Tracy E. Macaulay

Increased mortality among patients taking digoxin—analysis from the AFFIRM study

AIMS Digoxin is frequently used for rate control of atrial fibrillation (AF). It has, however, been associated with increased mortality. It remains unclear whether digoxin itself is responsible for the increased mortality (toxic drug effect) or whether it is prescribed to sicker patients with inherently higher mortality due to comorbidities. The goal of our study was to determine the relationship between digoxin and mortality in patients with AF. METHODS AND RESULTS The association between digoxin and mortality was assessed in patients enrolled in the AF Follow-Up Investigation of Rhythm Management (AFFIRM) trial using multivariate Cox proportional hazards models. Analyses were conducted in all patients and in subsets according to the presence or absence of heart failure (HF), as defined by a history of HF and/or an ejection fraction <40%. Digoxin was associated with an increase in all-cause mortality [estimated hazard ratio (EHR) 1.41, 95% confidence interval (CI) 1.19-1.67, P < 0.001], cardiovascular mortality (EHR 1.35, 95% CI 1.06-1.71, P = 0.016), and arrhythmic mortality (EHR 1.61, 95% CI 1.12-2.30, P = 0.009). The all-cause mortality was increased with digoxin in patients without or with HF (EHR 1.37, 95% CI 1.05-1.79, P = 0.019 and EHR 1.41, 95% CI 1.09-1.84, P = 0.010, respectively). There was no significant digoxin-gender interaction for all-cause (P = 0.70) or cardiovascular (P = 0.95) mortality. CONCLUSION Digoxin was associated with a significant increase in all-cause mortality in patients with AF after correcting for clinical characteristics and comorbidities, regardless of gender or of the presence or absence of HF. These findings call into question the widespread use of digoxin in patients with AF.

The Role of Angiotensin Receptor Blockers in Patients with Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema:

Objective: To assess the safety of using angiotensin II receptor blockers (ARBs) in patients who develop angioedema with the use of angiotensin-converting enzyme inhibitors (ACEIs). Data Sources: A literature search was performed using MEDLINE (1977-January 2011) and Cochrane Library, using the terms angiotensin receptor blocker, angiotensin-converting enzyme inhibitor, and angioedema. In addition, reference citations from publications identified were reviewed. Study Selection and Data Extraction: Only English-language publications were included. Randomized controlled trial data, observational studies (retrospective and prospective), and case reports on adults who received ACEI therapy and then an ARB as an alternative therapy were reviewed. Data Synthesis: Two randomized controlled trials and 1 meta-analysis evaluated ARB use in patients intolerant to ACEIs. Taken together, there is a conservative estimate of a 10% or less incidence of cross reactivity of angioedema in patients who receive an ARB after experiencing ACEI-associated angioedema. Angioedema related to ARBs is reported to be less severe and occurs earlier compared to angioedema that develops during ACEI therapy Conclusions: ARBS may be an alternative for patients who develop angioedema white using an ACEI but should be reserved for patients with high therapeutic need for angiotensin inhibition. Treatment should be started with observation, patients should be educated on the signs of angioedema, and proper emergency management should be emphasized to patients and care providers.

Key articles of dietary interventions that influence cardiovascular mortality.

Lifestyle modifications, particularly diet, are a key component to the reduction of cardiovascular events. Diets high in carbohydrates and saturated fat have been shown to negatively affect blood cholesterol, thereby increasing the risk for cardiovascular disease (CVD). Dietary interventions that emphasize the consumption of whole grains, fruits, and vegetables have been shown to be successful in reducing cardiovascular risk. Clinical pharmacist practitioners need to be knowledgeable regarding lifestyle modifications, specifically dietary issues, to develop a comprehensive, effective, and evidence‐based plan for patients who are either at risk for or who have established CVD. Numerous studies have been published over the past few years with regard to the rapidly growing field of dietary interventions that influence cardiovascular risk, and the amount of literature can be overwhelming. Thus we chose to focus our review on articles that assess changes in dietary patterns that affect overall mortality risk from CVD. As such, literature describing the impact of dietary factors that influence weight, lipid changes, or other risk factors alone were not included in this review. A group of practitioners with expertise and interest in CVD were involved in the compilation of this article.

Thrombin receptor antagonism --the potential of antiplatelet medication SCH 530348

Importance of the field: Coronary artery disease is a leading cause of morbidity and mortality worldwide. Platelet activation and subsequent thrombus formation play a central role in disease progression and development of acute coronary syndromes (ACS). Despite widespread use of single and dual antiplatelet therapies in atherothrombotic disease, ischemic complications remain common. Therefore, the need exists for new antiplatelet agents that are more effective, but with acceptable safety profiles (i.e., do not increase risk of bleeding). Antiplatelet agents available at present are effective in blocking the cyclo-oxygenase, ADP-mediated and final common (IIb/IIIa receptor) pathways for platelet activation. Recently, there has been more interest in inhibition of the proteinase-activated receptor-1 (PAR-1), which blocks thrombin-mediated platelet activation. Areas covered in this review: This review covers the pharmacology, pharmacokinetics and development of the new PAR1 antagonist, SCH 530348 in a review of all publications relevant to the topic over the last 10 years. Phase II clinical trials indicate that addition of this agent to current antiplatelet regimens may provide additional antithrombotic protection without an increase in bleeding. Results of the ongoing Phase III trials, examining the use of SCH 530348 in patients with ACS and for secondary prevention of ischemic events are anxiously awaited. What the reader will gain: The review is a summary of all pharmacologic properties and current clinical data available on the PAR1 antagonist SCH 530348. The readers will be introduced to its novel mechanism of action, advantages over current antiplatelet agents and potential future applications should ongoing clinical trials confirm its efficacy in reducing platelet activity. Take home message: SCH 530348 is a new, orally administered antiplatelet agent that blocks the protease-activated thrombin receptor on the platelet. Early clinical data indicate that it is associated with a lower risk of bleeding. However, its efficacy in improving clinical outcomes in patients with coronary disease remains to be confirmed in ongoing Phase III clinical trials.

Angioedema related to Angiotensin inhibitors.

Angiotensin inhibitors have been extensively evaluated in clinical trials and have demonstrated significant reductions in morbidity and mortality following myocardial infarction and stroke, as well as in patients with heart failure or who are at risk of cardiovascular disease. Further, both angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are frequently prescribed for the treatment of hypertension and to preserve renal function in patients with diabetes mellitus and chronic kidney disease. Angioedema is a known, but rare, adverse effect of ACEIs and ARBs. Therefore, it is important for clinicians to have a thorough understanding of risks and benefits of prescribing these medications, particularly in patients with a history of angioedema. This review describes the literature evaluating the incidence and cross-reactivity of angioedema with ACEIs and ARBs in order to provide guidance for clinical decision making.

Evaluation of a clinical scoring scale to direct early appropriate therapy in heparin-induced thrombocytopenia.

Background. Heparin-induced thrombocytopenia (HIT) is a serious adverse effect associated with heparin therapy. Current laboratory confirmation for immune mediated HIT often results in false positives and unnecessary treatment, exposing individuals to possible complications. As a result, clinical evaluation has been recommended in conjunction with laboratory testing. We hypothesize that utilization of a clinical scoring scale, the 4T’s, will result in the initial appropriate therapy for suspected HIT. Methods. This is a retrospective chart review of 108 patients who underwent ELISA testing for HIT at a university hospital. The 4T’s scale was applied, stratifying individuals into low, intermediate, and high-risk categories. Each risk score was compared to the ELISA results to determine if the 4T’s can predict the diagnosis of HIT and result in appropriate management. ELISA optical density scores as well as incidence of adverse events were also compared among risk categories. Study Results. Individuals with low risk correlate with a negative ELISA compared to intermediate and high-risk individuals (p = 0.01 and p<0.01) and also were significantly more likely to predict institution of appropriate therapy (p<0.01). Median optical density scores were 0.184 (0.046—2.116), 0.226 (0.067—1.887), and 0.476 (0.096—1.309) for low, intermediate, and high 4T scores. Major adverse events include thrombosis and bleeding. Conclusions. Individuals with low risk were more likely to receive initial, appropriate therapy and were also significantly more likely to have a negative ELISA test result. Individuals with low risk determined by the 4T score therefore may have therapy and serologic testing for HIT withheld.

Evaluation of Continuation of Stress Ulcer Prophylaxis at Hospital Discharge

Purpose Stress-related mucosal disease (SRMD) can adversely affect patient morbidity and mortality. The use of stress ulcer prophylaxis (SUP) in patients with no risk factors for clinically important bleeding, however, is contributing to health care-related adverse events, drug interactions, and costs. The objective was to determine the percentage of hospitalized patients who receive SUP without an approved indication and to evaluate the financial impact of inappropriate prescribing as well as the risk for significant drug-drug interactions. Methods A retrospective chart review was performed of hospitalized adult cardiology, family medicine, and internal medicine patients between July 1, 2006 and June 30, 2007. Prescribing of acid suppressive therapy (AST) during hospital admission and indications for SUP were evaluated. Concomitant medications, cost of therapy, and discharge medications were assessed as secondary outcomes. Results Of the 4,603 patients admitted during the study period, 418 were randomly selected for study inclusion. Approximately 53% (221/418) of the selected patients received SUP during hospital admission, 93% (206/221) of whom had no indication for prophylaxis. Of those who continued AST at discharge (14%; 31/221), 84% (26/31) had no approved indication. Overuse of SUP resulted in 77 potential drug-drug interactions and an estimated 30-day outpatient cost of

National survey of pharmacy residency on-call programs.

37,950 for patients receiving these medications at discharge. Conclusion SUP is frequently prescribed to non–critically ill patients when the risk of SRMD is low. Use of SUP for patients who do not meet evidence-based criteria appears to contribute to increased health care expenditures, potential adverse events, and drug interactions.

Drug-Drug Interactions Associated with Antiplatelet Therapy

PURPOSE The results of a national survey to evaluate on-call practices and responsibilities of pharmacy residents nationwide, as well as opinions related to duty-hour changes, are reported. METHODS A 39-question survey was distributed to 1292 residency program directors (RPDs) listed in the American Society of Health-System Pharmacists (ASHP) online residency directory, which includes programs in all stages of the accreditation process. The survey opened on November 7, 2011, and closed on November 28, 2011. The survey collected demographic information and answers to questions about the residencys on-call component (if applicable) and barriers to the creation of an on-call component. Respondents were also asked to indicate their support of or opposition to the adoption of the 2011 Accreditation Council for Graduate Medical Education (ACGME) duty-hour rules and identify the areas of greatest concern. RESULTS Of the 1292 RPDs listed in the ASHP online residency directory to whom the survey was sent, 521 surveys were completed, yielding a response rate of 40%. Of these, 471 identified their residency program as including or excluding an on-call component. Of the 138 programs with on-call services, 102 programs (74%) indicated the inclusion of an overnight experience. Programs that did not utilize an on-call component indicated barriers such as a perceived lack of demand (39%) and duty-hour limitations (21%). Common on-call activities included drug information consults and therapeutic drug monitoring. There was not a clear consensus from RPDs regarding the adoption of the 2011 ACGME duty-hour standards. CONCLUSION Among usable responses to a survey of pharmacy residency programs, 29% indicated that their program included an on-call component. On-call programs varied greatly in activities, location, hours, and requirements.

The Effect of Rosuvastatin on Platelet-Leukocyte Interactions in the Setting of Acute Coronary Syndrome

Antiplatelet therapy is of paramount importance in the treatment and prevention of adverse cardiovascular events and stroke. Drug-drug interactions (DDIs) among antiplatelet therapies have been growing in both prevalence and clinical importance. Most DDIs with antiplatelet therapies are pharmacodynamic in nature. DDIs with thienopyridines and proton pump inhibitors have resulted in advisories from regulatory agencies although the full significance of this interaction is unknown. Other DDIs with thienopyridines may potentially exist with statins, calcium channel blockers, and warfarin but lack demonstratable evidence of harm. Aspirin may interact with a variety of medications, including non-steroidal anti-inflammatory agents and angiotensin inhibitors. DDIs requiring some level of intervention may also be present with dipyridamole and cilostazol. Overall, DDIs with antiplatelet drugs are biologically plausible and potentially clinically relevant. However, the full significance of these DDIs is largely unknown due to reliance on research of voluntary reports, registries, and claims databases to determine significance.