Sheri L. Koshman

A systematic review of the evidence for pharmacist care of patients with dyslipidemia.

To evaluate the effect of pharmacist care on patients with dyslipidemia.

Supratherapeutic Response to Ezetimibe Administered with Cyclosporine

OBJECTIVE: To report the case of a patient who underwent orthotopic heart transplant (OHT) and demonstrated a supratherapeutic response to ezetimibe when administered with cyclosporine. CASE SUMMARY: Ezetimibe 10 mg/day was added to the lipid-lowering regimen (atorvastatin 40 mg/day) of a 64-year-old male patient after OHT to achieve a target low-density lipoprotein cholesterol (LDL-C) level ≤97 mg/dL, as recommended by national guidelines. After 2 months of ezetimibe, the patients LDL-C level had decreased by 60% to 51 mg/dL. Subsequently, the dose of ezetimibe was reduced to 5 mg/day and, after another 2 months, a repeat lipid panel revealed LDL-C 57 mg/dL. DISCUSSION: Hyperlipidemia is a common problem among heart transplant recipients. Combination therapy using a statin plus ezetimibe appears to be an attractive option to achieve target lipid levels in this population. However, the manufacturer warns that ezetimibe should be administered cautiously in patients concomitantly receiving cyclosporine. Unpublished data suggest a pharmacokinetic interaction between ezetimibe and cyclosporine that results in a significant 2.3- to 12-fold increase in exposure to total ezetimibe. An objective causality assessment in this case revealed that this supratherapeutic LDL-C reduction was probably related to coadministration of ezetimibe and cyclosporine. A potential mechanism to explain this interaction might be an alteration in glucuronidation induced by cyclosporine. CONCLUSIONS: When ezetimibe is prescribed for patients concomitantly receiving cyclosporine, it should be initiated at a lower than recommended dose (≤5 mg/day) and titrated upward. Careful and consistent monitoring of patients on this combination is also advised.

Omega-3 polyunsaturated fatty acid supplementation in the prevention of cardiovascular disease.

Introduction: Omega-3 polyunsaturated fatty acids (PUFAs) have purported protective cardiovascular (CV) effects. We sought to assess the evidence available for the use of omega-3 PUFAs for the prevention of cardiovascular disease (CVD). Methods: A systematic literature search was conducted using MEDLINE and EMBASE from 1999 to 2015. Placebo-controlled, randomized controlled trials (RCTs) that enrolled over 1000 patients with follow-up greater than 1 year and meta-analyses of RCTs were included. Results: Eight RCTs and 2 meta-analyses were included. In patients with preexisting CVD, only 1 of 5 included RCTs demonstrated a reduction in CV events with omega-3 PUFAs; however, the effect size was minimal, and the study was limited by an open-label design and lack of placebo control. Two meta-analyses concluded omega-3 PUFAs do not reduce CV events in addition to standard, evidence-based therapy in patients after myocardial infarction. Of the 3 predominantly primary prevention RCTs, only 1 demonstrated a minor reduction in major coronary events; however, it was also an open-label study. Furthermore, the safety of omega-3 PUFAs should be considered. While data from RCTs have not demonstrated serious safety concerns, omega-3 PUFAs can increase the risk of bleeding and may interact with other medications that affect hemostasis, such as antiplatelet agents and warfarin. Discussion and Conclusion: There is currently a lack of evidence to support the routine use of omega-3 PUFAs in the primary and secondary prevention of CVD. Pharmacists are ideally situated to engage patients in the discussion of the lack of benefit and possible risk of omega-3 PUFA supplements.

Adverse drug reactions: The importance of maintaining pharmacovigilance

In 2004, the anti-inflammatory drug rofecoxib was voluntarily withdrawn from the market due to cardiovascular safety concerns. Although this case was highly publicized, it was not an isolated example. Between 1997 and 2011, 25 drugs were withdrawn from the Canadian market due to safety concerns identified through postmarketing surveillance or pharmacovigilance. Identification and reporting of suspected adverse drug reactions through pharmacovigilance is an important patient safety activity that is the responsibility of all clinicians, especially pharmacists. It is particularly important for newer drugs, as rare adverse effects are not always identified in clinical trials and the prescribing of medications in the “real world” often yields new drug-related safety concerns. In this article, we aim to explore the ongoing monitoring and assessment of suspected drug-related adverse effects and discuss recent examples of newly identified drug safety concerns.

Vasopressin in Cardiac Arrest

Objective: To review the efficacy and safety of vasopressin in cardiac arrest. Data Sources: MEDLINE, EMBASE, and PubMed were searched (all to June 2005) for full-text English-language publications describing trials in humans. Search terms were vasopressin, epinephrine, adrenaline, heart arrest, cardiac arrest, and clinical trial. Study Selection and Data Extraction: Prospective, randomized, controlled trials that evaluated efficacy or safety endpoints of vasopressin in the management of cardiac arrest were included. Efficacy outcomes included return of spontaneous circulation, successful resuscitation, survival to hospital admission, 2hour survival, and survival to hospital discharge. Safety outcomes were as defined by each trial. Data Synthesis: Three prospective trials were identified and included in this review. Vasopressin does not appear to offer any therapeutic advantage compared with epinephrine in the treatment of both in-hospital and out-of-hospital cardiac arrest, regardless of the presenting arrest rhythm. Although there is a suggestion that vasopressin may be effective in treatment of asystole, the evidence for this arises from a subgroup analysis that should be viewed as hypothesis generating. There are limited data describing the safety of vasopressin in cardiac arrest. CONCLUSIONS: The current evidence for the use of vasopressin in cardiac arrest is indeterminate. Given the similarly equivocal evidence of efficacy for epinephrine, either drug could be considered the first-line agent in cardiac arrest. Placebo-controlled studies with appropriate statistical power are warranted to evaluate meaningful clinical outcomes, such as survival to hospital discharge. Further evaluation of the role of vasopressin in asystolic cardiac arrest and its use in combination with epinephrine is also justified.

Dabigatran in atrial fibrillation: New kid on the block

In Canada, atrial fibrillation (AF) is the most prevalent cardiac arrhythmia.1 It is associated with an increase in morbidity and mortality, with cardioembolic stroke being one of the most feared complications.2 Anticoagulation is an effective means of reducing the risk of stroke. Currently, warfarin is the preferred agent in patients at high risk of stroke.3,4 However, maintaining warfarin therapy within its narrow therapeutic window is challenging, even for specialized anticoagulation clinics.5 Many factors contribute to the variable dose response of warfarin, such as inter-individual variability, comorbidities and drug and food interactions.5 Dabigatran is a novel therapeutic alternative that provides more predictable anticoagulation with less laboratory monitoring, and it is poised to take over some of warfarins role in AF stroke prophylaxis. While other novel agents, such as rivaroxaban and apixaban, have proven to be beneficial in stroke prophylaxis in AF, discussion of their roles is beyond the scope of this article.

Impact of Pharmacist Interventions in Patients with Dyslipidemia: A Systematic Review

Purpose: To determine the effect of pharmacistled interventions in dyslipidemia on clinical and process outcomes. Methods: Search: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, International Pharmaceutical Abstracts, HealthSTAR, Pascal, MEDLINE In-Process & Other Non-Indexed Citations, CINAHL Plus with Full Text, Health-Source: Nursing Edition, Academic Search Complete, BIOSIS Previews, Science Citation Index Expanded and Social Sciences Citation Index were searched from their inception to September 2008. Where possible an RCT filter was used. Article screening and selection: Inclusion criteria were: 1) RCTs and 2) pharmacist-provided pharmaceutical care, either independently or as part of a health care team or a collaborative agreement (team-directed) with other health care providers. There were no restrictions on language, sample size, study duration or practice setting. Quality assessment: Risk of bias was assessed using the Cochrane Collaborations Risk of Bias tool and studies were judged as low, high or unclear risk of bias. Data Extraction: Data extraction was performed by 2 independent reviewers using a standardized data collection form. Outcomes: The primary outcome was absolute reduction in LDL cholesterol. Secondary outcomes included proportion of patients at target, initiation/modification of lipid therapy, compliance with lipid therapy, health-related quality of life and patient satisfaction. Data Analysis: Data were analyzed using a random effects model with analysis based on the Der-Simonian-Laird method. Calculations included odds ratio for dichotomous data and weighted mean difference (WMD) or standardized mean differences for continuous data. Subgroup analyses or meta-regression were conducted to investigate possible sources of heterogeneity. An indirect comparison of pharmacist-directed versus pharmacist collaborative care interventions was done. Sensitivity analysis was performed based on risk of bias. Results: A total of 8422 articles were retrieved from the search. From these, 114 articles were selected for full review, and 12 articles were included. The overall difference in LDL (n = 543 patients) was not statistically significant (WMD −0.09 mmol/L, 95% CI −0.23, 0.04). The difference in total cholesterol was statistically significant (WMD −0.16, 95% CI −0.30, −0.02). Patients followed by a pharmacist were 3 times more likely to be at target (OR 2.9, 95% CI 1.1–7.5) and 2 times more likely to have their cholesterol measured (OR 2.4, 95% CI 1.6–3.6). Conclusions: Pharmacist interventions in a variety of settings have an impact on the lowering of total cholesterol. Patients receiving interventions that included pharmacist care were more likely to be at target and have their lipid panel measured. The types of interventions provided by pharmacists vary in terms of setting and components.

Evaluating current practice and outcomes of therapeutic anticoagulation during intra-aortic balloon counterpulsation in a coronary care unit

Introduction: Therapeutic anticoagulation for intra-aortic balloon pumps (IABPs) in coronary care unit patients is common, and a strategy of selective anticoagulation may minimize bleeding and prevent thrombosis. objective: The present retrospective chart review aimed to determine the proportion of patients with an IABP in place for ≥12 h during coronary care unit admission at a university-affiliated tertiary care centre from January 1, 2007 to December 31, 2011 who were eligible for selective anticoagulation, and to determine the incidence of major bleeding and ischemic complications in this population. Methods: Data collection was performed by one researcher using a standardized form according to prespecified definitions. Data regarding patient characteristics, major bleeds, ischemic events and death were collected while the IABP was in situ and for 24 h after IABP removal. Descriptive statistical analysis was performed. Results : Of the 70 patients included, 50% required an IABP for cardiogenic shock. With respect to medications, 93% were anticoagulated and 67% received ≥3 medications that could increase bleed risk. Eighty percent of patients with IABPs had at least one indication for anticoagulation while the IABP was in situ. The incidence of major bleeds and limb ischemia was 31% and 4%, respectively. Twenty percent of patients died and 93% of these experienced a major bleed. Conclusions: Most patients with IABP have an indication for anticoagulation. The incidence of limb ischemia is relatively low. Given the high incidence of major bleeding, further consideration should be given to the use of anticoagulation and risk factors for bleeding in this patient population.

Real-life practice in the management of new-onset postoperative atrial fibrillation early after cardiac surgery

Objectives: To investigate the real-world pharmacological management of postoperative atrial fibrillation (POAF) in patients undergoing cardiac surgery. Methods: A retrospective cohort analysis consisting of adult patients who underwent coronary artery bypass grafting, valve or combined surgery from January to December 2011 was performed using a clinical registry. The peri- and postoperative pharmacological management (rate control, rhythm control, anticoagulant therapy) of POAF was evaluated. Stepwise multivariate regression analyses were used to identify determinants for medication use at discharge. Results: The cohort consisted of 1145 patients, of whom 377 (32.9%) developed POAF and 271 (23.7%) were included. At discharge, 251 patients (92.6%) received β-blocker therapy and 122 (45.0%) received antiarrhythmic therapy. Two hundred sixty-one (96.3%) received rateand/ or rhythm-control therapy. Forty-eight (17.7%) patients received warfarin on discharge, although 38 had an additional indication. Men and urgent inpatients were less likely to be discharged on warfarin. Among 145 patients discharged on antiarrhythmic and/or anticoagulant therapy, 121 (83.4%) attended follow-up. Only 28.1% (34 of 121) had an electrocardiogram or Holter monitoring performed; despite this, antiarrhythmic medications were either continued or not addressed in 47.7% (51 of 107) of patients discharged on therapy. Conclusions: Treatment of POAF with rate- and/or rhythm-control medications was consistent with current national guideline recommendations. However, anticoagulant therapy use was low and appeared to be limited to patients with another indication. Assessment of POAF medications and rhythm status at postoperative follow-up visit was inconsistent. Thus, efforts to improve the management of POAF should focus on appropriately discontinuing unnecessary medications at postoperative follow-up to minimize the risk of adverse effects.

Efficacy and safety of mineralocorticoid receptor antagonist therapy in heart failure with reduced ejection fraction

oBjECTIVES: To summarize the efficacy and safety of mineralocorticoid receptor antagonists (MRAs) compared with placebo for the treatment of heart failure with reduced ejection fraction (HFrEF) by assessing clinically relevant end points of randomized controlled trials. METhoDS: The Medline, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, ACP Journal Club, DARE and International Pharmaceutical Abstracts databases were searched from inception to June 2014. Three authors independently reviewed and identified relevant articles. Included were randomized, doubleblinded, placebo-controlled trials that investigated spironolactone or eplerenone in adult patients with HFrEF regardless of etiology or symptomatology. RESulTS: The search strategy identified 726 articles; three met the inclusion criteria and included a total of 11,032 participants. The primary outcome of death from any cause was statistically significantly reduced with MRAs over placebo (risk ratio [RR] 0.81 [95% CI 0.74 to 0.88]; P<0.001). Hyperkalemia (serum potassium ≥6.0 mmol/L) was significantly higher with MRA therapy (RR 1.41 [95% CI 1.16 to 1.72]; P<0.001). Other clinically relevant safety outcomes were not consistently reported. With respect to efficacy, MRAs reduced cardiovascular mortality (RR 0.80 [95% CI 0.73 to 0.87]; P<0.001) and hospitalizations due to heart failure (RR 0.76 [95% CI 0.64 to 0.90]; P=0.001), but not all-cause hospitalization (RR 0.91 [95% CI 0.79 to 1.06]; P=0.23). CoNCluSIoNS: The present review highlights the benefit of MRAs across the spectrum of HFrEF despite a higher incidence of hyperkalemia. Therefore, MRA therapy should not be withheld from appropriately selected patients with HFrEF because the risk of adverse events does not appear to exceed the overall benefit in mortality reduction.