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1350 THE NEW ENGLAND JOURNAL OF MEDICINE May 23, 1996 carvedilol while recognizing its potential to prolong life, demonstrated by the results of experimental stud- 7,8,21 ies. Carvedilol is a nonselective b-receptor antagonist that also blocks a1-receptors and, unlike other beta-blockers, exerts antioxidant effects, which may 22-24 contribute to its actions in heart failure. This report summarizes the effects of carvedilol on survival and on hospitalization for cardiovascular causes. Study Patients METHODS All patients in the study had had symptoms of heart failure for at least three months and had ejection fractions 0.35, despite at least two months of treatment with diuretics and an angiotensin-converting–enzyme inhibitor (if tolerated); treatment with digoxin, hydralazine, or nitrates was permitted but not required. Patients were excluded from the trial if they had had a major cardiovascular event or had undergone a major surgical procedure within three months of entry into the study, or if they had uncorrected, primary valvular disease; active myocarditis; sustained ventricular tachycardia or advanced heart block not controlled by antiarrhythmic intervention or a pacemaker; systolic blood pressure of more than 160 or less than 85 mm Hg or diastolic blood pressure of more than 100 mm Hg; a heart rate of less than 68 beats per minute; clinically important hepatic or renal disease; or any condition other than heart failure that could limit exercise or survival. Patients receiving calcium-channel blockers, a- or b-adrenergic agonists or antagonists, or class IC or III antiarrhythmic agents were also not enrolled. The protocol was approved by the institutional review boards of all 65 participating institutions; written informed consent was obtained from all patients. Study Procedures The patients’ eligibility was assessed during a three-week screening period, during which exercise capacity was measured by a sixminute corridor-walk test. Enrollment was stratified into one of four treatment protocols on the basis of the patients’ performance on the exercise test. According to the original design, patients able to walk between 426 and 550 m when tested were assigned to the mild-heartfailure protocol; those able to walk between 150 and 425 m were assigned either to the moderate-heart-failure protocol or to a dose-ranging protocol, depending on the location of the study center; and those able to walk only less than 150 m were assigned to the severe-heartfailure protocol. After a base-line evaluation, all patients received 6.25 mg of carvedilol twice daily for two weeks (the open-label portion of the study); if this dose was not tolerated, it could be temporarily reduced to 3.125 mg twice daily and then later increased. Patients who could tolerate 6.25 mg twice daily were randomly assigned to receive carvedilol or placebo on a double-blind basis, in addition to their usual medication. The allocation ratio (of patients given carvedilol to patients given placebo) was one-to-one in the moderate-heart-failure protocol and two-to-one in the mild- and severe-heart-failure protocols; for these patients, the dose of medication was initially 12.5 mg twice daily and was increased, if tolerated, to 25 to 50 mg twice daily. Patients assigned to the dose-ranging protocol were randomly assigned to one of four parallel treatment groups (placebo or 6.25 mg, 12.5 mg, or 25 mg of carvedilol, twice daily). For all four protocols, the dose was gradually adjusted upward to the target level over a period of 2 to 10 weeks, after which double-blind therapy was maintained for an additional 6 months (except in the mild-heart-failure protocol, in which patients were treated for an additional 12 months). During this time, the patients’ other drug therapies for heart failure were kept constant, unless side effects occurred that were thought to be related either to these other medications or to the study drug itself. Study Objectives and Monitoring Because of concern that new drugs for heart failure might increase the risk of death, the sponsors of the program agreed with the Food and Drug Administration in July 1992 to enroll a sufficient number of CAPS:CAPS Shipped Pages:may23.96:1pack.oa Wed May 22 96 12:04:56 patients in placebo-controlled trials of carvedilol to rule out (with 95 percent confidence) the risk of a 33 percent increase in mortality with active therapy, assuming an annual mortality rate of 12 percent in the placebo group. As a result of these discussions, an evaluation of mortality was prospectively defined for the present stratified trial program, primarily for reasons of safety, with the intent to enroll 1101 patients. However, since it was anticipated (on the basis of earlier studies) that carvedilol could reduce mortality, all statistical analyses were two-sided. All deaths were classified by investigators who had no knowledge of the patients’ treatment assignments. In addition, a major secondary objective of each of the component protocols was to evaluate the effect of carvedilol on cardiovascular morbidity, defined as hospitalization for heart failure or other cardiovascular causes. A data and safety monitoring board was constituted before recruitment began, met periodically to review the unblinded results, and was empowered to recommend early termination of the program if its members observed a clinically important treatment effect. No formal rules for stopping the trial were adopted before the initiation of enrollment. Statistical Analysis The base-line characteristics of the two treatment groups were compared with use of the t-test and the chi-square statistic. Cumulative survival curves were constructed as time-to-first-event plots by 25 Kaplan–Meier survivorship methods, and differences between the curves were tested for significance by the log-rank statistic with use of a Cox proportional-hazards regression model (which included the protocol as a covariate). 26 The analyses included all randomized patients, and all events were assigned to the patients’ original treatment group (on the intention-to-treat principle). In the analysis of mortality, data on patients were censored at the time of cardiac transplantation. Differences between treatment groups in post-randomization measures or events were evaluated by analysis of variance and with the chi-square statistic. All data are reported as means SD. RESULTS Randomization began on April 29, 1993, and the study was stopped early on the recommendation of the Data and Safety Monitoring Board on February 3, 1995. This decision was based on the finding of a significant effect of carvedilol on survival — an effect that exceeded all conventional boundaries used to stop clinical trials. 27,28 At the time of the study’s early termination, 1197 patients had entered the open-label, run-in period. Of these, 5.6 percent failed to complete this period because of adverse events (e.g., worsening heart failure in 1.4 percent and death in 0.6 percent); another 3.0 percent failed to do so because of violations of the protocol or for other administrative reasons. Accordingly, 1094 patients were randomly assigned to double-blind treatment: 398 with placebo and 696 with carvedilol. The placebo and carvedilol groups were similar in all pretreatment characteristics (Table 1). After randomization and the adjustment of dosage, patients received a mean total daily dose of 4527 mg of carvedilol or 6024 mg of placebo; these doses were maintained at similar levels throughout the study period. Eighty percent of the patients received target doses of the study drugs. The duration of therapy ranged from 1 day to 15.1 months (median, 6.5 months). No patient was lost to follow-up with respect to mortality. Effect of Carvedilol on Survival In the intention-to-treat analysis, there were 31 deaths (7.8 percent) in the placebo group and 22 deaths (3.2
Vol. 334 No. 21 CARVEDILOL AND MORBIDITY AND MORTALITY IN CHRONIC HEART FAILURE 1351 percent) in the carvedilol group; this difference represents a 65 percent decrease in the risk of death (95 percent confidence interval, 39 to 80 percent; P0.001) in patients assigned to carvedilol (Fig. 1). Treatment with the drug was associated with a large decrease in the risk of dying of progressive heart failure and in the risk of sudden death (Table 2). The reduction in mortality due to carvedilol was similar regardless of age, sex, the cause of heart failure, ejection fraction, exercise tolerance, systolic blood pressure, heart rate, or protocol assignment (Table 3). Effect of Carvedilol on Cardiovascular Morbidity During double-blind therapy, 98 patients (14.1 percent) in the carvedilol group and 78 patients (19.6 percent) in the placebo group had at least one hospitalization for cardiovascular causes; this difference represents a 27 percent reduction in the risk of hospitalization (95 percent confidence interval, 3 to 45 percent; P0.036). To avoid the analytic problem of competing risks (since patients who have died cannot be hospitalized), the effect of carvedilol on the combined risk of death or hospitalization for cardiovascular causes was evaluated with the use of a time-to-first-event analysis. As tested for significance with use of the log-rank test, the combined risk of either dying or being hospitalized for cardiovascular reasons was reduced from 24.6 percent in the placebo group to 15.8 percent in the carvedilol group, a 38 percent reduction (95 percent confidence interval, 18 to 53 percent; P0.001) (Fig. 2). Safety Table 1. Pretreatment Characteristics of Patients in the Study. * CHARACTERISTIC PLACEBO (N 398) *Plus–minus values are means SD. ACE denotes angiotensin-converting enzyme. †The cause of heart failure was not recorded for one patient in the placebo group and two in the carvedilol group. At the end of double-blind therapy, the mean heart rate decreased significantly more in the carvedilol group CAPS:CAPS Shipped Pages:may23.96:1pack.oa Wed May 22 96 12:05:04 CARVEDILOL (N 696) Age (yr) 58.112.3 57.912.2 Sex (M/F) 304/94 534/162 New York Heart Association class II III IV Cause of heart failure† Coronary artery disease Nonischemic dilated cardiomyopathy 208 177 13 189 208 374 303 19 332 362 Left ventricular ejection fraction 0.220.07 0.230.07 Six-minute walk (m) 38696 39090 Systolic blood pressure (mm Hg) 11517 11617 Diastolic blood pressure (mm Hg) 7311 7210 Heart rate (beats/min) 8312 8412 Medication (% of patients) Digitalis Loop diuretic ACE inhibitor Direct-acting vasodilator 90 95 95 32 91 95 95 32 than in the placebo group (by 12.612.8 beats per minute vs. 1.412.2, P0.001), although neither group had significant changes in systolic or diastolic blood pressure. Frequently reported adverse reactions are listed in Table 4; those necessitating discontinuation of the study drug are shown in Table 5. The most common side effect of carvedilol was dizziness, which occurred during the initiation of therapy or during the dose-adjustment period but which subsided either spontaneously or after the adjustment of concomitant medications; it did not generally lead to the withdrawal of treatment with the study drug. The most common reason for the discontinuation of double-blind treatment was worsening heart failure, which occurred more frequently in the placebo group. Overall, 7.8 percent of the placebo group and 5.7 percent of the carvedilol group discontinued the study medication because of adverse reactions; 1.5 percent and 1.1 percent, respectively, were withdrawn from the study medication after cardiac transplantation. When the program was terminated, more patients were receiving or had completed double-blind treatment in the carvedilol group than in the placebo group (89 percent vs. 83 percent, P0.002). DISCUSSION The present report indicates that the addition of carvedilol to conventional therapy is associated with a decrease in mortality among patients with chronic heart failure. Patients treated with carvedilol had a 65 percent lower risk of death than those given placebo during follow-up that averaged 6.5 months and extended to 15 months. The beneficial effect of carvedilol on survival was consistent in all evaluated subgroups and was reflected in a decrease in the risk of death from progressive heart failure as well as in the risk of sudden death. Probability of Survival NO. AT RISK Placebo Carvedilol 1.00 0.95 0.90 0.85 0.80 0.75 0.70 0.65 0.60 0.55 0 50 100 150 200 250 300 350 400 398 696 353 637 329 581 Days of Therapy 305 546 163 314 71 131 55 106 Carvedilol Placebo 43 83 3 11 Figure 1. Kaplan–Meier Analysis of Survival among Patients with Chronic Heart Failure in the Placebo and Carvedilol Groups. Patients in the carvedilol group had a 65 percent lower risk of death than patients in the placebo group (P0.001).
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