
roflumilast did not significantly reduce exacerbations compared to placebo. The largest limitation is that these placebo controlled studies did allow for the use of shortacting antimuscarinic and long-acting beta agonists with short-acting beta agonists for rescue therapy, but excluded the use of inhaled corticosteroids or longacting antimuscarinic drugs which are considered standard of therapy in severe disease. Safety: In clinical trials, the percent of patients discontinuing therapy was 14.8% on roflumilast compared to 9.9% taking placebo. GI complaints were the main cause of discontinuation compared to placebo (diarrhea 9.5% vs. 2.7%, weight loss 7.5% vs. 2.1%, and nausea 4.7% vs. 1.4%). Weight loss was considerable with 20% of patients experiencing moderate weight loss (5-10% of body weight), and 7% experiencing severe weight loss (>10% of body weight). Psychiatric events in somnia, depression, anxiety and suicidality - were reported in 5.9% on roflumilast compared to 3.3% on placebo. Place in Therapy: The use of roflumilast should be limited to those patients with severe COPD that also have a history of exacerbation. Risk versus benefit should be weighed given the significant side effects of weight loss and psychiatric events. Cost: Estimated cost for 30 tablets (500mcg) is $207 (Average Wholesale Price)
Key Point: The American Diabetes Association (ADA) released revised Standards of Medical Care in Diabetes in January. Additionally, the ADA and the European Association for the Study of Diabetes (EASD) have emphasized the utilization of the patient-centered care model to individualize the treatment of type 2 diabetes.
previous year. Additionally, the 2012 standards of care have been updated to adequately reflect the level of evidence supporting the embedded recommendations. Recommendations with the level of evidence “A” are from well-conducted, generalizable, randomized controlled trials that are adequately powered. Evidence “B” is supportive evidence from well-conducted cohort studies, “C” is supportive evidence from poorly controlled or uncontrolled studies, and “E” is expert consensus or clinical experience.
Background: The ADA standards of care are updated annually to incorporate evidence released within the
The patient-centered care model is a model of care defined by the incorporation of patient-specific
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preferences, needs, and values into the decision making process. This model is particularly relevant in the treatment of type 2 diabetes due to the large number of patient-specific contributory factors and the variable progression of the disease. Recommendations: Several medication specific recommendations have been updated. 1. At the time of type 2 diabetes diagnosis, initiate metformin therapy along with lifestyle interventions, unless metformin is contraindicated. (A) a. Women with a history of GDM found to have prediabetes should receive lifestyle interventions or metformin to prevent diabetes. (A) b. In newly diagnosed type 2 diabetes patients with markedly symptomatic and/or elevated blood glucose levels or A1C, consider insulin therapy, with or without additional agents, from the onset (E) c. If non-insulin monotherapy at maximal tolerated dose does not achieve or maintain the A1C target over 3-6 months, add a second oral agent, a GLP-1 receptor agonist, or insulin. (E) 2. Administer hepatitis B vaccine to adults with diabetes as per CDC recommendations (C) 3. Pharmacologic therapy for patients with diabetes and hypertension should be with a regimen that includes either an ACE inhibitor or an ARB. If one class is not tolerated, the other should be substituted. (C) a. Diuretic is no longer recommended as second line therapy due to a lack of supporting evidence b. One or more of the antihypertensive agents should be administered at bedtime The ADA and EASD joint task force recommends incorporating several patient factors when treating to patient-specific goals. These patient-specific factors include, but are not limited to: patient attitude, risk of adverse effects, and life expectancy. Furthermore, the joint task force has recommended that prescriberâ&#x20AC;&#x2122;s utilize decision aids to allow patients to participate in the exploration and selection of appropriate drug therapy. Conclusion: The updated ADA standards of care and the ADA/EASD combined task force recommend that the treatment of type 2 diabetes be patient-specific. It is the patientâ&#x20AC;&#x2122;s decision to adhere to the recommended drug and non-drug therapies. Utilizing a patient-centered approach to share the decision making process with the patient allows for greater patient buy-in and the establishment of attainable, patient-specific goals.
2012 American Geriatric Society 12 Beers Criteria Update Jonica Hazaert, PharmD, Univ. of MN, Fairview Advanced Therapies Clinic Background: The Beers Criteria first published its list of potentially inappropriate medications in the elderly in 1991. Updates were made in 1997, 2003 and most recently on March 1, 2012. New to the latest update is the collaboration with the American Geriatrics Society. This will allow for more regular, systematic updates with increased transparency and a wider distribution to clinicians and researchers. A panel of eleven interdisciplinary experts in the areas of pharmacotherapy and geriatrics conducted a comprehensive, systematic review to grade evidence of drug related adverse events in the elderly. These criteria are meant to be used in ambulatory and institutional settings in the care of adults age 65 and older. Fifty-three medications or medication classes are included on the Beers Criteria and are divided into three categories. This review will focus on differences between the 2003 and 2012 Beers Criteria. Table 2: Additions to Potentially inappropriate medications and classes to avoid in older adults. Medication or Class Megestrol
Rationale
Minimal effect on weight and increased risk of thrombotic events and death Long-Acting Greater risk of severe or Sulfonylureas prolonged hypoglycemia Sliding-Scale Avoid use in any care setting Insulin due to high risk of hypoglycemia and limited hyperglycemia improvement 1. Strength of recommendation is strong
Quality of Evidence Moderate1 High1 Moderate1
Table 3: Additions to Potentially inappropriate medications and classes to avoid in older adults due to drug-disease or drug-syndrome interactions. Medication or Class Glitazones
Disease or Syndrome Heart Failure
Rationale
Promote fluid retention and exacerbation of heart failure Acetylcholinesterase History of Increase risk of Inhibitors Syncope orthostatic hypotension Selective Serotonin History of Can produce Reuptake Inhibitors Fractures ataxia, impaired (SSRIs) or Falls psychomotor function, syncope, and additional falls 1. Strength of recommendation is strong
Quality of Evidence High1
Moderate1 High1
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Table 4: Medications to be used with caution in older adults. (New category to the Beers Criteria includes medications that were considered for the two previous categories but thought to be appropriate for some individuals or medications that are new to the market and evidence is still emerging) Medication or Class Aspirin
Dabigatran
Prasugrel
Vasodilators
Rationale Use with caution for primary prevention of cardiac events in individuals over the age of 80 Greater bleeding risk versus warfarin in individuals over the age of 75 or with a CrCl less than 30 ml/min. Risk of bleeding but the benefit may outweigh the risk in the highest risk individuals Use with caution in those with a history of syncope as symptoms may be exacerbated Use with caution as these may exacerbate or cause inappropriate antidiuretic hormone secretion or hyponatremia
Quality of Evidence Low2
Moderate2
Moderate2 Moderate2
Antipsychotics, Moderate1 Carbamazepine, Carboplatin, Cisplatin, Mirtazapine, SSRIs, SNRIs, TCAs, Vincristine 1. Strength of recommendation is strong, 2. Strength of recommendation is weak
Medications removed since the 2003 Beers Criteria: cimetidine, cyclandelate, daily fluoxetine, ferrous sulfate > 325 mg/day, guanethidine, halazepam, long-term use of stimulant laxatives, mesoridazine, propoxyphene, tripelennamine. Clinical Impact/Conclusions: The Beers Criteria are intended to be used by clinicians to identify medications whose risk may outweigh benefits for older adults. The medications included on this list have limited efficacy or high risk of adverse events and alternative medications or non-drug therapy may be more appropriate. Not all patient populations, such as individuals who are being treated in palliative care and hospice, are addressed in these criteria and individual clinical scenarios must be taken into account when making medication decisions.
Options to Continue Statin Treatment in Patients 13 with History of Myalgia Lisa Schleper, PharmD Westside Community Health Services Background: Statin (HMG-CoA reductase inhibitor) treatment is the mainstay of dyslipidemia management, with well-established morbidity and mortality benefits in patients with CHD and dyslipidemia. Studies show that up to 10% of patients discontinue statins within 1 year due to side effects. Several approaches to salvage
statin therapy have been proposed, and this article reviews the evidence for each alternative. All studies included patients with a past history of statin-associated myalgia. Alternative dosing schedule: Trials have explored every other day and twice weekly dosing of rosuvastatin and atorvastatin. Trial designs have varied. There were no prospective trials, some studies lacked a control group and others added ezetimibe and colesevelam to the alternate day statin regimens. The majority of patients (71-98%) tolerated these dosing schedules with LDL lowering ranging from 35-56%. Once weekly rosuvastatin showed 27% of patients reached their LDL goal. Addition of vitamin D supplementation: Levels of 25hydroxyvitamin D below 20 ng/mL have an established association with myalgia, and correction of vitamin D deficiency may prevent statin-related myalgia. One cohort study identified 82 patients with statin-associated myalgia with 25(OH) Vitamin D < 20. Of these patients, 38 successfully completed a regimen of vitamin D 50,000 units weekly for 12 weeks and 35 patients had no further myalgia. Evidence is limited in this area, with one prospective controlled trial in progress that may provide further evidence. Addition of Coenzyme Q10 (ubiquinone): Coenzyme Q10 (ubiquinone) is a core component of muscle metabolism that may be decreased during statin therapy. Three randomized controlled trials have demonstrated pain relief but no direct evidence of increased tolerance to statin therapy. These studies are limited by small sample sizes and varying definitions of myalgia. Statin substitution with red yeast rice: Red yeast rice contains lovastatin, a naturally occurring statin. A few randomized controlled trials have demonstrated similar myalgia rates and improved LDL lowering compared to placebo, and similar myalgia rates and LDL lowering compared to pravastatin. These trials are limited by small, low-powered sample sizes or lack of power calculation. Furthermore, as a natural supplement, concentration and quality of red yeast rice products is not regulated, prompting safety concerns for patients. Substitution with alternative statin: Finally, studies have examined substituting rosuvastatin or fluvastatin in patients who have failed other statins such as simvastatin. These studies show a high variability in patient tolerance (36% to 98%). In converting from one statin to another, it is also possible that patients were switched to a lower-potency dose relative to their previous statin.
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Conclusions and Clinical Impact: Overall, these approaches lack robust evidence of maintaining patients on statin therapy or reaching objective goals such as target LDL. Supplementation with Vitamin D or CoQ-10 while maintaining statin treatment appears to be a safe approach, while alternative dosing schedules with extended half-life statins also shows potential in current studies. Concerns about quality and safety should limit the use of red yeast rice extract as an alternative.
Clinical Impact: One study by Lipton et al. suggested that 3%-13% of patient that suffer from migraines use preventive therapy, but 38% of patients that experience migraines are eligible. The data published in the recent guideline will help direct therapy choices for patients found to be eligible for migraine prevention. Choice of medication therapy should be based on each individual patient situation, comorbid conditions, and potential side effects.
Updated Guideline for Episodic 14-17 Migraine Prevention in Adults Mark Kasella, PharmD, St. Cloud VA Health Care Services
Patient-Centered Care: Turning the 18-20 Rhetoric into Reality Maggie Wallace, PharmD, Hennepin County Medical Center
Key Point: An updated evidence based guideline of pharmacological treatments for migraine prevention in adults has been established by the American Academy of Neurology and the American Headache Society. This is an update of a previous version published in 2000.
I was recently in a job interview describing a patient care experience in my family medicine clinic. As I was describing the scenario, I referenced “the patient” and my interviewer promptly corrected me, saying “the person.” I was immediately caught off guard. My interviewer went on to explain to me that the individuals that we work with in our clinics spend much more time as mothers, fathers, children, employees, friends, and neighbors than they do as patients. He continued to tell me that when we refer to them as patients, it is easy to forget about all of the other things in their lives that they most likely value more than being a patient within the healthcare system. He urged me to think of them first and foremost as individuals with complete lives outside of the clinic. What a simple, yet powerful and humbling perspective…
Background: Database searches were performed to collect randomized, controlled trials of medications used for migraine prevention published from 1999-2009. A total of 284 articles were identified, and 29 were classified as either Class I or Class II and utilized for the updated guideline. The classification system is based on the quality of the trial and measurement of appropriate outcomes. A panel of headache and study design experts reviewed the evidence. The National Headache Foundation reviewed multiple migraine prevention guidelines and recommended the following: Preventive therapy should be considered in those with greater or equal to 2 migraines per month with disability greater or equal to 3 days per month Recurring migraines that, in the patient’s opinion, significantly interfere with daily routine Use of acute OTC or prescription medications more than twice per week Acute medications are ineffective, not tolerated, or contraindicated The purpose of this review is not to define the criteria for use, but to offer evidence based recommendations for which agents to choose for the prevention of migraines. Conclusion: The review of medications was categorized by drug class and the results of the analysis are categorized based on levels of efficacy (Table 1). The updated guidelines do not identify a preferred agent within levels as evidence is not available to make such recommendations. Table 5: Review of Migraine Prevention Medications Categorized by Level of Efficacy (see page 13)
Definition: Patient-centered care is respectful of and responsive to individual patient preferences, needs, and values, and ensuring that patient values guide all clinical 1 decisions. Patient-centered decision-making sounds great, in theory, but we are at a time when disease-based outcomes measures are driving quality ratings and thirdparty payment. How can we afford to let patients drive the decision-making process - potentially at the detriment of hard clinical outcomes? Several strategies for approaching this conundrum have been proposed, including goal-oriented patient care and shared decision making. Goal-oriented patient care acknowledges that many individuals have multiple chronic conditions. While disease-based outcomes measures often work relatively well for patients with a single condition, they may be inappropriate or even harmful for patients with multiple conditions. To address this disconnect, Reuben and Tinetti propose considering an individual’s health goals across a range of dimensions (symptoms, physical functioning, social functioning) to guide treatment. This
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method simplifies decision making for patients with multiple conditions by concentrating on outcomes that span conditions and allows for aligning treatments toward common goals. The decision to deescalate treatment of one condition to optimize treatment for another can be made in the context of the therapy that is most likely to help the patient to achieve his or her goals. An individual with hypertension and orthostatic hypotension may choose to have a higher blood pressure than guidelines prescribe in order to walk with less angst about falling. Goal-oriented care encourages individuals to express which conditions are important to them and to prioritize goals. This allows patients to be in control when treatment options require tradeoffs (i.e., better symptom control with more medication side 2 effects). Shared decision making is rooted in the idea that the most important element of patient-centered care is the engagement of patients and caregivers in healthcare decisions. This concept raises many questions regarding methods for effectively distilling information from medical literature and training in a way that informs patients and families about options available without overwhelming them with information that they are not able to understand. For some decisions, the path is clear â&#x20AC;&#x201C; a child with appendicitis needs surgery. For most decisions, however, there are several reasonable paths for management. Statins for primary prevention of cardiovascular disease, genetic testing, therapy for early-stage prostate cancer â&#x20AC;&#x201C; these decisions require patients to evaluate their wishes and values regarding their health. In a shared decision making model, the clinician describes the risks and benefits of the options for management, and the patient expresses preferences and values. This allows both parties a better understanding of relevant factors and shares the responsibility in deciding how to proceed. Decision aids may be useful in facilitating this conversation by helping patients to process the relevant clinical evidence. For shared decision making resources, visit: http://shareddecisions.mayoclinic.org/resources-tools/.
Revisiting Aspirin Primary Prophylaxis Vincent Murphy, PharmD Westside Community Health Services
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Key Point: Patients at least 50 years of age with a 10year cardiovascular risk of at least 5% are likely to benefit from low-dose aspirin for primary myocardial infarction prevention. Women at least 55 years with a 10-year cardiovascular risk of at least 3% are likely to benefit from low-dose aspirin for primary stroke prevention. Patients with diabetes may possess a
significantly increased risk of extra-cranial hemorrhage compared to a patient without diabetes. Background: There are multiple guidelines available to guide practitioners on the use of aspirin for primary prophylaxis. These guidelines vary slightly despite being based on similar sources of information. This can create debate among clinicians as to whether a patient should or should not be receiving aspirin for primary prevention. Evidence: General Population Primary Prophylaxis The primary source of data for the current aspirin recommendations comes from a 2006 meta-analysis performed by Berger et al. The 2012 CHEST guidelines summarize the key outcomes including total mortality, non-fatal myocardial infarction, stroke and gastrointestinal bleeding based on 10-year cardiovascular risks in the general population: Table 6: CHEST Data Synthesis Low Risk <5% Total Mortality MI CVA Extracranial Bleeding
Moderate Risk 15%
High Risk 25%
6 fewer 6 fewer 1 fewer 4 more
19 fewer 3 fewer 16 more
31 fewer 5 fewer 22 more
Statistics
0.94 (0.881.00) 0.77 (0.690.86) 0.95 (0.851.06) 1.54 (1.31.82)
Women Population Primary Prophylaxis The most recent USPSTF aspirin guidelines from 2008 found a differential effect in primary prophylaxis dependent on sex. The major data source for this recommendation was the Womenâ&#x20AC;&#x2122;s Health Initiative Study which was included in the Berger et al. metaanalysis. In women, there was no significant benefit in MI reduction; however, there was a 24% reduction in ischemic stroke (0.76 [0.63-0.93]). Patients with Diabetes In 2010, the ADA, AHA and ACCF jointly revamped the aspirin recommendations in patients with diabetes. This guideline analyzed the risks and benefits in approximately 4000 patients included in the Berger et al. meta-analysis in addition to three additional studies. When patients with diabetes were compared to patients without diabetes, there was a 55% relative increase in the risk of bleeding for the patients with diabetes (1.55 [1.13-2.14]). Conclusion: There is most likely some level of differential in benefit in specific patient populations. However, in general, low-dose aspirin is associated with only mild to moderate benefit as primary prophylaxis in the general population.
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Evaluation of Multiple Methods of Billing for 25 Reimbursement Katie O’Brien, PharmD St. Cloud VA Health Care System Background: Historically, pharmacists have had the ability to bill only for product delivery as a service. Pharmacists now face the challenge of creating sustainable reimbursement models through the development of medication management services. Current Procedural Terminology (CPT) codes have been developed for such services, but are not widely used due to a lack of consistency regarding third party reimbursement. Design: A recent retrospective analysis was designed to analyze charges and reimbursement for medication management services. An additional objective of the study was to determine the number of patient visits needed in order to cover a pharmacist’s salary and benefits. A sensitivity analysis was utilized to determine the impact of visit charges on the number of patients needed to cover these costs. The cost of a pharmacist was estimated to be $120,000 annually, assuming an annual salary of $100,000 and fringe benefits totaling $20,000. Billing data was collected over a four-year period (2006 to 2010) in an ambulatory practice setting in North Carolina, which was recognized as a Patient Centered Medical Home (PCMH). The majority of patients seen by pharmacists were for management of anticoagulation, osteoporosis, and pharmacotherapy (polypharmacy, diabetes, or medication assistance). Anticoagulation and pharmacotherapy visits were typically billed using the “incident to” method. This billing is submitted under a recognized CMS provider and is usually coded as a level 1 encounter. Osteoporosis encounters were billed as level 4 visits, since both a pharmacist and physician saw each patient. The treatment decisions in osteoporosis visits are also considered to be “complex.” Results: There were 6,930 pharmacist encounters documented from 2006 to 2010. The charges billed to third party payers using the “incident to” method accounted for an average annual charge of $51,322. The authors determined the mean charge per visit to be $41, and reimbursement to be $19 per encounter. Therefore, the mean reimbursement rate was 47%, with a range from 29% to 67%. Using these estimations, they determined 12 encounters per day would be
necessary to generate adequate charges to cover the cost of one pharmacist annually. If the 47% reimbursement rate were included in this estimation, the pharmacist would need to see a total of 24 patients per day to generate adequate collections to cover their cost. This would likely only be feasible in a setting where numerous patients are seen using a streamlined process, such as an anticoagulation management clinic. A sensitivity analysis was utilized to estimate the number needed to be seen if a higher billing level was used. A total of 10 level 4 visits per day were necessary to cover a pharmacist’s salary, taking the 47% reimbursement rate into account. Conclusions: The number of patient encounters needed per day was clearly more feasible if pharmacists were billing patients for a higher level of service. One limitation to the analysis was exclusion of support staff and overhead costs thus creating an underestimate of the true number of encounters required to achieve a cost neutrality to the health care organization. This study demonstrates the need to determine adequate reimbursement for pharmacist services. For example, providing collaborative care with physicians during osteoporosis visits allowed pharmacists to bill at higher levels for increased reimbursement in this study. In the future, pay for performance initiatives may also help offset the cost of pharmacists with incentives for providing improved quality of care while decreasing overall healthcare costs. Multiple methods of billing for reimbursement may be necessary to generate adequate compensation to cover the cost of pharmacists. The Pharmacists’ Role in the Patient-Centered Medical Home (PCMH): A white paper created by the Health Policy Committee of the Pennsylvania 26 Pharmacists Association Heidi Mandt, PharmD, Fairview Pharmacy Services Background: In 2004, the American Academy of Family Physicians announced that to provide more comprehensive care through ongoing relationships with integrated providers, a “personal medical home” should be developed to serve all patients effectively. The academy states that the purpose of the Patient-Centered Medical Home (PCMH) is to “provide patients with access to comprehensive and integrated healthcare, focusing on quality and safety through ongoing relationships with medical professionals.”As a response to the increasing interest in the patient centered medical
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home (PCMH) model nationwide, the Pennsylvania Pharmacist Associationâ&#x20AC;&#x2122;s Health Policy Committee developed a sub-group called the Patient-Centered Medical Home workgroup. It is well-documented that medication-related costs are a significant component in the ever-increasing cost of healthcare. It is estimated that every $1.25 spent on medications is matched by another dollar spent on problems caused by that medication. In patients who average high pill burdens such as the elderly, as much as 30% of the problems caused by these medications are preventable. Medication therapy management (MTM) and other pharmacist services may provide solutions for many of these patients. Pharmacists in the Medical Home: According to the National Committee for Quality Assurance, the six standards used to determine if a practice functions as a medical home are enhanced access and continuity, ability to identify and manage patient populations, plan and manage care, provide self-care and community support track and coordinate care, and measure and improve performance. Pharmacists can contribute across to each of these standards through collaborative drug therapy management, medication therapy management, preventative care, medication reconciliation, monitoring for potential intervention, and assisting in accreditation of the PCMH.
Logistics Trump Desire in Collaborative Care Mollie McFaggen, PharmD Community-University Health Care Clinic
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A recently published Canadian study examined the development of collaborative relationships between pharmacists, nurse practitioners (NPs), and family physicians working in a primary health care setting. This was the first time that physicians in the study had worked with either a pharmacist or NP. The study found that bringing together a team and integrating practitioners is independent of a patientâ&#x20AC;&#x2122;s medical complexity. Developing collaborative relationships and learning to work together as a team is not easy and takes time. For this particular study it took roughly 6 months for the teams to understand and define each practitionerâ&#x20AC;&#x2122;s respective roles and how they could
Barriers and Solutions to Pharmacists in the Medical Home: An opportunity exists to define the role of pharmacists within the medical home model because the model itself is still evolving. However, to accomplish this, pharmacists must be aware of the landscape shaping medical home policies and practices and proactively engage in this work. Defining a systemsbased approach to managing medication use within the medical home model is critical to support patient health and safety and pharmacists would bring a unique perspective to this effort. Despite decades of pharmacist growth and experience in outpatient roles, physicians and patients still do not regularly recognize and actively seek out service provided by pharmacists., As nurse practitioners and physician assistants define their respective roles in the medical home, its possible that a perception of competition for resources may arise. Pharmacists recognize these challenges and perceptions, define the roles in which they can uniquely support patient care and seek to be collaborative with practitioners, administrators and policy makers in order to most effectively contribute to PCHM programs. Key Point: Pharmacists must define the manner in which they can uniquely contribute to improved patient care in the PCMH and proactively bring ideas and commitment to the stakeholders leading PCMH design. The White Paper developed by the Pennsylvania Pharmacists Association is an example of how the profession can engage the PCMH landscape.
work together. Team synergy between the pharmacist and physicians took less time to develop than that between NP and physician, likely due to less overlap in the clinical roles of physician and pharmacist. The pharmacist was found to be invaluable by both NPs and physicians. Despite participants appreciating the opportunity for dialogue and problem-solving in case conference meetings, scheduling demands made face-to-face collaboration difficult. To overcome these challenges, the team had to rely heavily on technological tools to communicate. Factors that promote successful collaboration include clear definition of roles, effective and clear communication, and trust among team members. Ongoing support and education regarding these factors is important for the development of a functional health care team.
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Table 5: Review of Migraine Prevention Medications Categorized by Level of Efficacy
Recommendation Level Level A
Definition Effective and should be offered for those eligible for migraine preventive therapy
Medications Divalproex sodium Sodium valproate Topiramate Metoprolol Propranolol Timolol Amitriptyline Venlafaxine Atenolol Nadolol
Level B
Considered probably effective and should be considered for migraine prevention
Level C
Possibly effective for migraine prevention and may be considered
Lisinopril Candesartan Clonidine Guanfacine Carbamazepine Nebivolol Pindolol
Level U
Evidence is conflicting or inadequate to support or refute the use of the medication
Level A Negative
Ineffective and should not be considered for migraine prevention Probably ineffective and should not be considered for migraine prevention Possibly ineffective and may not be considered for migraine prevention
Gabapentin Fluoxetine Fluvoxamine Protriptyline Acenocoumarol, Coumadin Picotamide Bisoprolol Nicardipine Nifedipine Nimodipine Verapamil Acetazolamide Cyclandelate Lamotrigine
Level B Negative
Level C Negative
Short term use with menstrual cycle associated migraines Frovatriptan
Naratriptan Zolmitriptan
Clomipramine
Acebutolol Clonazepam Nabumetone Oxcarbazepine Telmisartan
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