Toni L. Ripley

β-Blockers A Review of Their Pharmacological and Physiological Diversity in Hypertension

OBJECTIVE To review the pharmacology, pharmacokinetics, and pharmacodynamic properties of commonly used β-blockers (atenolol, carvedilol, metoprolol succinate, metoprolol tartrate, and nebivolol). DATA SOURCES A MEDLINE literature search (1966-May 2013) was performed using the following key terms: hypertension, β-blockers, atenolol, carvedilol, metoprolol tartrate, metoprolol succinate, nebivolol, pharmacology, pharmacodynamics, pharmacokinetics, blood pressure, metabolic, lipid, central aortic pressure, diabetes, and insulin resistance. References from publications reviewed were included. STUDY SELECTION AND DATA EXTRACTION English-language articles identified were reviewed. Animal studies and studies in patients for a primary diagnosis of coronary artery disease were excluded. DATA SYNTHESIS β-Blockers are no longer recommended first-line therapy for primary hypertension, based on data showing that β-blockers are inferior to other antihypertensives and no better than placebo, in spite of provision of blood pressure reduction. Because atenolol is the β-blocker used in 75% of these studies, uncertainty about widespread application to all β-blockers exists. Different pharmacological and physiological properties, both within β-blockers and compared with other antihypertensives, may explain divergent effects. Evidence shows that β-blockers have a truncated effect on central aortic pressure, an independent predictor of cardiovascular events, compared with other antihypertensive classes; differences within the class may exist, but the evidence is inconclusive. Metabolic effects differ within the β-blocker class, with evidence that carvedilol causes less metabolic dysregulation. CONCLUSION Emerging evidence reveals physiological differences within the β-blocker class and in comparison to other antihypertensives. These differences provide insight into the diverse clinical effects β-blockers provide in cardiovascular disease.Objective: To review the pharmacology, pharmacokinetics, and pharmacodynamic properties of commonly used β-blockers (atenolol, carvedilol, metoprolol succinate, metoprolol tartrate, and nebivolol). Data Sources: A MEDLINE literature search (1966-May 2013) was performed using the following key terms: hypertension, β-blockers, atenolol, carvedilol, metoprolol tartrate, metoprolol succinate, nebivolol, pharmacology, pharmacodynamics, pharmacokinetics, blood pressure, metabolic, lipid, central aortic pressure, diabetes, and insulin resistance. References from publications reviewed were included. Study Selection and Data Extraction: English-language articles identified were reviewed. Animal studies and studies in patients for a primary diagnosis of coronary artery disease were excluded. Data Synthesis: β-Blockers are no longer recommended first-line therapy for primary hypertension, based on data showing that β-blockers are inferior to other antihypertensives and no better than placebo, in spite of provision of blood pressure reduction. Because atenolol is the β-blocker used in 75% of these studies, uncertainty about widespread application to all β-blockers exists. Different pharmacological and physiological properties, both within β-blockers and compared with other antihypertensives, may explain divergent effects. Evidence shows that β-blockers have a truncated effect on central aortic pressure, an independent predictor of cardiovascular events, compared with other antihypertensive classes; differences within the class may exist, but the evidence is inconclusive. Metabolic effects differ within the β-blocker class, with evidence that carvedilol causes less metabolic dysregulation. Conclusion: Emerging evidence reveals physiological differences within the β-blocker class and in comparison to other antihypertensives. These differences provide insight into the diverse clinical effects β-blockers provide in cardiovascular disease.

Etoricoxib: A Highly Selective COX-2 Inhibitor

OBJECTIVE: To review the available literature evaluating the pharmacology, pharmacokinetics, clinical efficacy, and adverse effects of etoricoxib, a highly selective cyclooxygenase-2 (COX-2) inhibitor that is not currently approved for use in the US. DATA SOURCES: Literature retrieval was accessed through MEDLINE (1966–December 2004), Current Contents (1998–December 2004), and Cochrane Library (4th quarter 2004). References from retrieved articles, information from the manufacturer, and abstracts from the American College of Rheumatology and Annual European Congress of Rheumatology meetings were searched. STUDY SELECTION AND DATA EXTRACTION: All clinical trials published in English evaluating etoricoxib were included in this review. An abstract was excluded if it presented preliminary data from trials that are now published, analyzed data previously reported in a published clinical trial, or compared etoricoxib with placebo for an indication with published active-comparator controlled trials. DATA SYNTHESIS: Twelve clinical trials evaluating efficacy were reviewed. Efficacy for acute pain has been evaluated in acute gout, primary dysmenorrhea, and dental surgery and for chronic pain in rheumatoid arthritis, osteoarthritis, and chronic lower back pain. For safety, 3 clinical trials and 6 retrospective analyses of gastrointestinal, renovascular, or cardiovascular adverse effects were reviewed. CONCLUSIONS: Available studies demonstrate the efficacy of etoricoxib compared with nonsteroidal antiinflammatory drugs, but no published studies to date have compared etoricoxib with other selective COX-2 inhibitors. While these agents have demonstrated a significant reduction in gastrointestinal adverse effects, the cardiovascular adverse effects of selective COX-2 inhibition are not well defined. Further study is necessary to delineate the benefits and risks of etoricoxib compared with alternative treatment regimens.

Side effects of using nitrates to treat heart failure and the acute coronary syndromes, unstable angina and acute myocardial infarction

Nitrates are potent venous dilators and anti-ischemic agents. They are widely used for the relief of chest pain and pulmonary congestion in patients with acute coronary syndromes and heart failure. Nitrates, however, do not reduce mortality in patients with acute coronary syndromes. Combination of nitrates and hydralazine when given in addition to β-blockers and angiotensin-converting enzyme (ACE) inhibitors reduce mortality and heart failure hospitalizations in patients with heart failure due to left ventricular systolic dysfunction who are of African–American origin. Side effects during nitrate therapy are common but are less well described in the literature compared with the reported side effects in patients with stable angina pectoris. The reported incidence of side effects varies highly among different studies and among various disease states. Headache is the most commonly reported side effect with an incidence of 12% in acute heart failure, 41 – 73% in chronic heart failure, 3 – 19% in unstable angina and 2 – 26% in acute myocardial infarction. The reported incidence of hypotension also differs: 5 – 10% in acute heart failure, 20% in chronic heart failure, 9% in unstable angina and < 1 – 48% in acute myocardial infarction, with the incidence being much higher with concomitant nitrate therapy plus angiotensin-converting enzyme inhibitors. Reported incidence of dizziness is as low as 1% in patients with acute myocardial infarction to as high as 29% in patients with heart failure. Severe headaches and/or symptomatic hypotension may necessitate discontinuation of nitrate therapy. Severe life threatening hypotension or even death may occur when nitrates are used in patients with acute inferior myocardial infarction associated with right ventricular dysfunction or infarction, or with concomitant use of phosphodiesterase-5 inhibitors or N-acetylcysteine. Despite the disturbing observational reports in the literature that continuous and prolonged use of nitrates may lead to increased mortality and recurrent myocardial infarction in patients with stable coronary artery disease, no such adverse effects of nitrates have been reported in the large randomized trials in patients with acute myocardial infarction or chronic heart failure.

Effect of heart failure exacerbations on anticoagulation: a prospective, observational, pilot cohort study.

BACKGROUND Some studies have suggested that heart failure (HF) is associated with excessive anticoagulation, but definitive data or data showing causation do not exist. Knowledge of risk factors for excessive anticoagulation is critical to manage warfarin therapy safely. OBJECTIVE This study characterized the relation between HF-associated hypervolemia and excessive anticoagulation in patients with HF taking chronic warfarin therapy. METHODS This was a prospective, observational pilot study conducted in a university-based HF clinic. Patients aged 18 to 85 years with HF and taking warfarin were enrolled and were observed for episodes of hypervolemia. Hypervolemia was determined based on multiple clinical factors, including patient-reported symptoms and physical examination. Anticoagulation was assessed longitudinally per standard of care by measurement of the international normalized ratio (INR). A chi(2) analysis was used to determine whether hypervolemia was associated with an increased risk of excessive anticoagulation. Paired and unpaired t tests were used for ad hoc analyses. RESULTS Forty patients with 41 HF episodes who were taking warfarin were enrolled between December 2003 and July 2007. Mean (SD) age was 67.2 (11.1) years and mean weight was 218.5 (62.8) pounds; 29 patients (72.5%) were men and 34 (85.0%) were white. Most had systolic dysfunction (n = 26; 65.0%) and were taking warfarin for atrial fibrillation (n = 33; 82.5%); the mean weekly warfarin dose was 30.8 (17.5) mg. There were 41 evaluable hypervolemia episodes over a mean follow-up of 14.5 (9.0) months. The mean INR change during hypervolemia was -0.02 (0.82) INR unit (P = NS vs baseline). No association was found between hypervolemia episodes and INR increases of > or =50% (P = NS); the results remained nonsignificant for both diastolic and systolic HF when analyzed separately. There was no significant change from baseline INR between patients classified with mild, moderate, or severe hypervolemia or between patients classified according to New York Heart Association (NYHA) functional class (all, P = NS). Patients with NYHA class III had a lower weekly warfarin dose than those with NYHA class II (25.73 vs 31.75 mg; P < 0.01). CONCLUSION Mild hypervolemia did not appear to be related to excessive anticoagulation in these patients with HF taking chronic warfarin therapy.

Anticoagulation in patients with heart failure and normal sinus rhythm.

PURPOSE The evidence evaluating the risk of thrombosis and the efficacy and risk of anticoagulation in patients with systolic heart failure (HF) and normal sinus rhythm is reviewed. SUMMARY Although a subject of investigation for over 50 years, use of anticoagulation in patients with HF remains an area of controversy and clinical debate. While early studies reported variable thromboembolism rates in HF (1.9-42.4 events per 100 patient years), the annual rate from larger and more recent trials ranged from 1% to 3%. The trials evaluating the role of oral anticoagulants to reduce thromboembolism and mortality outcomes in patients with a reduced ejection fraction (EF) have provided ambiguous results. Early studies and post hoc analyses of large clinical trials have demonstrated a reduction in thromboembolic events, risk of stroke, and mortality. In contrast, recent underpowered prospective controlled studies found no benefit in the use of warfarin in patients with systolic HF and normal sinus rhythm. The low-to-moderate risk of thromboembolism in patients with HF and the questionable benefit of anticoagulation need to be weighed against the potential for hemorrhagic complications caused by this therapy. The available data collectively suggest that the risk of using warfarin in patients with reduced EF may outweigh any possible benefit, if one exists at all. CONCLUSION Anticoagulation therapy in patients with HF and normal sinus rhythm is not supported by the limited evidence. The benefits of anticoagulation in such patients may not compensate for the relatively high risk of major bleeding caused by the treatment.

Collaborative Practice Model Between Cardiologists and Clinical Pharmacists for Management of Patients With Cardiovascular Disease in an Outpatient Clinic

The increasing prevalence of cardiovascular disease (CVD) has prompted leading cardiovascular organizations to advocate utilization of a team approach to patient care that includes nonphysician providers. In spite of that, the American College of Cardiology reported that nonphysician providers are underutilized in the management of patients with CVD. A survey of cardiologists revealed that the underutilization is a result of lack of understanding of how best to involve nonphysician providers in the health care team. Clinical pharmacists are one category of nonphysician providers that have recognized effectiveness in managing patients with CVD. No example of a comprehensive model of collaboration between cardiologists and clinical pharmacists is described in the literature that could serve to close this gap in understanding. The objective of this report is to describe a model of cardiologist–clinical pharmacist collaboration in the longitudinal management of patients with CVD that has been successfully implemented in 2 diverse settings. The implementation, evolution, scope of practice, required pharmacist training, logistical elements needed for success, and implementation barriers are reviewed. A summary of the patients referred to the clinic are examined as well.

Key Articles and Guidelines in the Management of Peripheral Arterial Disease

Peripheral arterial disease (PAD) affects approximately 8 million people in the United States, with less than half of these patients experiencing symptoms. The frequent asymptomatic presentation, combined with a lack of disease awareness by patients and health care practitioners, may result in missed diagnoses and inadequate treatment. Clinicians should recognize PAD as a marker of systemic atherosclerosis and appreciate the increased cardiovascular morbidity and mortality associated with the disease. Furthermore, intermittent claudication can significantly affect the quality of life of patients with acute and chronic leg ischemia. Consequently, a comprehensive treatment approach is needed, targeting both cardiovascular risk reduction and treatment of claudication pain. Although peripheral atherosclerosis can affect arterial beds throughout the body, our focus is on the key articles and guidelines addressing lower limb disease. We hope this compilation will serve as a resource for pharmacists, physicians, nurses, residents, and students responsible for the care of patients with PAD.

Propofol-associated QTc prolongation

Objectives: Propofol is a preferred agent for sedation in patients in the intensive care unit (ICU) due, in part, to its established safety profile. Despite this, recent case reports have suggested a potential for prolongation of the corrected QT interval (QTc) in ICU patients receiving propofol, though limited empirical work has been conducted to evaluate this association. As such, the purpose of this study was to assess the relationship between propofol infusion and QTc prolongation in a historical cohort of ICU patients. Methods: A single-center, historical, observational, pre-post cohort analysis of medical records from admitted patients ⩾18 years old with cardiovascular disease was conducted, involving cases who received propofol infusion for ⩾3 hours with sequential electrocardiogram monitoring from 2006 to 2012. A multivariable, generalized linear model regression was employed to assess the primary outcome of on-propofol QTc interval (QTc2), controlling for various demographic and clinical factors. Results: A total of 96 patients met inclusion criteria, averaging 56.1 ± 14.1 years of age and 86.1 ± 25.0 kg, with 37.5% being female. A mean prolongation in QTc interval of 30.4 ± 55.5 ms (p < 0.001) was observed during the propofol infusion, with 43.8% of cases exhibiting an on-infusion QTc2 of ⩾ 500 ms. Regression analyses suggested that prolongation in on-propofol QTc was independently associated with baseline QTc interval and amiodarone use, while weight as inversely associated with QTc2 (p < 0.05). Conclusion: This historical cohort analysis of adult ICU patients receiving propofol suggests that on-infusion QTc prolongation was associated with increasing baseline QTc interval and with amiodarone use. Further research is needed to evaluate the clinical significance and cause-and-effect relationship between potential QTc changes and propofol use in the ICU.

Key Articles and Guidelines in the Management of Hypertension 2015 Update

Hypertension is a major risk factor for cardiovascular disease. Evidence for optimal pharmacotherapy continues to accumulate at a very rapid pace; maintaining an up-to-date library of key articles for hypertension management can be challenging for busy clinicians. Further, there has been controversy surrounding the hypertension guidelines that were released in late 2013 and early 2014. The lack of congruence and simplicity in the current hypertension recommendations could result in delays with application of evidence to clinical practice. In order to facilitate clinicians’ efficient access to high-impact clinical trials evaluating the management of hypertension, this compilation of annotated bibliographies was created to serve as a resource for any health care professional participating in the management of adult patients with hypertension.

Controversies in Cardiac Resynchronization Therapy: Do Sex Differences in Response Exist?

Cardiac resynchronization therapy (CRT) is well established in the treatment of patients with heart failure, but lacks data addressing sex differences in response. Women with heart failure outnumber men, but have additional comorbidities and typically are older. Women continue to be underrepresented in clinical trials, but examining their response to a therapy across multiple studies could provide significant insight into the treatment effect. The major clinical trials did have a significant percentage of female patients, but present minimal in subgroup analysis. A few small studies comparing the effect of CRT between men and women indicate a more positive effect in women. This early data suggests CRT is at least as effective in women as it is in men, and may have additional benefit in this population.