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.

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.

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 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.

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.

Nebivolol: a third-generation beta-blocker for hypertension.

BACKGROUND: Nebivolol is a third-generation beta(1)-selective beta-blocker that is approved for the treatment of hypertension. OBJECTIVE: This article reviews the clinical pharmacology of nebivolol and its efficacy and safety profile in clinical studies of hypertension (the US Food and Drug Administration-approved indication) and heart failure (off-label use). METHODS: Pertinent articles were identified through searches of MEDLINE and Current Contents from 1966 through December 15, 2008, using the terms nebivolol, drug interaction, pharmacokinetics, and pharmacology. The reference lists of the identified publications were reviewed for additional references. Abstracts presented at meetings of the American Heart Association and the American Society of Hypertension from 2006 through 2008 were also reviewed. All human clinical trials were included, regardless of design. RESULTS: Twelve published clinical trials were identified that evaluated the use of nebivolol in the management of hypertension; 1 was placebo controlled, 1 was placebo and active controlled, and 10 involved direct comparisons with other antihypertensive agents. Nebivolol was reported to be as effective in lowering blood pressure (BP) as other beta-blockers (atenolol and bisoprolol), angiotensin-converting enzyme inhibitors (lisinopril and enalapril), the angiotensin-receptor blocker telmisartan, and calcium channel blockers (nifedipine and amlodipine). No published studies were identified that evaluated the effect of nebivolol on long-term cardiovascular outcomes. In data from a study in heart failure, nebivolol was associated with a 14% reduction in all-cause mortality and cardiovascular hospitalization at 12 months (P < 0.05). In comparative clinical studies, nebivolol appeared to be well tolerated relative to the other antihypertensive agents studied. The most commonly reported adverse events with nebivolol were fatigue (4%-79%), headache (2%-24%), paresthesia (7%-13%), bradycardia (6%-11%), rhinitis (1%-7%), and dizziness (2%-5%). Because of differences in its pharmacologic properties, nebivolol may have potential advantages in patients who are unable to tolerate traditional beta-blockers (eg, patients with asthma or chronic obstructive pulmonary disease, or men who experience erectile dysfunction while taking antihypertensive therapy). CONCLUSIONS: Nebivolol is a cardioselective beta-blocker that has been reported to be efficacious and well tolerated for achieving BP control in patients with hypertension. Preliminary evidence suggests a potential for reduced mortality in patients with heart failure.

Updates on cytochrome P450-mediated cardiovascular drug interactions.

Cytochrome P (CYP) 450 is a superfamily of hemoproteins that play an important role in the metabolism of steroid hormones, fatty acids, and many medications. Many agents used for management of cardiovascular diseases are substrates, inhibitors, or inducers of CYP450 enzymes.When two agents that are substrates, inhibitors, or inducers of CYP450 are administered together, drug interactions with significant clinical consequences may occur. This review discusses CYP450-mediated cardiovascular drug interactions as well as noncardiovascular drug interactions that produced significant cardiovascular side effects. The principles in predicting drug interactions are also discussed.

Ambrisentan for the management of pulmonary arterial hypertension.

BACKGROUND: Approved by the US Food and Drug Administration in 2007, ambrisentan is the second oral endothelin A-receptor antagonist available for the management of pulmonary arterial hypertension (PAH) in patients with World Health Organization class II or III symptoms. OBJECTIVE: This article examines the clinical pharmacology of ambrisentan, its efficacy and adverse effects, and future directions for research. METHODS: Pertinent articles and abstracts were identified through searches of MEDLINE and Current Contents from 1966 to January 15, 2008, using the term ambrisentan. The reference lists of identified articles were searched for additional publications. Abstracts presented at professional meetings from 2005 through 2007 were also reviewed. RESULTS: The literature review identified 3 studies of ambrisentan in PAH: 1 dose-ranging study; 2 randomized, double-blind, placebo-controlled studies; and 1 drug-conversion study. In the dose-ranging study, ambrisentan at doses of 1 to 10 mg was associated with significant improvements from baseline in the 6-minute walk distance at 12 weeks that ranged from 33.9 m with ambrisentan 1 mg (P = 0.003) to 38.1 m with ambrisentan 5 mg (P = 0.001). In the placebo-controlled studies, ambrisentan at doses of 2.5 to 10 mg/d was associated with significant improvements versus placebo in the 6-minute walk distance at 12 weeks that ranged from 22 m with ambrisentan 2.5 mg (P = 0.022) to 59 m with ambrisentan 5 mg (P

Vernakalant in the management of atrial fibrillation.

OBJECTIVE: To review the pharmacology and clinical evidence of the use of vernakalant in the management of atrial fibrillation (AF). DATA SOURCES: Peer-reviewed articles published in the English language were identified from MEDLINE and Current Contents databases (both 1966-March 5, 2008) using the search terms RSD 1235 and vernakalant. Citations from available articles and recent meeting abstracts were reviewed for additional references. During the preparation of this article, vernakalant was being reviewed by the Food and Drug Administration (FDA). Therefore, information posted on the FDA Web site was also evaluated. STUDY SELECTION AND DATA EXTRACTION: Phase 2 and Phase 3 clinical studies of both intravenous and oral vernakalant were reviewed. The design and results of the studies were critically evaluated. DATA SYNTHESIS: Vernakalant is a sodium and ultra-rapid potassium channel blocker with atrial selective effects. In 2 clinical studies evaluating use of intravenous vernakalant in cardioversion of patients with recent-onset AF, vernakalant improved the chance of restoration of normal sinus rhythm (combined results 51% vs 3.8% with placebo; p < 0.001). In postoperative AF, intravenous vernakalant also improved the chance of restoration of normal sinus rhythm (45% vs 15% with placebo; p = 0.0002). Early Phase 2 studies demonstrated that oral vernakalant 300 mg or 600 mg twice daily successfully maintained sinus rhythm compared with placebo. No proarrhythmias relating to vernakalant have been reported to date. Common adverse effects include dysgeusia, sneezing, and paresthesia. CONCLUSIONS: Vernakalant is a new atrial-selective antiarrhythmic agent. Phase 3 clinical trials of the intravenous formulation and early Phase 2 studies of the oral formulation demonstrated vernakalant to be efficacious and safe in converting recent-onset AF to sinus rhythm. Further studies are needed to explore the efficacy and safety of vernakalant use in patients with severe heart failure and AF, as well as its relative efficacy and safety compared with other antiarrhythmic agents, especially with long-term use.

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.

A review of isosorbide dinitrate and hydralazine in the management of heart failure in black patients, with a focus on a new fixed-dose combination.

BACKGROUND: It is estimated that 25% to 30% of patients with heart failure (HE) in the United States are black. Compared with nonblack patients, black patients have a reduced ability to produce endogenous nitric oxide, which may be associated with enhanced responsiveness to drugs that increase the delivery of nitric oxide, such as nitrates. When used with nitrates, hydralazine (HYD) acts as an antioxidant and prevents development of nitrate tolerance. OBJECTIVE: This article reviews the clinical pharmacology of isosorbide dinitrate (ISDN) and HYD and clinical trials of their use in the treatment of HF, with a particular focus on the new fixed-dose combination for the treatment of HF in black patients. METHODS: Articles or abstracts reporting the results of randomized, double-blind, controlled studies of ISDN and HYD in HF were identified through a search of the English-language literature indexed on MEDLINE and Current Contents/Clinical Medicine from 1966 to February 5, 2005, using the terms hydralazine, isosorbide dinitrate, nitrates, and heart failure. The reference lists of identified articles were reviewed for additional publications. Selected information provided by the manufacturer was also reviewed. RESULTS: The combination of ISDN and HYD was studied in 3 large randomized controlled trials, the first and second Vasodilator in Heart Failure trials (V-HeFT I and V-HeFT II), which included approximately 27% black men, and the African-American Heart Failure Trial (A-HeFT), which included 100% self-identified black patients of both sexes. In V-HeFT I, which compared ISDN 40 mg QID and HYD 75 mg QID with prazosin 20 mg/d or placebo in 642 patients with mild to severe HF (New York Heart Association [NYHA] class II-III), those receiving ISDN and HYD had a 34% reduction in mortality risk compared with those receiving placebo (P < 0.038). In V HeFT II, which compared the same dosages of ISDN and HYD with enalapril 20 mg/d in 804 patients with NYHA class II-IV HF, those receiving enalapril had a 28% reduction in mortality risk compared with those receiving ISDN and HYD (P = 0.016). A predetermined subanalysis of VHeFT I and V-HeFT II found that black patients receiving ISDN and HYD had a 47% reduction in relative mortality risk compared with nonblack patients (hazard ratio = 0.53 vs 130, respectively; P = 0.04). In A-HeFT, which compared combination ISDN/HYD 40/75 mg TID with placebo in 1050 patients with moderate to severe HF (NYHA class III-IV), ISDN/HYD was associated with fewer deaths compared with placebo (32 vs 54, respectively; P = 0.02), a lower incidence of first hospitalizations for HF (85 vs 130; P = 0.002), and a larger number of patients with marked improvement (>10 units) in quality-of-life scores, as measured on the Minnesota Living with Heart Failure Questionnaire (180 vs 166; P = 0.01). In A-HeFT, adverse events occurring with a greater incidence in the ISDN/HYD group than the placebo group were headache (49.5% vs 21.1%, respectively), dizziness (30.1% vs 13.7%), nausea and vomiting (9.7% vs 6.1%), hypotension (7.9% vs 4.4%), sinus congestion (4.3% vs 1.7%), and tachycardia (4.1% vs 2.7%). A pharmacoeconomic analysis based on health care resource utilization in A-HeFT found the ISDN/HYD combination product to be cost-effective over a wide range of acquisition costs (up to 12 US dollars/d ). CONCLUSIONS: The findings of these 3 large controlled clinical trials support the efficacy of ISDN and HYD in patients with HE Using a composite end point of mortality, HT hospitalization, and quality of life, the A-HeFT study found benefits to adding the fixed-dose ISDN/HYD combination product to standard therapy in self-identified black patients of African descent with moderate to severe HF.

Ranolazine for the management of coronary artery disease.

BACKGROUND: Despite coronary revascularization and standard antianginal therapy, many patients continue to experience symptoms of stable angina and progression of their disease. Ranolazine is a new class of antianginal agent. Unlike standard antianginal agents, it alters glucose and fatty acid metabolism for a different approach to the management of coronary artery disease. OBJECTIVE: This article discusses the clinical pharmacology of ranolazine and its use in the management of chronic stable angina. METHODS: Peer-reviewed articles and abstracts were identified from MEDLINE and the Current Contents database (both from 1966 to September 20, 2006) using the search terms ranolazine, angina, pharmacokinetics, and pharmacology. Citations from available articles were reviewed for additional references. Abstracts presented at recent professional meetings were also reviewed. RESULTS: Ranolazine is a cell membrane inhibitor of the late sodium current. Extended-release ranolazine was recently approved in the United States for the treatment of chronic angina. Ranolazine is metabolized in the liver by the cytochrome P-450 (CYP) 3A4 system. Because of its potential to prolong corrected QT (QTc) intervals, ranolazine should not be used in patients with hepatic impairment, those with QTc prolongation, or those taking drugs known to prolong QTc intervals or drugs that are potent CYP 3A4 inhibitors. Other adverse effects of ranolazine include dizziness, headache, constipation, and nausea. Placebo-controlled clinical studies performed to date have found that sustained-release ranolazine 500 to 1500 mg PO BID was associated with significantly increased time to onset of angina (range of increase, 27.0-144.0 s; P < 0.05 [varied among studies]), exercise duration (range of increase, 23.8-99.0 s; P < 0.05 [varied among studies] ), and time to 1-mm ST depression (range of increase, 27.6-146.2 s; P < 0.05 [varied among studies]). In addition, exercise duration was found to be significantly longer with ranolazine compared with atenolol (453 vs 430 s; P = 0.006). CONCLUSIONS: Ranolazine is a new antianginal agent that is effective in the management of chronic angina. Its unique mechanism of action warrants further study in other cardiovascular conditions such as heart failure and arrhythmias. Ongoing studies will address whether ranolazine can reduce clinical end points such as cardiovascular death and myocardial infarction.

Use of non-aspirin nonsteroidal antiinflammatory drugs and the risk of cardiovascular events.

OBJECTIVE: To review published evidence on the use of nonselective, non-aspirin nonsteroidal antiinflammatory drugs (NANSAIDs) and the risks of cardiovascular events and examine the justification for Food and Drug Administration (FDA) in recommending that a cardiovascular risk warning statement be included in all NANSAIDs' product information inserts. DATA SOURCES: Peer-reviewed articles in MEDLINE (1966-August 2006) and Current Contents were identified using the key words NSAID, naproxen, ibuprofen, heart diseases, myocardial infarction, and cardiovascular events. Citations from available articles and related FDA Web sites were reviewed for additional references. STUDY SELECTION AND DATA EXTRACTION: No randomized, placebo-controlled studies have been published evaluating this subject. Epidemiologic evidence published in English was examined. Sixteen relevant studies were identified (5 cohort, 3 nested case-control, 8 case-control). DATA SYNTHESIS: Six of the 16 studies demonstrated increased risk for one or more NANSAIDs (rate or ORs varied from 1.13 to 3.08). Five studies demonstrated cardioprotective effect for one or more NANSAIDs used (rate or ORs varied from 0.48 to 0.84). None of the other studies demonstrated an association between use of NANSAIDs and risk of cardiovascular events. CONCLUSIONS: After adjustment of baseline risk factors for cardiovascular events, epidemiologic studies demonstrated conflicting results regarding the risk of cardiovascular events with long-term use of nonselective NANSAIDs. However, considering the large number of patients consuming NANSAIDs and the potential public health impact, until data from long-term, randomized, controlled trials become available, the FDA's recommendation that a warning statement be included in all nonselective NANSAIDs product package inserts is justified.

Drug therapy recommendations from the 2005 ACC/AHA guidelines for treatment of chronic heart failure.

OBJECTIVE: To review and discuss key aspects of the drug therapy recommendations in the American College of Cardiology (ACC)/American Heart Association (AHA) 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure (HF) in the Adult. DATA SOURCES: Data were obtained from the ACC/AHA 2005 Guideline Update for Chronic HF. English-language clinical trials, observational studies, and pertinent review articles evaluating the pharmacotherapy of chronic HF were identified, based on MEDLINE searches through January 2006. STUDY SELECTION: Articles presenting information that impacts the evidence base for recommendations regarding the use of various drug therapies in patients with chronic HF were evaluated. DATA SYNTHESIS: The ACC/AHA 2005 Guideline Update for HF provides revised, evidence-based recommendations for the treatment of chronic HF. The new guidelines are based on a staging system that recognizes both the development and progression of HF. Recommendations are provided for 2 stages of patients (A and B) who do not yet have clinical HF but are clearly at risk and 2 stages (C and D) that include patients with symptomatic HF. The guidelines continue to emphasize the important role of neurohormonal blockade with angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, beta-adrenergic blockers, and aldosterone antagonists. Based on recent trials, updated recommendations address the roles of combination therapy and the selective addition of hydralazine and isosorbide dinitrate. Along with specific drug recommendations, information on the practical use of various drugs is provided. Although the guidelines primarily focus on HF due to systolic dysfunction, general recommendations are also provided for patients with preserved systolic function. CONCLUSIONS: The ACC/AHA 2005 Guideline Update provides evidence-based recommendations for healthcare professionals involved in the care of adults with chronic HF. Recent clinical trial findings have further clarified the evolving role of neurohormonal-blocking drugs in the prevention and treatment of HF.

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.