Ronald S. Freudenberger

Warfarin and Aspirin in Patients with Heart Failure and Sinus Rhythm

BACKGROUND It is unknown whether warfarin or aspirin therapy is superior for patients with heart failure who are in sinus rhythm. METHODS We designed this trial to determine whether warfarin (with a target international normalized ratio of 2.0 to 3.5) or aspirin (at a dose of 325 mg per day) is a better treatment for patients in sinus rhythm who have a reduced left ventricular ejection fraction (LVEF). We followed 2305 patients for up to 6 years (mean [±SD], 3.5±1.8). The primary outcome was the time to the first event in a composite end point of ischemic stroke, intracerebral hemorrhage, or death from any cause. RESULTS The rates of the primary outcome were 7.47 events per 100 patient-years in the warfarin group and 7.93 in the aspirin group (hazard ratio with warfarin, 0.93; 95% confidence interval [CI], 0.79 to 1.10; P=0.40). Thus, there was no significant overall difference between the two treatments. In a time-varying analysis, the hazard ratio changed over time, slightly favoring warfarin over aspirin by the fourth year of follow-up, but this finding was only marginally significant (P=0.046). Warfarin, as compared with aspirin, was associated with a significant reduction in the rate of ischemic stroke throughout the follow-up period (0.72 events per 100 patient-years vs. 1.36 per 100 patient-years; hazard ratio, 0.52; 95% CI, 0.33 to 0.82; P=0.005). The rate of major hemorrhage was 1.78 events per 100 patient-years in the warfarin group as compared with 0.87 in the aspirin group (P<0.001). The rates of intracerebral and intracranial hemorrhage did not differ significantly between the two treatment groups (0.27 events per 100 patient-years with warfarin and 0.22 with aspirin, P=0.82). CONCLUSIONS Among patients with reduced LVEF who were in sinus rhythm, there was no significant overall difference in the primary outcome between treatment with warfarin and treatment with aspirin. A reduced risk of ischemic stroke with warfarin was offset by an increased risk of major hemorrhage. The choice between warfarin and aspirin should be individualized. (Funded by the National Institute of Neurological Disorders and Stroke; WARCEF ClinicalTrials.gov number, NCT00041938.).

Impact of oxypurinol in patients with symptomatic heart failure. Results of the OPT-CHF study.

OBJECTIVES This study evaluated whether a xanthine oxidase (XO) inhibitor, oxypurinol, produces clinical benefits in patients with New York Heart Association functional class III to IV heart failure due to systolic dysfunction receiving optimal medical therapy. BACKGROUND Increased XO activity may contribute to heart failure pathophysiology. METHODS Patients (n = 405) were randomized to oxypurinol (600 mg/day) or placebo. Efficacy at 24 weeks was assessed using a composite end point comprising heart failure morbidity, mortality, and quality of life. RESULTS The percentage of patients characterized as improved, unchanged, or worsened did not differ between those receiving oxypurinol or placebo. Oxypurinol reduced serum uric acid (SUA) by approximately 2 mg/dl (p < 0.001). In a subgroup analysis, patients with elevated SUA (>9.5 mg/dl, n = 108) responded favorably to oxypurinol (p = 0.02 for interaction term), whereas oxypurinol patients with SUA <9.5 mg/dl exhibited a trend towards worsening. In addition, SUA reduction to oxypurinol correlated with favorable clinical response. Within the entire oxypurinol patient cohort, those characterized as either improved or unchanged had significantly greater reductions in SUA compared with patients who worsened (-2.3 +/- 2.1 mg/dl vs. -1.0 +/- 1.9 mg/dl, p = 0.0006). In placebo patients, lower baseline SUA, but not change in SUA, correlated with improved clinical outcome. CONCLUSIONS Oxypurinol did not produce clinical improvements in unselected patients with moderate-to-severe heart failure. However, post-hoc analysis suggests that benefits occur in patients with elevated SUA in a manner correlating with the degree of SUA reduction. Serum uric acid may serve as a valuable biomarker to target XO inhibition in heart failure. (Oxypurinol Compared With Placebo for Class III-IV NYHA Congestive Heart Failure; NCT00063687).

Effects of BG9719 (CVT-124), an A1-Adenosine receptor antagonist, and furosemide on glomerular filtration rate and natriuresis in patients with congestive heart failure

OBJECTIVES To determine the effects of furosemide and the selective A1 adenosine receptor BG9719 on renal function in patients with congestive heart failure (CHF). BACKGROUND Studies suggest that adenosine may affect renal function by various mechanisms, but the effects of blockade of this system in humans is unknown. In addition, the effects of a therapeutic dose of furosemide on glomerular filtration rate (GFR) and renal plasma flow (RPF) in heart failure patients are controversial. METHODS On different days, 12 patients received placebo, BG9719 and furosemide. Glomerular filtration rate, RPF and sodium and water excretion were assessed immediately following drug administration. RESULTS Glomerular filtration rate was 84 +/- 23 ml/min/1.73m2 after receiving placebo, 82 +/- 24 following BG9719 administration and a decreased (p < 0.005) 63 +/- 18 following furosemide. Renal plasma flow was unchanged at 293 +/- 124 ml/min/1.73m2 on placebo, 334 +/- 155 after receiving BG9719 and 374 +/- 231 after receiving furosemide. Sodium excretion increased from 8 +/- 8 mEq following placebo administration to 37 +/- 26 mEq following BG9719 administration. In the six patients in whom it was measured, sodium excretion was 104 +/- 78 mEq following furosemide administration. CONCLUSIONS Natriuresis is effectively induced by both furosemide and the adenosine A1 antagonist BG9719 in patients with CHF. Doses of the two drugs used in this study did not cause equivalent sodium and water excretion but only furosemide decreased GFR. These data suggest that adenosine is an important determinant of renal function in patients with heart failure.

Effects of exercise training on peak performance and quality of life in congestive heart failure patients.

BACKGROUND Exercise programs for patients with heart failure have often enrolled and evaluated relatively healthy, young patients. They also have not measured the impact of exercise performance on daily activities and quality of life. METHODS AND RESULTS We investigated the impact of a 6-month supervised and graded exercise program in 33 elderly patients with moderate to severe heart failure randomized to usual care or an exercise program. Six of 17 patients did not tolerate the exercise program. Of those who did, peak oxygen consumption increased by 2.4 +/- 2.8 mL/kg/min (P < .05) and 6-minute walk increased by 194 ft (P < .05). However, outpatient energy expenditure did not increase, as measured by either the doubly labeled water technique or Caltrac accelerometer. Perceived quality of life also did not improve, as measured by the Medical Outcomes Study, Functional Status Assessment, or Minnesota Living With Heart Failure questionnaires. CONCLUSION Elderly patients with severe heart failure can safely exercise, with an improvement in peak exercise tolerance. However, not all patients will benefit, and daily energy expenditure and quality of life do not improve to the same extent as peak exercise.

Risk of Thromboembolism in Heart Failure An Analysis From the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)

Background— In patients with heart failure, rates of clinically apparent stroke range from 1.3% to 3.5% per year. Little is known about the incidence and risk factors in the absence of atrial fibrillation. In the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), 2521 patients with moderate heart failure were randomized to receive amiodarone, implanted cardioverter-defibrillators (ICDs), or placebo. Methods and Results— We determined the incidence of stroke or peripheral or pulmonary embolism in patients with no history of atrial fibrillation (n=2114), predictors of thromboembolism and the relationship to left ventricular ejection fraction. Median follow-up was 45.5 months. Kaplan-Meier estimates (95% CIs) for the incidence of thromboembolism by 4 years were 4.0% (3.0% to 4.9%), with 2.6% (1.1% to 4.1%) in patients randomized to amiodarone, 3.2% (1.8% to 4.7%) in patients randomized to ICD, and 6.0% (4.0% to 8.0%) in patients randomized to placebo (approximate rates of 0.7%, 0.8%, and 1.5% per year, respectively). By multivariable analysis, hypertension (P=0.021) and decreasing left ventricular ejection fraction (P=0.023) were significant predictors of thromboembolism; treatment with amiodarone or ICD treatment was a significant predictor of thromboembolism-free survival (P=0.014 for treatment effect; hazard ratio [95% CI] versus placebo, 0.57 [0.33 to 0.99] for ICD; 0.44 [0.24 to 0.80] for amiodarone). Inclusion of atrial fibrillation during follow-up in the multivariable model did not affect the significance of treatment assignment as a predictor of thromboembolism. Conclusions— In the SCD-HeFT patient cohort, which reflects contemporary treatment of patients with moderately symptomatic systolic heart failure, patients experienced thromboembolism events at a rate of 1.7% per year without antiarrhythmic therapy. Those treated with amiodarone or ICDs had lower risk of thromboembolism than those given placebo. Hypertension at baseline and lower ejection fraction were independent predictors of risk.

Intestinal Infarction after Intravenous Cocaine Administration

Cocaine is a leading and rapidly growing cause of drug toxicity and drug-related mortality (1). Although it is well known that cocaine can produce myocardial and cerebral infarction (2-4), little i...

Rationale, design and organisation of an efficacy and safety study of oxypurinol added to standard therapy in patients with NYHA class III - IV congestive heart failure.

Oxypurinol, the active metabolite of allopurinol and a potent xanthine oxidase inhibitor (XOI), is under evaluation as a novel agent for the treatment of congestive heart failure (HF). Several lines of evidence provide the rationale for the hypothesis that XOIs will improve clinical outcomes in patients with HF. First, XOIs have unique positive inotropic effects, improving myocardial contraction and performance while simultaneously improving myocardial energy metabolism. Second, XOIs ameliorate endothelial dysfunction in humans with HF. Finally, XO activity is upregulated in the heart and vasculature of subjects with HF, which may in turn contribute to oxidative stress and/or increased uric acid levels. Together these findings form the rationale for the Controlled Efficacy and Safety Study of Oxypurinol Added to Standard Therapy in Patients with New York Heart Association (NYHA) class III – IV Congestive Heart Failure (OPT-CHF) trial (Food and Drug Adminstration IND 65,125), a Phase II – III prospective, randomised, double-blind, placebo-controlled trial, which will include patients with stable symptomatic HF in NYHA class III – IV congestive HF who are deemed clinically stable on a standard and appropriately maximised heart failure therapy regimen. The efficacy end point for OPT-CHF is a composite that incorporates measures of patient outcome and well-being.

What is the Appropriate Approach to Prevention of Thromboembolism in Heart Failure

Many studies suggest a higher incidence of thromboembolic syndromes such as stroke, peripheral arterial thrombosis and pulmonary embolism in patients with heart failure (HF), particularly those with left ventricular systolic dysfunction. As a result, some clinicians have chosen to treat patients with HF with anticoagulants as primary prevention against thromboembolic events. However, this practice is not well-supported by scientific data. Retrospective analyses of large HF trials have yielded contradictory results and randomised trials designed to specifically address this question have been under-populated and under-powered. As a result, there is no general consensus among professional societies in either recommending or advising against anticoagulants in HF. We hope that ongoing clinical trials, WARCEF in particular, will yield results that will guide clinicians in deciding for or against routine use of anticoagulants in HF.

Alcohol use and congestive heart failure: incidence, importance, and approaches to improved history taking

Alcohol use, abuse, and dependence have the potential to result in alcoholic cardiomyopathy (ACM). This distinct form of congestive heart failure (CHF) is responsible for 21–36% of all cases of nonischemic dilated cardiomyopathy in Western society. Without complete abstinence, the 4-year mortality for ACM approaches 50%. Therefore, accurate and detailed assessment of alcohol use in congestive heart failure is essential. The prevalence of problematic alcohol use is unrecognized by many clinicians. Clinical assessment of alcohol intake is often reduced to a simple question such as, “Do you drink?” Denial and minimization are hallmarks of alcohol abuse, with many individuals underreporting their use of alcohol. Clinicians can overcome these hurdles by implementing practical history taking measures to improve the accuracy of self-reported alcohol use. The data regarding the dangers of ongoing alcohol use in individuals with ACM make attempts to engage individuals in treatment to support abstinence essential. Suggestions for detailed and accurate assessment are discussed.

Oral Anticoagulation in Patients with Cardiomyopathy or Heart Failure in Sinus Rhythm

Background: Despite many prospective randomized studies defining the benefits of anticoagulation in atrial fibrillation (AF), there have been no adequate studies in cardiomyopathy (CM) in sinus rhythm. Methods: We review the current knowledge of the risk of stroke in CM, left ventricular systolic dysfunction and heart failure as well as the indications for antithrombotic agents and compare this with AF. Results: The current knowledge of risk factors for stroke and indications for antithrombotic agents in CM is similar to that of AF prior to the treatment studies of the 1980s–1990s. Conclusion: Prospective randomized trial data are urgently needed to determine the role of antithrombotic drugs in CM.