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The success of beta-blocking agents in clinical trials of heart failure (HF) has led to a widespread call for their increased use, which assumes these agents will perform as well in the usual care setting. Given the traditional contraindication of the use of beta-blocking agents in HF, and their perception as difficult to use in HF, observing how they perform in the usual care setting could be critical in accelerating their widespread application. Carvedilol is the only beta-blocking agent currently approved in the United States for use in HF.The Coreg (brand of carvedilol; SmithKline Beecham Pharmaceuticals, Philadelphia, PA) Heart Failure Registry (COHERE) is intended to collect data on outcomes and other clinical variables in a typical HF population and to observe experience with carvedilol in the hands of community practitioners. COHERE does not include any specific patient selection or exclusion criteria. The decision to use carvedilol is entirely at the discretion of the participant physician, based on evidence of HF as judged by assessments the practitioner usually uses. All patients will be followed for 1 year, with information on outcomes and other clinical variables collected and analyzed at baseline, the end of titration, and at 6 and 12 months after reaching the maximum tolerated dose. About 600 participant physicians selected to be as representative as possible of the community practice setting will enroll approximately 6,000 patients.COHERE will be the first and largest prospective observational experience with a new treatment, ie, carvedilol, in patients with HF managed in the usual care setting and should provide valuable information about this new treatment in this environment compared with the more rigid clinical trials setting.

Carvedilol is a nonselective beta-receptor antagonist with vasodilating properties primarily due to selective alpha-1 antagonism. This 4-treatment, 5-period, double-blind, crossover study evaluated the efficacy and safety of 3 doses of carvedilol (12.5, 25, and 50 mg given twice daily) versus placebo in 122 patients with chronic stable angina. Carvedilol in doses of 25 mg twice daily and 50 mg twice daily was statistically superior to placebo with respect to time to angina (placebo: 316 seconds; 25 mg carvedilol: 337 seconds, p = 0.0039; 50 mg: 345 seconds, p0.0001) and time to 1-mm ST-segment depression (placebo: 301 seconds; 25 mg: 313 seconds; 50 mg: 323 seconds; p0.0001). The percentage of patients reporting any adverse experience was slightly less in those receiving placebo (placebo: 28.4%; 12.5 mg: 33.1%; 25 mg: 34.5%; 50 mg: 31.9%). Carvedilol is effective and safe in treating patients with chronic stable angina.

Many patients remain markedly symptomatic despite optimal current therapy for heart failure. Beta-blockers have often been viewed as contraindicated in this group because of their potential adverse short-term effects on cardiac function.One hundred thirty-one patients with severe congestive heart failure were enrolled into a double-blind, placebo-controlled study of the vasodilating beta-blocker carvedilol. All patients had symptomatic, advanced heart failure while on standard triple therapy, as evidenced by a mean ejection fraction of 0.22, marked reduction in distance traveled in a 6-minute corridor walk test, and severe impairment in quality of life measured by the Minnesota Living With Heart Failure Questionnaire. After a 2-week, open-label test of 6.25 mg twice daily carvedilol, 105 patients were randomized (2:1) to receive either carvedilol (up to 25 mg twice daily, n = 70) or matching placebo (n = 35) for 6 months while background therapy with digoxin, diuretics, and an angiotensin-converting enzyme inhibitor remained constant. Ten patients (8%) did not complete the open-label period because of adverse events and 11.4% in both the carvedilol and placebo groups dropped out in the double-blind phase. The study was terminated early by the Data Safety and Monitoring Board and follow-up evaluation was therefore aborted before the projected number of patients and follow-up time was achieved. Quality of life, which was the primary endpoint, improved similarly in the carvedilol and placebo groups, whereas the global assessment by the physicians and the patient exhibited a better response to carvedilol (P.05). Hospitalization and mortality rate were too low to evaluate a difference, and exercise time and New York Heart Association classification did not change significantly in response to the drug. Left ventricular ejection fraction rose significantly (+0.09) in the carvedilol group compared with the placebo group (+0.02, P = .004).The beta-blocker carvedilol can be safely employed in patients with severe heart failure. Improved left ventricular function with a trend for some improvement in symptoms combined with the experience with the drug in the larger population of less severe patients in this multicenter trial suggests that carvedilol may have a favorable long-term effect in heart failure of diverse severity.

We tested the hypothesis that carvedilol inhibits clinical progression in patients with mildly symptomatic heart failure due to left ventricular (LV) systolic dysfunction.Patients (n = 366) who had mildly symptomatic heart failure with an LV ejection fraction (LVEF)or = 0.35, had minimal functional impairment (defined as the ability to walk 450 to 550 m on a 6-minute walk test), and were receiving optimal standard therapy, including ACE inhibitors, were randomized double-blind to carvedilol (n = 232) or placebo (n = 134) and followed up for 12 months. The primary end point was clinical progression, defined as death due to heart failure, hospitalization for heart failure, or a sustained increase in heart failure medications. Clinical progression of heart failure occurred in 21% of placebo patients and 11% of carvedilol patients, reflecting a 48% (P = .008) reduction in the primary end point of heart failure progression (relative risk, 0.52; CI, 0.32 to 0.85). This effect of carvedilol was not influenced by sex, age, race, cause of heart failure, or baseline LVEF. Carvedilol also significantly improved several secondary end points, including LVEF, heart failure score, NYHA functional class, and the physician and patient global assessments. Carvedilol reduced all-cause mortality but had no effects on the Minnesota Living With Heart Failure scale, the distance walked in 9 minutes on a self-powered treadmill, or cardiothoracic index. The drug was well tolerated.Carvedilol, when added to standard therapy, including an ACE inhibitor, reduces clinical progression in patients who are only mildly symptomatic with well-compensated heart failure.

Carvedilol has improved the symptomatic status of patients with moderate to severe heart failure in single-center studies, but its clinical effects have not been evaluated in large, multicenter trials.We enrolled 278 patients with moderate to severe heart failure (6-minute walk distance, 150 to 450 m) and a left ventricular ejection fractionor = 0.35 at 31 centers. After an open-label, run-in period, each patient was randomly assigned (double-blind) to either placebo (n = 145) or carvedilol (n = 133; target dose, 25 to 50 mg BID) for 6 months, while background therapy with digoxin, diuretics, and an ACE inhibitor remained constant. Compared with placebo, patients in the carvedilol group had a greater frequency of symptomatic improvement and lower risk of clinical deterioration, as evaluated by changes in the NYHA functional class (P = .014) or by a global assessment of progress judged either by the patient (P = .002) or by the physician (P.001). In addition, treatment with carvedilol was associated with a significant increase in ejection fraction (P.001) and a significant decrease in the combined risk of morbidity and mortality (P = .029). In contrast, carvedilol therapy had little effect on indirect measures of patient benefit, including changes in exercise tolerance or quality-of-life scores. The effects of the drug were similar in patients with ischemic heart disease or idiopathic dilated cardiomyopathy as the cause of heart failure.These findings indicate that, in addition to its favorable effects on survival, carvedilol produces important clinical benefits in patients with moderate to severe heart failure treated with digoxin, diuretics, and an ACE inhibitor.

Bone marrow transplantation (BMT) is now an option for some patients with sickle cell disease (SCD). Many SCD patients are multiply transfused with red blood cells (RBCs), and may be immunized to alloantigens other than erythrocyte antigens. Because platelet refractoriness is a significant complication during BMT, we wished to determine the prevalence of alloimmunization to platelets in transfused SCD patients. Sera collected from 47 transfused and 14 untransfused SCD patients were screened for HLA and platelet-specific antibodies. Transfusion and RBC antibody histories were reviewed. A subset of the patients were rescreened 1 year later. Eighty-five percent of patients with at least 50 RBC transfusions (22 of 26), 48% of patients with less than 50 transfusions (10 of 21), and none of 14 untransfused patients demonstrated platelet alloimmunization (P.05). Platelet alloimmunization was more prevalent than RBC alloimmunization (20% to 30%). Half of the platelet reactivity was chloroquine-elutable. Eighteen of 22 patients (82%) on chronic RBC transfusion remained platelet-alloimmunized 11 to 22 months after initial testing. In summary, 85% of heavily transfused SCD patients are alloimmunized to HLA and/or platelet-specific antigens. These patients may be refractory to platelet transfusion, a condition that would increase their risk during BMT. Leukodepletion in the transfusion support of SCD patients should be considered to prevent platelet alloimmunization.