Michael P. Dorsch

Chlorthalidone Reduces Cardiovascular Events Compared With Hydrochlorothiazide A Retrospective Cohort Analysis

There is significant controversy around whether chlorthalidone (CTD) is superior to hydrochlorothiazide (HCTZ) in hypertension management. The objective of this analysis was to evaluate the effects of CTD compared with HCTZ on cardiovascular event (CVE) rates. We performed a retrospective observational cohort study from the Multiple Risk Factor Intervention Trial data set from the National Heart, Lung, and Blood Institute. The Multiple Risk Factor Intervention Trial was a cardiovascular primary prevention trial where participants were men 35 to 57 years of age enrolled and followed beginning in 1973. CVEs were measured yearly, and time to event was assessed by Cox regression. Systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, potassium, glucose, and uric acid were measured yearly. The difference between groups was evaluated by repeated-measures mixed modeling, and each model was adjusted for predictors of each variable. CVEs were significantly lower in those on CTD (adjusted hazard ratio: 0.51 [95% CI: 0.43 to 0.61]; P<0.0001) and on HCTZ (adjusted hazard ratio: 0.65 [95% CI: 0.55 to 0.75]; P<0.0001) compared with those who took neither drug. When comparing the 2 drugs, CTD had significantly fewer CVEs compared with HCTZ (P=0.0016). CTD displayed significantly lower SBP (P<0.0001), lower total cholesterol (P<0.0001), lower low-density lipoprotein cholesterol (P=0.0009), lower potassium (P=0.0003), and higher uric acid (P<0.0001) over time compared with HCTZ. In conclusion, both HCTZ and CTD reduce CVEs compared with neither drug. When comparing both drugs, CTD reduces CVEs more than HCTZ, suggesting that CTD may be the preferred thiazide-type diuretic for hypertension in patients at high risk of CVEs.

Vitamin D and cardiovascular disease.

The hormonal derivative of vitamin D, 1,25‐dihydroxyvitamin D (1,25[OH]2D) or calcitriol, has been implicated in many physiologic processes beyond calcium and phosphorus homeostasis, and likely plays a role in several chronic disease states, in particular, cardiovascular disease. Experimental data suggest that 1,25(OH)2D affects cardiac muscle directly, controls parathyroid hormone secretion, regulates the renin‐angiotensin‐aldosterone system, and modulates the immune system. Because of these biologic effects, vitamin D deficiency has been associated with hypertension, several types of vascular diseases, and heart failure. We conducted a MEDLINE search of the English‐language literature (1950–2008) to identify studies that examined these relationships; additional citations were obtained from the articles retrieved from the literature search. Treatment with vitamin D lowered blood pressure in patients with hypertension and modified the cytokine profile in patients with heart failure. Measurement of serum 25‐hydroxyvitamin D concentration usually provides the best assessment of an individuals vitamin D status. Serum levels below 20 ng/ml represent vitamin D deficiency, and levels above 30 ng/ml are considered optimal. Although the observational data linking vitamin D status to cardiovascular disease appear robust, vitamin D supplementation is not recommended as routine treatment for heart disease until definitive prospective, randomized trials can be carried out to assess its effects. However, such supplementation is often appropriate for other reasons and may be beneficial to cardiovascular health in certain patients.

Indications for Dual Antiplatelet Therapy with Aspirin and Clopidogrel: Evidence-Based Recommendations for Use

OBJECTIVE: To review the literature assessing dual antiplatelet therapy with aspirin and clopidogrel and subsequently provide evidence-based recommendations for appropriate indications and length of therapy. DATA SYNTHESIS: An English-language MEDLINE search (1950–December 2007) was conducted using the search terms antiplatelet, aspirin, thienopyridine, and clopidogrel to identify articles assessing dual antiplatelet therapy. Evaluation of references from identified trials for possible inclusion was also conducted. STUDY SELECTION AND DATA EXTRACTION: All studies that assessed treatment with the combination of aspirin and clopidogrel for any indication were included. DATA SYNTHESIS: Aspirin and clopidogrel have complementary mechanisms of action to inhibit platelet function. Indications that have been studied include coronary artery disease (CAD), atherosclerotic ischemic stroke, and atrial fibrillation. This combination has been beneficial in patients with acute coronary syndrome (ACS) with or without percutaneous coronary intervention (PCI), and in PCI patients without an acute event. There is a small but significant risk for increased bleeding with dual antiplatelet therapy for these indications. When used in patients with a history of atherosclerotic ischemic stroke or for prevention of cardioembolic stroke in patients with atrial fibrillation, this combination has been shown to increase bleeding, providing no clinical benefit, and to increase outcomes including stroke, myocardial infarction, and death, respectively. CONCLUSIONS: There is evidence to support use of aspirin in combination with clopidogrel for patients presenting with all ACS types, as well as for patients presenting with PCI for any indication. The treatment duration varies, but patients who have received stenting should receive at least 1 year of combination therapy. There is no evidence to support this combination for primary prevention of CAD or atherosclerotic ischemic events, secondary prevention of stable CAD, or prevention of cardioembolic stroke in patients with atrial fibrillation. The possible benefits of dual antiplatelet therapy also must be weighed against the risk of bleeding.

Genetic Causes of Clopidogrel Nonresponsiveness: Which Ones Really Count?

Clopidogrel decreases the morbidity and mortality associated with several cardiovascular diseases. However, clopidogrel is a prodrug that needs to be metabolized to the active thiol metabolite by the cytochrome P450 (CYP) system. This activation is a source of significant interindividual variability in clopidogrel responsiveness. Drug interactions with and genetic variation in CYP3A4, CYP3A5, and CYP2C19 enzymes have been implicated in decreasing active metabolite production. In addition, polymorphisms in the genes encoding P‐glycoprotein (an efflux transporter) and purinergic receptor P2Y12 (the active site for clopidogrel) have been studied for their role in clopidogrel responsiveness. Several large studies have recently assessed the role of genetic variation in clopidogrel responsiveness as characterized by clinical outcomes. In this review, we summarize the genetic causes of clopidogrel nonresponsiveness, with a focus on larger outcomes‐based studies. A MEDLINE search of the English‐language literature (1990–2008) was conducted to identify studies that examined these relationships; additional citations were obtained from the articles retrieved from the literature search. Polymorphisms in CYP2C19 and, to a lesser extent, the adenosine 5`‐triphosphate‐binding cassette gene, ABCB1, contribute to variability in clopidogrel responsiveness. Specifically patients possessing at least one variant CYP2C19 allele (CYP2C19* 2,* 3) have impaired clopidogrel responsiveness due to decreased formation of the active metabolite. In addition, one study found that considering ABCB1 genotype in addition to CYP2C19 allowed better prediction of clopidogrel nonresponsiveness. However, routine genotyping for CYP2C19 or ABCB1 polymorphisms in order to predict clopidogrel responsiveness cannot be recommended at this time because of logistic and cost considerations.

Aspirin Resistance in Patients with Stable Coronary Artery Disease with and without a History of Myocardial Infarction

Background: Aspirin therapy is a cornerstone in the prevention of atherothrombotic events, but recurrent vascular events are estimated to occur in 8-18% of patients taking aspirin for secondary prevention after 2 years. Estimates of biologic aspirin resistance vary from 5% to 60%, depending on the assay used. However, the relationship between biologic measurements of aspirin resistance and adverse clinical events remains unclear. Objective: To determine whether patients with documented myocardial infarction (Ml) while on aspirin therapy (cases) were more likely to be aspirin resistant than were patients with coronary artery disease (CAD) who had no history of Ml (controls) and to assess clinical predictors of aspirin resistance in patients with stable CAD. Methods: This case-control study examined aspirin responses using the VerifyNow Aspirin Assay system in 50 cases and 50 controls who had taken a dose of aspirin within 48 hours of presentation to the clinic visit. Odds ratios were estimated to determine the association between aspirin resistance and MI, Independent predictors of aspirin resistance were determined using univariate and multivariate analyses. Results: An increase in the prevalence of aspirin resistance among cases (16% vs 12% in controls) was not observed (OR 1.40; 95% CI 0.45 to 4.37; p = 0.566). In the overall CAD population, female sex was independently associated with aspirin resistance (OR 4.01; 95% CI 1.15 to 13.92; p = 0.029). Conclusions: Additional large studies are required to understand whether biologically defined aspirin resistance is associated with increased risk for cardiovascular events, with special attention paid to sex differences.

Nutrition and Heart Failure: Impact of Drug Therapies and Management Strategies

Nutrition impairment commonly occurs in patients with heart failure and affects disease progression. Vitamin and mineral deficiencies are associated with early mortality, particularly in patients classified as cachectic. Guideline-based therapies approved for heart failure, such as loop diuretics, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, aldosterone antagonists, and beta-adrenergic blockers, can lead to electrolyte abnormalities and predispose to some vitamin and micronutrient deficits. Clinical trial evidence in support of supplementary vitamin and mineral therapies for heart failure patients is limited with the exception of documented calcium and possibly vitamin D, thiamine, and coenzyme Q10 deficiencies. This area is gaining significant attention, and research is ongoing. The clinician can help minimize morbidity from nutrition impairment through appropriate monitoring and correction of baseline and medication-induced electrolyte imbalances, in addition to vitamin and mineral supplementation when appropriate.

Antiplatelet Therapy After Placement of a Drug-Eluting Stent: A Review of Efficacy and Safety Studies

BACKGROUND Dual antiplatelet therapy with a thienopyridine (ticlopidine or clopidogrel) and aspirin is used to reduce the risk of late stent thrombosis and complications (myocardial infarction [MI] and death) after placement of a drug-eluting stent (DES). OBJECTIVE This article reviews available clinical efficacy and safety data on antiplatelet therapies for the prevention of stent thrombosis and cardiac events after DES placement. METHODS MEDLINE, EMBASE, and International Pharmaceutical Abstracts (1966-June 2010) were searched for studies relating to the clinical efficacy and safety of antiplatelet therapy after DES placement using the terms antiplatelet therapy, thienopyridine, aspirin, clopidogrel, cilostazol, prasugrel, ticlopidine, paclitaxel-eluting stent, sirolimus-eluting stent, and drug-eluting stent. The reference lists of the identified articles were reviewed for additional relevant publications. RESULTS Ten studies were identified that evaluated the efficacy of antiplatelet therapies after DES placement; of these, 5 also assessed safety. In a prospective, observational cohort study, early discontinuation of clopidogrel (within the first 6 months after DES placement) was a major predictor of stent thrombosis (hazard ratio [HR] = 13.74; 95% CI, 4.04-46.68; P < 0.001). In an observational cohort study, early discontinuation of clopidogrel was associated with significantly higher rates of long-term clinical events (death and death or MI) (discontinuation at 6 months: P = 0.004; discontinuation at 12 months: P < 0.001). A multicenter, randomized, double-blind, prospective study found a reduction in the composite end point of death, MI, and target-vessel revascularization within 30 days after DES placement in patients who received a high loading dose of clopidogrel (600 mg) compared with the conventional loading dose (300 mg) (4% vs 12%, respectively; P = 0.041). In a multicenter, randomized, prospective study in patients with long coronary lesions undergoing DES placement, triple antiplatelet therapy (clopidogrel, cilostazol, and aspirin) was associated with significant reductions at 6 months compared with dual antiplatelet therapy (clopidogrel and aspirin) in in-stent late loss (mean [SD], 0.22 [0.48] vs 0.32 [0.51] mm, respectively; P = 0.03) and in-segment late loss (0.34 [0.49] vs 0.51 [0.49] mm; P = 0.001). In a similar study in patients with diabetes mellitus, triple therapy was associated with significant reductions at 6 months in rates of in-segment restenosis (8.0% vs 15.6%; RR = 0.51; 95% CI, 0.27-0.96; P = 0.033), target-lesion revascularization (2.5% vs 7.0%; RR = 0.36; 95% CI, 0.13-0.97; P = 0.034), and major adverse cardiac events (2.8% vs 7.6%; P = 0.016). In a multicenter, retrospective study comparing triple and dual antiplatelet therapy in patients with ST-segment elevation MI undergoing DES placement, triple therapy was associated with significant reductions at 8 months compared with dual therapy in rates of cardiac deaths (2.0% vs 3.2%; P = 0.019), total deaths (3.1% vs 4.9%; P = 0.006), and total major adverse cardiac events (7.6% vs 9.3%; P = 0.049). Overall, use of triple therapy was not associated with an increased risk of major or minor bleeding events compared with dual therapy. In a multicenter, randomized, double-blind, prospective study in patients with acute coronary syndrome (ACS) who underwent DES placement and received the combination of prasugrel or clopidogrel and aspirin, the prasugrel regimen was associated with significant reductions in rates of the composite end point of cardiovascular death, nonfatal MI, and nonfatal stroke (HR = 0.82; 95% CI, 0.69-0.97; P = 0.019) and late stent thrombosis (0.42% vs 0.91%, respectively; P = 0.04). However, the combination of prasugrel and aspirin was associated with significant increases compared with clopidogrel and aspirin in rates of total bleeding events (5.0% vs 3.8%; P = 0.002), major bleeding events (2.4% vs 1.8%; P = 0.03), and life-threatening bleeding events (1.4% vs 0.9%; P = 0.01). CONCLUSIONS The combination of clopidogrel (loading dose, 300-600 mg; maintenance dose, 75 mg/d) and low-dose aspirin (75-162 mg/d) for 12 months is the preferred regimen for the prevention of stent thrombosis and cardiac complications after DES placement. The combination of prasugrel and aspirin may be appropriate in patients with ACS, although it was associated with a significantly increased risk for bleeding. Triple antiplatelet therapy may be beneficial in certain high-risk patients.

Team-based learning to improve learning outcomes in a therapeutics course sequence.

Objective. To compare the effectiveness of team-based learning (TBL) to that of traditional lectures on learning outcomes in a therapeutics course sequence. Design. A revised TBL curriculum was implemented in a therapeutic course sequence. Multiple choice and essay questions identical to those used to test third-year students (P3) taught using a traditional lecture format were administered to the second-year pharmacy students (P2) taught using the new TBL format. Assessment. One hundred thirty-one multiple-choice questions were evaluated; 79 tested recall of knowledge and 52 tested higher level, application of knowledge. For the recall questions, students taught through traditional lectures scored significantly higher compared to the TBL students (88%±12% vs 82%±16%, p=0.01). For the questions assessing application of knowledge, no differences were seen between teaching pedagogies (81%±16% vs 77%±20%, p=0.24). Scores on essay questions and the number of students who achieved 100% were also similar between groups. Conclusion. Transition to a TBL format from a traditional lecture-based pedagogy allowed P2 students to perform at a similar level as students with an additional year of pharmacy education on application of knowledge type questions. However, P3 students outperformed P2 students regarding recall type questions and overall. Further assessment of long-term learning outcomes is needed to determine if TBL produces more persistent learning and improved application in clinical settings.

The Effect of Cardiovascular Credentialed Pharmacists on Process Measures and Outcomes in Myocardial Infarction and Heart Failure

The purpose of this study was to determine if institutions with inpatient cardiovascular credentialed pharmacists exhibit improved quality measures for acute myocardial infarction (AMI) and heart failure (HF) care compared with institutions without inpatient cardiovascular credentialed pharmacists.

Baseline Albumin Is Associated with Worsening Renal Function in Patients with Acute Decompensated Heart Failure Receiving Continuous Infusion Loop Diuretics

To identify baseline predictors of worsening renal function (WRF) in an acute decompensated heart failure (ADHF) patient population receiving continuous infusion loop diuretics.