Sodium-Glucose Cotransporter 2 Inhibitors Among Heart Failure With Mildly Reduced and Preserved Ejection Fraction.

OBJECTIVE: Results from large placebo-controlled randomized trials in patients with heart failure with mid-range ejection fraction (HFmrEF) and HF with preserved EF (HFpEF) have become available recently. This article discusses results of these clinical trials. DATA SOURCES: Peer-reviewed articles were identified from MEDLINE (1966 to December 31, 2022) using search terms dapagliflozin, empagliflozin, SGLT-2Is, HFmrEF, and HFpEF. STUDY SELECTION AND DATA EXTRACTION: Eight completed, pertinent clinical trials were included. DATA SYNTHESIS: EMPEROR-Preserved, and DELIVER demonstrated that empagliflozin and dapagliflozin reduce CV death and heart failure hospitalization (HHF) in patients with HFmrEF and HFpEF, with/without diabetes when added to a standard heart failure (HF) regimen. The benefit is primarily due to reduction in HHF. Additional data from post hoc analyses of trials of dapagliflozin, ertugliflozin, and sotagliflozin suggest that these benefits may be a class effect. Benefits appear greatest in patients with left ventricular ejection fraction 41% up to about 65%. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: While many pharmacologic treatments have been proven to reduce mortality and improve cardiovascular (CV) outcomes in people with HFmrEF and HF with reduced EF (HFrEF), there are few therapy which improve CV outcome in people with HFpEF. SGLT-2I become one of the first class of pharmacologic agent that can be used to reduce HHF and CV mortality. CONCLUSION: Studies showed that empagliflozin and dapagliflozin reduce the combined risk of CV death or HHF in patients with HFmrEF and HFpEF when added to a standard HF regimen. Given that benefit has now been demonstrated across the spectrum of HF, SGLT-2Is should be considered one of the standard HF pharmacotherapy.

Focused Updates: SGLT2 Inhibitors in Patients With Heart Failure and/or Chronic Kidney Disease.

Sodium-glucose cotransporter (SGLT2) inhibitors have demonstrated cardiovascular (CV) benefits in large-scale clinical trials of people who have type 2 diabetes and either established CV disease or multiple CV risk factors. These studies also indicated early signals in benefiting heart failure (HF) patients and those with chronic kidney diseases. This article reviews recent and future clinical studies that focus on evaluation of the use of SGLT2 inhibitors in HF management and renal protection.

Cardiovascular Pharmacology in the Time of COVID-19: A Focus on Angiotensin-Converting Enzyme 2.

Coronavirus disease-2019 (COVID-19) has emerged as a pandemic affecting millions of adults. Severe acute respiratory syndrome coronavirus-2019 (SARS-CoV-2), the causative virus of COVID-19, infects host cells through angiotensin-converting enzyme 2 (ACE2). Preclinical models suggest that ACE2 upregulation confers protective effects in acute lung injury. In addition, renin-angiotensin aldosterone system inhibitors reduce adverse atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease outcomes, but may increase ACE2 levels. We review current knowledge of the role of ACE2 in cardiovascular physiology and SARS-CoV-2 virology, as well as clinical data to inform the management of patients with or at risk for COVID-19 who require renin-angiotensin-aldosterone system inhibitor therapy.

Managing Diabetes and Preventing Heart Disease: Have We Found a Safe and Effective Agent?

OBJECTIVE: While improving glycemic control with antihyperglycemics has been demonstrated to reduce microvascular complications, the benefits of reduction in cardiovascular diseases (CVDs) have not been demonstrated with older agents. This article reviews current evidence of the CV outcomes of newer antihyperglycemics approved since 2008. DATA SOURCES: Peer-reviewed articles were identified from MEDLINE (1966 to October 31, 2018) using search terms exenatide, liraglutide, lixisenatide, dulaglutide, semaglutide, alogliptin, linagliptin, saxagliptin, sitagliptin, canagliflozin, dapagliflozin, empagliflozin, mortality, myocardial infarction (MI), heart failure (HF), and stroke. STUDY SELECTION AND DATA EXTRACTION: A total of 12 pertinent double-blinded randomized controlled trials were included. DATA SYNTHESIS: Liraglutide, empagliflozin, and canagliflozin have been shown in patients with CV diseases and high risk of developing CV disease to be superior to placebo in improving CV outcomes. Saxagliptin and alogliptin have both been demonstrated to increase HF hospitalization, whereas sitagliptin has not. Relevance to Patient Care and Clinical Practice: In contrast to older-generation antihyperglycemics, selected new antihyperglycemic agents have been shown to be superior to placebo in improving CV outcomes. Clinicians may now be able to provide high-risk patients agents that not only help in providing glycemic control, but also prevent both macrovascular and microvascular complications. CONCLUSION: Liraglutide, empagliflozin, and canagliflozin have been shown to be superior to placebo in improving CV outcomes. However, there are differences among agents in terms of HF and peripheral arterial disease outcomes. Future studies should focus on evaluating other clinical CV outcomes in patients without existing CVD and perhaps single drug regimens for diabetes.

Antidiabetic agents and cardiovascular outcomes in patients with heart diseases.

INTRODUCTION: This article reviews evidence of the benefits and risk of antidiabetic agents in cardiovascular (CV) outcomes, with a focus on medications approved by the FDA since 2008. STUDY SELECTION: Peer-reviewed articles were identified from MEDLINE and Current Content databases (both 1966 to 1 October 2016) using the search terms insulin, metformin, rosiglitazone, pioglitazone, glyburide, glipizide, glimepiride, acarbose, miglitol, albiglutide, exenatide, liraglutide, lixisenatide, dulaglutide, pramlintide, meglitinide, alogliptin, linagliptin, saxagliptin, sitagliptin, canagliflozin, dapagliflozin, empagliflozin, colesevalam, bromocriptine, mortality, myocardial infarction (MI), heart failure (HF), and stroke. Trials were included if they were randomized clinical trials evaluating adult patients (≥18 years) with type 2 diabetes; had a period of intervention and follow-up of ≥12 months; and assessed CV outcomes (CV death, fatal/non-fatal MI or HF) as endpoints. Twenty-three randomized trials were included. Antidiabetic agents: Of agents approved prior to 2008, metformin has not been associated with measurable harm in patients with diabetes in terms of mortality and CV events (and has a trend of benefit). Controversial results existed with the use of sulfonylureas and thiazolidinediones (TZDs) for CV outcomes. Among agents approved after 2008, liraglutide and empagliflozin have been shown to be superior to placebo in improving CV outcomes. CONCLUSIONS: The FDA regulatory mandate to demonstrate CV safety in order to approve new diabetes drugs led to an increase in the number of CV outcome trials. However, these trials have placebo-controlled, non-inferiority designs aiming to show absence of CV toxicity. More studies are needed to address other questions, including comparative effectiveness, and longer-term risk versus benefits.

Direct oral anticoagulants in patients with atrial fibrillation and renal impairment, extremes in weight, or advanced age.

A growing number of patients with an indication for stroke prevention in atrial fibrillation have kidney-, age-, or weight-related alterations in pharmacokinetics that affect dosing of direct oral anticoagulants. Because these patients were excluded from or comprised a small number of patients in clinical trials, there is a lack of evidence to guide clinicians. As a consequence, many patients do not receive oral anticoagulation despite a high risk for atrial fibrillation-related stroke. Here, we present a review of direct oral anticoagulant pharmacokinetics and a review of the available clinical evidence in patients with weight-, kidney-, and age-related disease.

Comparison of Ambulatory, High-Dose, Intravenous Diuretic Therapy to Standard Hospitalization and Diuretic Therapy for Treatment of Acute Decompensated Heart Failure.

Innovative treatment strategies for decompensated heart failure (HF) are required to achieve cost savings and improvements in outcomes. We developed a decision analytic model from a hospital perspective to compare 2 strategies for the treatment of decompensated HF, ambulatory diuretic infusion therapy, and hospitalization (standard care), with respect to total HF hospitalizations and costs. The ambulatory diuretic therapy strategy included outpatient treatment with high doses of intravenous loop diuretics in a specialized HF unit whereas standard care included hospitalization for intravenous loop diuretic therapy. Model probabilities were derived from the outcomes of patients who were treated for decompensated HF at Brigham and Women's Hospital (Boston, MA). Costs were based on Centers for Medicare and Medicaid reimbursement and the available reports. Based on a sample of patients treated at our institution, the ambulatory diuretic therapy strategy was estimated to achieve a significant reduction in total HF hospitalizations compared with standard care (relative reduction 58.3%). Under the base case assumptions, the total cost of the ambulatory diuretic therapy strategy was $6,078 per decompensation episode per 90 days compared with $12,175 per 90 days with standard care, for a savings of $6,097. The cost savings associated with the ambulatory diuretic strategy were robust against variation up to 50% in costs of ambulatory diuretic therapy and the likelihood of posttreatment hospitalization. An exploratory analysis suggests that ambulatory diuretic therapy is likely to remain cost saving over the long-term. In conclusion, this decision analytic model demonstrates that ambulatory diuretic therapy is likely to be cost saving compared with hospitalization for the treatment of decompensated HF from a hospital perspective. These results suggest that implementation of outpatient HF units that provide ambulatory diuretic therapy to well-selected subgroup of patients may result in significant reductions in health care costs while improving the care of patients across a variety of health care settings.

Vorapaxar in atherosclerotic disease management.

OBJECTIVE: To review the pharmacology, efficacy, and safety of vorapaxar, a protease activator receptor-1 (PAR-1) antagonist, in the management of atherosclerotic diseases. DATA SOURCES: Peer-reviewed clinical trials and review articles were identified from MEDLINE and Current Content database (both 1966 to December 31, 2014) using the search terms vorapaxar and protease activator receptor antagonist. STUDY SELECTION AND DATA EXTRACTION: A total of 30 clinical studies were identified (16 clinical trials, including subanalyses, 14 related to pharmacology, pharmacokinetics, and pharmacodynamics and drug interactions). DATA SYNTHESIS: Two phase III clinical trials with vorapaxar have been published. In patients with non-ST segment elevation myocardial infarction (MI), vorapaxar failed to significantly reduce the primary efficacy end point (composite of cardiovascular death, MI, stroke, recurrent ischemia with hospitalization, and urgent coronary revascularization). Conversely, in a study of secondary prevention for patients with cardiovascular disease, the composite end point of cardiovascular death, MI, or stroke was significantly reduced. In both trials, the safety end points of major/minor bleeding were increased compared with placebo. In the secondary prevention trial, an increased incidence of intracranial hemorrhage led to the exclusion of patients with a prior history of stroke. CONCLUSION: Vorapaxar is approved for use with aspirin and/or clopidogrel in the secondary prevention of cardiovascular events in stable patients with peripheral arterial disease or a history of MI. However, the addition of vorapaxar to other antiplatelets can significantly increase the risk of bleeding. It is, therefore, essential to balance the need for further reduction of risk of thrombotic event with patient's individual bleeding risk.

Updates in antiplatelet agents used in cardiovascular diseases.

BACKGROUND: Antiplatelet therapy is a cornerstone in coronary artery disease management. However, patients with acute coronary syndrome still remain at risk of recurrent cardiovascular events despite the advance of medical therapy. OBJECTIVE: This article provides a review of antiplatelet agents used in cardiovascular diseases and focus on updates in the past 5 years. METHOD: Peer-reviewed clinical trials and relevant treatment guidelines were identified from MEDLINE and Current Content database (from 1966 to April 15, 2013) using search terms aspirin, clopidogrel, prasugrel, ticagrelor, glycoprotein IIb/IIIa inhibitors, antiplatelet agents, coronary artery disease, acute coronary syndrome, pharmacology, pharmacokinetics, and pharmacodynamics. Citations from the available articles were also reviewed for additional references. RESULTS: In unstable angina and non-ST-segment elevation myocardial infarction (MI), dual antiplatelet therapy (aspirin and clopidogrel) demonstrated a reduction in death from cardiovascular causes, nonfatal MI, or stroke (relative risk 0.80; 95% confidence interval [CI], 0.72-0.90). In ST-segment elevation MI, dual antiplatelet therapy reduced the rate of occluded infarct-related artery/death or recurrent MI (95% CI, 24%-47%). Newer agents such as prasugrel, when compared to clopidogrel, reduced death from vascular causes, MI, or stroke in patients undergoing percutaneous coronary intervention (PCI; hazard ratio [HR], 0.81; 95% CI 0.73-0.90) but not in those receiving medical management only. When compared to clopidogrel, ticagrelor reduces death from vascular causes, MI, or stroke (HR: 0.84; 95% CI, 0.77-0.92) in patients undergoing PCI or receiving medical management only. Both the agents, however, increase the risk of bleeding in certain patient population. CONCLUSIONS: In the last 5 years, newer antiplatelet agents, including prasugrel and ticagrelor, have been demonstrated to reduce recurrent cardiovascular events compared to standard therapy and, however, also caused increase bleeding in selected patient populations. Newer agents including shorter acting P2Y12 inhibitor or antiplatelets that target other receptors are being evaluated to improve/maintain therapeutic efficacy yet minimize the risk of bleeding.

A review of the use of angiotensin receptor blockers for the prevention of cardiovascular events in patients with essential hypertension without compelling indications.

OBJECTIVE: To review the role of angiotensin receptor blockers (ARBs) for the prevention of cardiovascular events in patients with essential hypertension without other compelling indications. DATA SOURCES: Peer-reviewed clinical trials, review articles, and relevant treatment guidelines were identified from MEDLINE and Current Content database (both 1966-November 15, 2012) using the search terms angiotensin receptor blockers (ARBs), azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, hypertension, myocardial infarction, stroke, heart failure, and cardiovascular outcomes. Results were limited to human trials published in English. Citations from articles were also reviewed for additional references. STUDY SELECTION AND DATA EXTRACTION: The focus was on clinical trials evaluating cardiovascular end points of ARBs used in patients with essential hypertension without compelling indications. DATA SYNTHESIS: Data supporting the use of ARBs for reducing cardiovascular events in patients with essential hypertension without compelling indications are inconsistent. To date, only candesartan and losartan have shown a significant reduction in cardiovascular morbidity within this sizable subgroup of patients. In the Study on Cognition and Prognosis in the Elderly (SCOPE) trial, candesartan showed a 27.8% reduction in nonfatal stroke versus placebo (95% CI 1.3-47.2; p = 0.04). Moreover, losartan demonstrated a decrease in all cardiovascular events compared to atenolol in the Cardiovascular Morbidity and Mortality in the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study (RR 0.87; 95% CI 0.77-0.98; p = 0.021). CONCLUSIONS: Data supporting the use of ARBs for reducing cardiovascular events in patients with essential hypertension without compelling indications are limited and inconclusive. More studies are needed before ARBs can be routinely recommended as first-line therapy for hypertension management in patients without other compelling indications.

Oral terbutaline in replacement for intravenous dopamine in a patient with end-stage heart failure.

OBJECTIVE: To describe the replacement of intravenous dopamine with oral terbutaline in a patient with American College of Cardiology/American Heart Association stage D heart failure (HF). CASE SUMMARY: A 54-year-old male was admitted for acute decompensated HF, which was successfully managed by aggressive diuresis and intravenous dopamine 3 µg/kg/min. Multiple attempts to taper dopamine to discontinuation led to hypotension and bradycardia. In view of his hemodynamic response to dopamine weaning, oral terbutaline 5 mg every 8 hours was recommended to replace intravenous dopamine. With the addition of terbutaline, the patient continued to be hemodynamically stable, and dopamine was successfully discontinued, allowing the patient to be discharged home. DISCUSSION: Radioligand binding studies have shown that both ß-1 and ß-2 receptors exist in human myocardium. Terbutaline is a ß-2 agonist available in oral dosage form. Small single-dose studies have demonstrated that terbutaline improved cardiac output and increased heart rate, either directly by its positive inotropic effect or indirectly by its pulmonary vasodilatory effect. There are no long-term efficacy and safety data on the use of oral terbutaline in the management of HF. However, in our case, in which symptomatic improvement and comfort measure were our main goals of therapy, the use of oral terbutaline allowed us to successfully discontinue dopamine and maintain hemodynamic stability. CONCLUSIONS: The use of oral terbutaline to replace intravenous dopamine led to a successful maintenance of hemodynamic stability in a patient with advanced stage HF. To our knowledge, there have been no previous reports describing the use of oral terbutaline to replace intravenous inotropes for maintaining hemodynamic stability.

A cardiovascular pharmacotherapy elective course to enhance pharmacy students' literature evaluation skills and ability to apply clinical evidence.

OBJECTIVES: To design and implement a cardiovascular pharmacotherapy elective course to enhance pharmacy students' ability to evaluate medical literature and apply clinical evidence. DESIGN: In weekly class sessions, students were provided an overview of the important literature supporting therapeutic guidelines for the management of major cardiovascular diseases. Students worked in groups to complete outside-of-class assignments involving a patient case and then discussed the case in class. During the semester, each student also independently completed a literature search on an assigned topic, summarized the studies found in table format, and presented 1 of the studies to the class. ASSESSMENT: Students' grades on weekly patient case assignments steadily increased over the semester. Also, the average grade on the final examination was higher than the grade on the midterm take-home examination. On the course evaluation, students rated the course favorably in terms of improvement of confidence in evaluating the primary literature and applying it to practice. CONCLUSION: Completion of the cardiovascular pharmacotherapy elective increased pharmacy students' level of confidence in evaluating literature and applying clinical evidence in making patient care decisions.

Ticagrelor: oral reversible P2Y(12) receptor antagonist for the management of acute coronary syndromes.

BACKGROUND: The clinical benefits of dual antiplatelet treatment (aspirin + clopidogrel) in the management of acute coronary syndromes (ACS) are well established. However, clopidogrel is a prodrug that requires hepatic activation. Concerns regarding its delayed onset of action, variability in antiplatelet effects, and prolonged recovery of platelet function after discontinuation have prompted the development of P2Y(12) receptor antagonists. Ticagrelor is the most recently developed P2Y(12) receptor antagonist available in the United States. Ticagrelor is a nonthienopyridine antiplatelet agent and is the first reversible oral antagonist of the P2Y(12) receptors. OBJECTIVE: This article reviews the pharmacology, clinical efficacy, and tolerability of ticagrelor use in management of ACS. METHODS: Peer-reviewed clinical trials, review articles, and relevant treatment guidelines published from 1966 to March 15, 2012, were identified from the MEDLINE and Current Content databases using the search terms ticagrelor, ACS, pharmacokinetics, pharmacodynamics, pharmacoeconomics, and cost-effectiveness. Citations from available articles were also reviewed for additional references. RESULTS: Nine pharmacokinetics/pharmacodynamics studies in humans and 1 clinical study were identified. In addition, the findings from 6 subanalyses based on the clinical study were included. Compared with clopidogrel, ticagrelor was associated with a significantly reduced composite rate of death from cardiovascular causes, myocardial infarction, or stroke (ticagrelor, 9.8%; clopidogrel, 11.7%; hazard ratio [HR] = 0.84; 95% CI, 0.77-0.92; P < 0.001). The difference in the rates of major bleeding was not significant (ticagrelor, 11.6%; clopidogrel, 11.2%). Ticagrelor was associated with a higher rate of non-coronary artery bypass graft surgery related major bleeding (4.5% vs 3.8%; P = 0.03), including fatal intracranial bleeding (0.1% vs 0.01%; P = 0.02), and fewer cases of other types of fatal bleeding (0.1% vs 0.3%; P = 0.03). Other adverse events reported with ticagrelor use included dyspnea (13.8%), headache (6.5%), and bradyarrhythmia (5.8%). The effects of ticagrelor have not been compared to those of other antiplatelet agents, including prasugrel. CONCLUSIONS: Based on the findings from the present review, ticagrelor provides reversible inhibition of adenosine diphosphate-induced platelet aggregation, with a faster onset of action than clopidogrel, and is effective in the treatment of patients with ACS. More data are required to definitively position ticagrelor with respect to other antiplatelet agents, including prasugrel.

Dabigatran etexilate: an oral direct thrombin inhibitor for the management of thromboembolic disorders.

BACKGROUND: Until recently, warfarin was the only oral anticoagulant available in the United States. Its narrow therapeutic index, interpatient variability in dose response, and drug and food interactions make it difficult to use. Dabigatran etexilate (DE) is a new oral direct thrombin inhibitor that was approved in the US and in Canada for the prevention of thromboembolic events in patients with atrial fibrillation (AF), as well as in Europe and Canada for the prevention of venous thromboembolism (VTE). OBJECTIVE: To discuss the role of DE for the prevention and treatment of VTE, as well as for the prevention of stroke in patients with AF. METHODS: Peer-reviewed clinical trials, review articles, and treatment guidelines were identified from MEDLINE and the Current Contents database (both 1966-February 15, 2012) using the search terms dabigatran, VTE, Afib, pharmacokinetics, pharmacodynamics, pharmacoeconomics, and cost-effectiveness. Citations from available articles were also reviewed for additional references. RESULTS: For VTE prophylaxis, DE 150 or 220 mg orally daily has demonstrated either superiority or noninferiority to subcutaneous enoxaparin once daily in most studies. However, one study failed to demonstrate noninferiority to subcutaneous enoxaparin dosed BID in the composite end point of VTE, and all-cause mortality. For VTE treatment, DE 150 mg BID orally was shown to be noninferior to warfarin in preventing recurrent events. For AF, DE 150 mg BID orally is superior to warfarin in the prevention of thromboembolism, whereas 110 mg BID is noninferior to warfarin. Pharmacoeconomic analyses performed in the United Kingdom and Ireland found that DE can be cost-saving compared with enoxaparin in the prevention of VTE. Adverse effects of DE reported in clinical studies include dyspepsia (12%-13%) and bleeding (minor bleeding: 6%-22%). CONCLUSIONS: DE exhibited a safety profile and efficacy comparable to enoxaparin for VTE prophylaxis; comparable safety profile and efficacy to warfarin for VTE treatment; and superiority (150 mg BID orally) in the prevention of stroke and systemic embolism compared with warfarin in patients with AF. The relative ease of oral administration, no need for routine monitoring, and lack of significant drug interactions, may favor use of DE over other anticoagulants. However, there is no antidote for DE currently available.

Azilsartan medoxomil: a new Angiotensin receptor blocker.

BACKGROUND: Azilsartan medoxomil is an angiotensin receptor blocker, approved on February 25, 2011 by the US Food and Drug Administration (FDA) for hypertension management. OBJECTIVE: The purpose of this study was to review the pharmacology, pharmacokinetics, efficacy, safety profile, and role of azilsartan for hypertension management. METHODS: Peer-reviewed clinical trials, review articles, and relevant treatment guidelines were identified from MEDLINE and Current Contents (both 1966 to August 31, 2011) using the search terms azilsartan, TAK-491, TAK-536, pharmacology, pharmacokinetics, pharmacodynamics, pharmacoeconomics, and cost-effectiveness. The FDA Web site and manufacturer prescribing information were also reviewed to identify other relevant information. RESULTS: Compared with olmesartan 40 mg daily, azilsartan 80 mg reduced mean systolic blood pressure (SBP) by an additional 2.1 mm Hg (P = 0.038), whereas azilsartan 40 mg was noninferior to olmesartan 40 mg. Azilsartan 40 mg or 80 mg added to chlorthalidone 25 mg daily significantly reduced SBP to a greater extent than did chlorthalidone alone (P < 0.05), but there was no difference between azilsartan 40 mg and 80 mg (40 mg: -31.72 mm Hg; 80 mg: -31.3 mm Hg [P > 0.05]). When coadministered with amlodipine 5 mg daily, both azilsartan 40 mg and 80 mg + amlodipine decreased SBP significantly more than amlodipine alone (amlodipine: -13.6 mm Hg; with azilsartan 40 mg: -24.79 mm Hg; with azilsartan 80 mg: -24.51 mm Hg [P < 0.05]). Compared with ramipril 10 mg daily, both azilsartan 40 mg and 80 mg resulted in significantly (P < 0.001) greater reductions in mean SBP (-20.63 and -21.24 mm Hg, respectively; ramipril: -12.22 mm Hg). The most common adverse events reported were dizziness (4%), dyslipidemia (3.3%), and diarrhea (2%). CONCLUSIONS: At the recommended dose of 80 mg once daily, azilsartan is reported to be an efficacious BP-lowering agent. With once-daily dosing and a favorable side-effect profile, azilsartan is an attractive option for the treatment of hypertension. There is a lack of data supporting the use of azilsartan for improvement in cardiovascular outcomes; therefore, azilsartan is not approved for indications other than the treatment of hypertension.

Pharmacologic management of heart failure with preserved ejection fraction.

OBJECTIVE: To provide an overview of heart failure with preserved ejection fraction (HFPEF), as well as its pathophysiology, diagnosis, and clinical evidence regarding its pharmacologic management. DATA SOURCES: Peer-reviewed articles were identified from MEDLINE, International Pharmaceutical Abstracts, and Current Contents (all 1966-August 2010) using the search terms heart failure with preserved ejection fraction, diastolic dysfunction, diastolic heart failure, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), digoxin, ß-blockers, calcium-channel blockers, and vasodilators. Citations from available articles were also reviewed for additional references. STUDY SELECTION AND DATA EXTRACTION: Fourteen published manuscripts relating to pharmacologic management of HFPEF were identified. DATA SYNTHESIS: The prevalence of HFPEF has continued to increase. Compared to heart failure with left ventricular systolic dysfunction, HFPEF has been largely understudied. Unlike in the management of heart failure with left ventricular systolic dysfunction, ACE inhibitors, ARBs, ß-blockers, and aldosterone antagonists did not demonstrate mortality benefit in HFPEF, with the exception of one small study evaluating the use of propranolol. However, this study enrolled a small number of patients with recent history of myocardial infarction, which limited the generalizability of the results. Most of the current evidence centers on morbidity benefits and symptom reduction. One study showed that treatment with candesartan reduced hospital admissions in this population of patients. Management of HFPEF still focuses on optimally managing underlying diseases (eg, hypertension). CONCLUSIONS: Much remains to be learned about the appropriate pharmacologic management of patients with HFPEF. Hypertension is in most cases the predominant contributor to its development and progression. For this reason, antihypertensive treatment, including ACE inhibitors, ARBs, ß-blockers, and calcium-channel blockers, has been evaluated and is recommended to control the disease in this patient population, although these agents have not demonstrated significant benefit beyond blood pressure control. Further research into the pathophysiology of HFPEF may contribute to identifying the most optimal agent in managing this disease.

Dronedarone: a review of characteristics and clinical data.

Atrial fibrillation (AF) is a common arrhythmia associated with increased cardiovascular mortality, stroke, and hospitalization in the United States. Amiodarone is generally considered as the agent with the best efficacy for maintaining normal sinus rhythm. Despite its efficacy, amiodarone use is often limited by its extensive side effect profile. Dronedarone is a noniodinated benzofuran derivative of amiodarone that has been recently approved by the Food and Drug Administration to reduce cardiovascular hospitalization in patients with AF or atrial flutter. Structural modification of dronedarone was introduced to shorten the half-life, decrease lipophilicity, and minimize noncardiovascular toxicity as compared to amiodarone. This article reviews the pharmacology, adverse effects, and clinical evidence available to date of the use of dronedarone in the management of AF.

New and emerging antiarrhythmic and anticoagulant agents for atrial fibrillation.

PURPOSE: To compare and contrast the pharmacology, efficacy, and safety of new, emerging, and established antiarrhythmic and anticoagulant medications and describe nonpharmacologic interventions for the treatment of atrial fibrillation (AF). SUMMARY: Shortcomings of established antiarrhythmic agents include a risk for proarrhythmias and intolerable adverse effects. Dronedarone is a recently introduced amiodarone congener for maintenance of sinus rhythm after cardioversion in patients with AF that is better tolerated than amiodarone. Vernakalant is an emerging antiarrhythmic agent for conversion of AF to normal sinus rhythm with atrial-selective activity that appears to minimize the risk for proarrhythmia. An unpredictable dose-response relationship and the need for laboratory monitoring are among the many shortcomings of warfarin. Rivaroxaban, an emerging oral direct factor Xa inhibitor, and dabigatran, an emerging oral direct thrombin inhibitor, have predictable dose-response relationships and do not require laboratory monitoring. Additional data from comparative clinical trials will clarify the role of these emerging agents in the treatment of AF. Various nonpharmacologic interventions may be used for rhythm control, rate control, or cardioversion in patients whose AF cannot be managed with pharmacotherapy because of a lack of efficacy or intolerable adverse effects. CONCLUSION: New and emerging antiarrhythmic and anticoagulant agents offer advantages over established agents and may improve outcomes in patients with AF.