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(Circulation. 1996;94:2793-2799.)
© 1996 American Heart Association, Inc.

Articles

Double-Blind, Placebo-Controlled Study of the Effects of Carvedilol in Patients With Moderate to Severe Heart Failure

The PRECISE Trial

Milton Packer, MD; Wilson S. Colucci, MD; Jonathan D. Sackner-Bernstein, MD; Chang-seng Liang, MD, PhD; David A. Goldscher, MD; Israel Freeman, MD; Marrick L. Kukin, MD; Vithal Kinhal, MD; James E. Udelson, MD; Marc Klapholz, MD; Stephen S. Gottlieb, MD; David Pearle, MD; Robert J. Cody, MD; John J. Gregory, MD; Nikki E. Kantrowitz, MD; Thierry H. LeJemtel, MD; Sarah T. Young, PhD; Mary Ann Lukas, MD; Neil H. Shusterman, MD; for the PRECISE Study Group*

the College of Physicians and Surgeons, Columbia University, New York, NY (M.P., J.D.S.-B., M.K.); Boston (Mass) University School of Medicine (W.S.C.); University of Rochester (NY) School of Medicine (C.-S.L.); Good Samaritan Hospital, Baltimore, Md (D.A.G.); Nassau County Medical Center, East Meadow, NY (I.F.); Mount Sinai School of Medicine, New York, NY (M.L.K., N.E.K.); Henry Ford Hospital, Grosse Pointe, Mich (V.K.); Tufts University School of Medicine, Boston, Mass (J.E.U.); University of Maryland, Baltimore (S.S.G.); Georgetown University School of Medicine, Washington, DC (D.P.); Ohio State University School of Medicine, Columbus (R.J.C.); Overlook Hospital, Summit, NJ (J.J.G.); Albert Einstein School of Medicine, Bronx, NY (T.H.L.); and SmithKline Beecham Pharmaceuticals, King of Prussia, Pa (S.T.Y., M.A.L., N.H.S.).

Reprint requests to Dr Milton Packer, Division of Circulatory Physiology, Columbia University College of Physicians and Surgeons, 630 W 168th St, New York, NY 10032.

	Abstract

Top Abstract Introduction Methods Results Discussion Appendix References

 
Background 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.

Methods and Results We enrolled 278 patients with moderate to severe heart failure (6-minute walk distance, 150 to 450 m) and a left ventricular ejection fraction 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.

Conclusions 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. (Circulation. 1996;94:2793-2799.)

Key Words: heart failure • carvedilol • blockers, beta-adrenergic

	Introduction

Top Abstract Introduction Methods Results Discussion Appendix References

 
ß-Adrenergic blocking drugs have emerged as a promising approach to the treatment of patients with heart failure. Placebo-controlled, multicenter studies have shown that long-term treatment with metoprolol, bisoprolol, and carvedilol is associated with a decrease in the risk of progression to end-stage disease,¹ a reduction in the frequency of hospitalization for heart failure and other cardiovascular causes,^{2 3} and a favorable effect on survival.³ The results of these large-scale trials indicate an important role for ß-blockers to reduce morbidity and mortality in chronic heart failure.

Despite evidence that ß-blockers can reduce the risk of disease progression, the effect of these drugs on the symptoms of heart failure is less clear. Although nearly all placebo-controlled trials with ß-blockers in patients with left ventricular dysfunction have shown a striking improvement in cardiac function,⁴ these studies have reported inconsistent effects on clinical status. The lack of symptomatic benefits in some reports may have been related to the small size or short duration of the studies.^{5 6} Alternatively, the end points used to assess the symptomatic response to these drugs may not have been appropriate for the evaluation of a ß-adrenergic–blocking drug in patients with chronic heart failure. For example, although exercise capacity has been used routinely for the past decade to assess the clinical effects of new drugs in this disorder,⁷ this variable may not accurately reflect changes in functional status if it is used to evaluate drugs that attenuate the exercise response to therapeutic interventions.^{8 9 10}

Because of uncertainties regarding the most appropriate end points to use for the evaluation of a ß-blocker for heart failure, we decided to assess a large number of clinical variables in designing a multicenter study to assess the efficacy of carvedilol in patients with moderate to severe heart failure. Carvedilol is a nonselective ß-receptor antagonist that also blocks ₁-receptors and exerts antioxidant effects.^{11 12} The drug has been shown to have a wide range of clinical benefits in three single-center trials and to reduce the risk of death in a multicenter study.^{3 13 14 15}

	Methods

Top Abstract Introduction Methods Results Discussion Appendix References

 
Patient Population
Patients with chronic heart failure despite conventional therapy were enrolled at 31 centers in the United States. Heart failure was defined as dyspnea or fatigue at rest or on exertion for 3 months in association with a left ventricular ejection fraction 0.35 as assessed by radionuclide ventriculography. These clinical and hemodynamic abnormalities were present despite 2 months of treatment with diuretics and an ACE inhibitor (if tolerated); therapy with digoxin, hydralazine, and nitrates was allowed but not required. The clinical status and background medications received by each patient were stable for 1 month before enrollment in the study.

Patients were excluded from participation if they had uncorrected primary valvular disease, active myocarditis, or an obstructive or restrictive cardiomyopathy; a myocardial infarction, stroke, unstable angina, or coronary artery bypass graft surgery within 3 months; symptomatic or sustained ventricular tachycardia not controlled by antiarrhythmic drugs or an implantable defibrillator; sick sinus syndrome or advanced heart block (unless treated by a pacemaker); any condition other than heart failure that could limit exercise (eg, angina, peripheral vascular disease, pulmonary disease); systolic blood pressure >160 or <85 mm Hg or diastolic blood pressure >100 mm Hg; heart rate <68 bpm; significant hepatic, renal, or endocrine disease; drug or alcohol abuse; or any condition that could limit survival. Patients receiving calcium-channel blockers, - or ß-adrenergic agonist or antagonist drugs, or specific antiarrhythmic drugs (disopyramide, flecainide, encainide, moricizine, amiodarone, propafenone, or sotalol) were not enrolled.

The protocol was approved by the institutional review boards of all participating institutions, and written informed consent was obtained from all study patients.

Measures of Efficacy
During a 3-week screening period, the clinical status of each patient was evaluated to ensure eligibility for the study and stability before the addition of any new therapeutic intervention. The evaluations performed during the screening period consisted of both direct and indirect measures of patient benefit.

The direct measures consisted of evaluations that are carried out as part of the usual interactions and procedures followed in the routine management of heart failure. These included (1) global assessment of heart failure syndrome (assessed by both the patient and physician as unchanged or mildly, moderately, or markedly improved or worse); (2) functional capacity (as classified by NYHA class); and (3) left ventricular ejection fraction (quantified by radionuclide ventriculography).

The indirect measures consisted of evaluations that are designed for use in clinical trials but are not used routinely in clinical practice. These included the assessment of (1) quality-of-life scores (by the Minnesota Living With Heart Failure Questionnaire¹⁶ ) and (2) exercise tolerance. Exercise capacity was quantified by (1) a 6-minute corridor walk¹⁷ (which requires a submaximal effort) and (2) a 9-minute self-powered treadmill test¹⁸ (which necessitates a near-maximal effort¹⁹ ). The 6-minute corridor walk (but not the 9-minute test) has been used in previous studies of heart failure.^{14 15 20}

Study Protocol
The present study was designed as one of four component protocols that together composed a single stratified program to evaluate the effects of carvedilol in chronic heart failure.³ Stratification of patients was based on their performance on a 6-minute corridor walk test. Patients were enrolled in the present study if they had a 6-minute corridor walk distance (following three practice tests) between 150 and 425 m; the upper limit was subsequently increased as a result of a protocol amendment to 450 m. Patients with a 6-minute walk distance <150 or >425 to 450 m were enrolled in other protocols; the results of these parallel studies are reported elsewhere.

After a baseline clinical evaluation, all patients entered an open-label, run-in period during which they received carvedilol 6.25 mg BID for 2 weeks, or if this dosage was not tolerated, the dosage could be temporarily reduced to 3.125 mg BID and then subsequently increased. Patients who could tolerate 6.25 mg BID were randomly assigned (double-blind) to receive long-term therapy with carvedilol or matching placebo (in a 1:1 ratio), in addition to their usual medications for heart failure. The dosage of double-blind medication was initially 12.5 mg BID and was increased gradually, if tolerated, over a period of 2 to 6 weeks (up-titration phase) to 25 mg BID (or to 50 mg BID in patients weighing >85 kg). Double-blind therapy was then maintained for an additional 6 months (maintenance phase), during which time background therapy with digoxin, diuretics, and/or an ACE inhibitor was kept constant, but the dosages of these drugs could be decreased if side effects occurred that were thought to be related to these medications or to the study drug. If the patient's condition deteriorated, the investigator could use any clinically indicated interventions, but patients were not permitted to receive open-label therapy with carvedilol.

During the double-blind phase of the study, all direct and indirect measures of patient benefit were reassessed periodically at predefined time points. Serial evaluations of NYHA functional class and global assessments of patient progress were carried out each month; exercise testing was repeated at 2, 4, and 6 months; and other efficacy measures (quality-of-life scores and ejection fraction) were reexamined after 6 months.

Protocol-Specified End Points
Exercise tolerance (as assessed by both the 6-minute corridor walk and the 9-minute treadmill test) was designated as the primary end point in this study. This decision was made because in 1992, the US Food and Drug Administration regarded exercise capacity to be a principal variable for the evaluation of new drugs for heart failure, even though it was understood that exercise testing might not be an appropriate measure of the efficacy of a ß-blocker in heart failure.⁷ Secondary end points included changes in all other direct and indirect measures (ie, global assessments, NYHA functional class, left ventricular ejection fraction, and quality-of-life scores). In addition, a prespecified end point in this study was the frequency of hospitalization for cardiovascular causes.

Statistical Analyses
The baseline characteristics of the two treatment groups at the time of randomization were compared by Student's t test (for continuous variables) and the ² statistic (for noncontinuous variables). Changes in the primary end point of exercise tolerance were analyzed in two ways. (1) A carry-forward analysis excluded patients who dropped out before their first double-blind exercise test at 2 months; patients who withdrew after 2 months had their last value carried forward, and the data were analyzed parametrically by a multivariate ANOVA model that included center, treatment group, and their interaction. (2) An intention-to-treat analysis included all patients randomized into the study; changes in exercise tolerance were compared nonparametrically after rank transformation, and patients who did not complete the study after randomization were assigned worst rank. Changes in the secondary end points were also analyzed in two ways: (1) for continuous variables (ejection fraction and quality of life), the ANOVA model described above was used; and (2) for noncontinuous variables (NYHA class, global assessments, and hospitalizations), a Cochran-Mantel-Haenszel procedure²¹ was used with the study centers as strata. All analyses used the last double-blind value that was available for the patient; worst-rank assignments were not used for the analysis of secondary end points. All data are expressed as mean±SD.

	Results

Top Abstract Introduction Methods Results Discussion Appendix References

 
After a baseline evaluation, 301 patients met criteria for entry into the study and received open-label therapy with carvedilol. Eight percent (23 patients) did not complete the 2-week, open-label period because of either adverse reactions (17 patients) or administrative reasons (6 patients). The adverse reactions included death in 5 patients (1.7%), worsening heart failure in 5 patients (1.7%), and dizziness in 3 patients (1.0%). Accordingly, 278 patients were randomized into the double-blind phase of the study: 145 patients to placebo and 133 patients to carvedilol.

The two groups were similar with respect to all pretreatment characteristics (Table 1). The majority of patients had class III symptoms, and the mean ejection fraction was 0.22±0.07. After randomization and completion of the up-titration period, patients received an average dosage of 28±13 mg daily of carvedilol and the equivalent of 32±13 mg daily of placebo. Eighty-seven percent received their target dosages of the drug, and these dosages were maintained throughout the follow-up period. Twenty patients were considered to be noncompliant (ie, took <80% of prescribed dosages of study medication at two consecutive visits): 17 were assigned to placebo and 3 to carvedilol.

View this table: [in this window] [in a new window]   Table 1. Pretreatment Characteristics of Patients in the Study

Effect of Carvedilol on Indirect Measures of Patient Benefit
Compared with placebo, carvedilol therapy was associated with small changes in exercise tolerance. By the carry-forward analysis, the 6-minute walk distance increased from 351 to 368 m in the carvedilol group and from 352 to 358 m in the placebo group (17 versus 6 m, P=.162). By the intention-to-treat analysis, the 6-minute walk distance increased by 9 m in the carvedilol group but decreased by 3 m in the placebo group (P=.048). Differences between the two groups in the distance traversed on the 9-minute treadmill test were not significant by either the carry-forward (P=.728) or the intention-to-treat (P=.324) analysis.

There was no difference between the two treatment groups in quality-of-life scores, assessed either as a total score or separately for the physical and emotional dimensions.

Effect of Carvedilol on Direct Measures of Patient Benefit
Carvedilol produced a significant improvement in NYHA functional class, as indicated by a shift in the distribution of patients from greater to lesser severity of heart failure (P=.014, Table 2). Whereas the proportion of patients with class III to IV symptoms remained unchanged in the placebo group (from 58% to 51%), this proportion decreased in the carvedilol group (from 64% to 41%). A deterioration in NYHA class was observed in 15% of the placebo group but in only 3% of the carvedilol group (P=.001).

View this table: [in this window] [in a new window]   Table 2. Distribution of NYHA Class at Randomization and After Long-term Therapy With Placebo or Carvedilol

Carvedilol therapy was also associated with an improvement in the global assessment of disease severity as assessed both by the physician (P<.001) and by the patient (P=.002) (Table 3). As evaluated by the physician, 53% of the placebo group but 81% of the carvedilol group showed symptomatic improvement, whereas 12% of the placebo group but only 2% of the carvedilol group experienced clinical deterioration. A similar pattern of response in favor of carvedilol was reported by patients (Table 3).

View this table: [in this window] [in a new window]   Table 3. Global Assessment of Progress During Double-Blind Therapy With Placebo or Carvedilol Assessed by Patient and by Physician

In addition to changes in symptoms, other measures of clinical efficacy were improved by carvedilol. Therapy with the drug was accompanied by an increase in left ventricular ejection fraction (+0.08 on carvedilol versus +0.03 on placebo, P<.001 between the groups), which was paralleled by a reduction in cardiovascular morbidity. By the protocol-specified, carry-forward approach, 24.4% of the placebo group but only 14.5% of the carvedilol group experienced a cardiovascular hospitalization (P=.029); by the intention-to-treat approach, 25.5% of the placebo group but only 16.5% of the carvedilol group required hospitalization for cardiovascular reasons (P=.060). By intention-to-treat analysis, there were 11 deaths (7.6%) in the placebo group and 6 deaths (4.5%) in the carvedilol group (P=.26). When deaths and cardiovascular hospitalizations were combined in a time-to-first-event analysis to account for competing risks, the probability of a major fatal or nonfatal event was reduced by carvedilol from 31.0% to 19.6% (P=.029).

The favorable effects of carvedilol on NYHA class, global assessment by both patient and physician, and left ventricular ejection fraction were similar in patients with ischemic heart failure or idiopathic dilated cardiomyopathy as the cause of heart failure (P>.05 for interaction between complementary subgroups for all four variables).

Safety
The most common side effect of initiating therapy with carvedilol was dizziness, which was seen in 41 of the 301 patients (13.6%) who entered the open-label, run-in phase. Heart failure was reported during the open-label period in 22 patients (7.3%). Occurrence of an adverse reaction led to a reduction in the dosage of carvedilol (from 6.25 to 3.125 mg BID) in 21 patients (7.0%), but in all but one patient, the dosage could subsequently be increased to 6.25 mg BID without recurrence of the side effect. Thus, the development of early symptomatic hypotension or heart failure did not generally lead to withdrawal of patients from the study.

Adverse reactions affecting the cardiovascular system occurring after randomization are shown for the up-titration and maintenance phases of double-blind therapy in Table 4. Dizziness and hypotension were the most common side effects of carvedilol during both phases but generally subsided spontaneously or after adjustment in concomitant therapy and did not require withdrawal of the drug. In contrast, patients in the carvedilol group had fewer complaints of chest pain. Although heart failure was somewhat more common in the carvedilol group during the up-titration phase, it was less frequent in the carvedilol group during the maintenance phase (11.6% versus 22.3%, P=.021). Adverse reactions serious enough to require the withdrawal of double-blind medication occurred in 8.3% of the placebo group but in only 5.3% of the carvedilol group.

View this table: [in this window] [in a new window]   Table 4. Most Frequent Adverse Reactions Reported in Trial

At the end of double-blind therapy, heart rate decreased significantly in the carvedilol group compared with the placebo group (-16.3 versus -1.9 bpm, P=.0001), and this was accompanied by small but significant decreases in systolic blood pressure (-5.8 versus -0.7 mm Hg, P=.002) and diastolic blood pressure (-4.7 versus -0.3 mm Hg, P=.0001). Bradycardia was reported as an adverse reaction during double-blind therapy in 8.3% of the carvedilol group versus 0.7% of the placebo group, P=.002, whereas hypotension was reported as an adverse reaction in 12.8% of the carvedilol group versus 4.1% of the placebo group, P=.009.

Overall, 30 patients (20.7%) in the placebo group and 19 patients (14.4%) in the carvedilol group failed to complete the trial. The discontinuations were more frequent in the placebo group than in the carvedilol group for all three major reasons for withdrawal: deaths, adverse reactions, and administrative causes.

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix References

 
The present study indicates that the addition of carvedilol to conventional therapy with digoxin, diuretics, and an ACE inhibitor produces significant hemodynamic and clinical benefits in patients with moderate to severe heart failure. During a treatment period of 6 months, patients in the carvedilol group were more likely to show symptomatic improvement and were less likely to experience clinical deterioration than patients in the placebo group. These functional benefits were accompanied by both an increase in left ventricular ejection fraction and a decrease in the risk of major cardiovascular events, including cardiovascular hospitalizations and death. These findings indicate that, in addition to its favorable effects on survival,³ carvedilol ameliorates the clinical syndrome of heart failure.

The benefits observed in the present study are similar to those reported in earlier studies of ß-blocking drugs in heart failure. In most trials of adequate size, long-term ß-blockade has been associated with a striking lessening of disability,^{1 2 13 14 15 22} an effect that has been most apparent when patients are asked directly about the severity of symptoms²³ in a manner similar to that routinely used in clinical practice to measure patient progress. Yet, this direct approach has not been used as a primary end point in clinical trials because it has long been regarded as being insensitive to the changes produced by drug therapy.^{7 24} Unlike exercise testing, however, the direct assessment of symptoms has reliably distinguished effective drugs from placebo^{25 26 27} and has confirmed the lack of benefit of ineffective agents.^{28 29 30} It is therefore noteworthy that, by direct assessment methods, clinical improvement has been reported consistently in placebo-controlled studies of ß-blockers in heart failure, including trials with metoprolol, bisoprolol, and carvedilol.^{1 2 13 14 15 22 23} The most notable exception to this pattern of consistency has been the only two studies^{31 32} that used a parallel, dose-response design, possibly because such a design assigns a large proportion of randomized patients to receive potentially subtherapeutic doses of the active drug.

An important finding in the present study was that carvedilol produced clinical improvement in patients with and without ischemic heart disease as the cause of heart failure. Earlier trials with bucindolol, bisoprolol, and carvedilol have reported no benefit of ß-blockade in patients with ischemic cardiomyopathy,^{2 33 34} and some studies have excluded such patients entirely.^{1 5 6 14 35 36 37} The lack of effect has been attributed to the absence of marked ß-receptor downregulation in the hearts of these patients,³⁸ which may decrease the hemodynamic response to sympathetic antagonism.³³ However, recent studies indicate that ß-receptor upregulation is not a prerequisite for a favorable response to ß-blockade³⁹ and that patients with ischemic and nonischemic cardiomyopathies show similar hemodynamic and symptomatic benefits,^{15 22 31} as was observed in the present study. These findings suggest that the lack of functional benefits in many trials of ß-blockers in patients with an ischemic cardiomyopathy may have been related to the mild symptoms of the patients enrolled in these studies^{33 34} rather than the cause of left ventricular dysfunction. Functional improvement may be difficult to demonstrate in those with little disability before treatment; in such patients, the primary measure of benefit may be the prevention of clinical deterioration during long-term follow-up.

Evaluation of the risk of symptomatic progression may be the most sensitive means of measuring the benefits of ß-blockers in heart failure, regardless of the severity of disease. Nearly all placebo-controlled trials 4 months in duration have noted a reduction in the frequency of clinical deterioration with ß-blockade, even those that failed to demonstrate any functional improvement because they enrolled patients with only mild symptoms.^{1 2 3 14 15 22 32 34} In the present study, carvedilol reduced the risk of clinical progression as assessed by a broad range of measures, including (1) a decrease in the frequency of deterioration using direct measures of progress (ie, global assessment and NYHA class), (2) a reduction in the number of patients reporting heart failure as an adverse reaction, (3) a decrease in the proportion of patients who withdrew from the study or who were noncompliant with medications, and (4) a reduction in the frequency of major cardiovascular events (morbidity and mortality). Interestingly, the proportional decrease in the risk of symptomatic deterioration with carvedilol was greater than the proportional increase in the number of patients who showed clinical improvement with the drug. This difference may have both methodological and biological explanations. From a methodological viewpoint, the frequency of favorable responses in the placebo group may be so high (up to 62% in the present study) that it may be difficult to show any further benefits with active therapy.⁴⁰ In contrast, clinical deterioration in a controlled trial of patients who were stable at the time of enrollment is uncommon; it generally reflects a true event and thus may provide a sensitive target for drug therapy. From a biological viewpoint, ß-blockers are believed to exert their effects in heart failure by interfering with the adverse actions of sympathetic stimulation on the heart.^{41 42} Yet, insofar as the known toxicities of catecholamines are largely irreversible, we would expect the benefits of ß-blockade to be most easily discerned by measures that reflect the prevention of further injury rather than the recovery of impaired myocardium.

In contrast to the favorable effects of carvedilol on direct measures of clinical benefit, treatment with the drug produced inconsistent effects on indirect measures of efficacy (eg, exercise tolerance and quality-of-life tests). These indirect measures have been developed principally for use in clinical trials and are not generally used in the routine care of patients. The lack of general use of these measures is explained by their complexity and by the fact that they do not evaluate the syndrome of heart failure but instead quantify the impact of heart failure on a specific aspect of the patient's life under the conditions of the test. As a result, changes in these indirect measures may not reflect the clinical progress of the patient.^{10 24} In the present study, carvedilol produced only small increases in submaximal but no improvement in maximal exercise capacity. The lack of effect on peak exercise was not unexpected, because ß-blockers attenuate the exercise response to therapeutic interventions^{8 9 10} ; in fact, no placebo-controlled trial of ß-blockade in heart failure has shown an improvement in maximal exercise tolerance after 3 to 6 months of treatment. In contrast, although ß-blockers inhibit submaximal as well as maximal exercise capacity,⁴³ these drugs have enhanced submaximal exercise performance in several studies.^{14 15} Yet, because submaximal testing is not well standardized, its use is accompanied by significant interobserver variability. This may explain why ß-blockers have improved submaximal exercise tolerance only in single-center studies,^{14 15} in which interobserver variability is minimized.

Although the effects of carvedilol in the present study are similar to those observed in studies with other ß-blockers, pharmacological differences between carvedilol and other ß-blockers may alter the clinical responses to the drug in heart failure. Unlike most ß-blockers, carvedilol blocks ₁-adrenergic receptors and thus produces greater peripheral vasodilation than most agents in this class. These vasodilator effects may increase the risk of dizziness but decrease the risk of worsening heart failure during initiation of therapy with the drug. Unlike metoprolol and bisoprolol, carvedilol blocks ß₂-adrenergic receptors, reduces cardiac norepinephrine, and prevents the upregulation of cardiac ß-receptors^{44 45 46} ; as a result, carvedilol may provide a greater degree of sympathetic antagonism than other ß-blockers. These additional antiadrenergic actions may impair the ability of the drug to improve exercise tolerance^{43 47 48} but at the same time enhance its ability to block the toxic effects of catecholamines on the failing heart. Finally, unlike other ß-blockers, carvedilol also exerts antioxidant effects¹² and thus may prevent the loss of cardiac myocytes that occurs in heart failure as a result of oxidative stress.^{49 50} For all of these reasons, the effects of carvedilol in heart failure (perhaps more than other ß-blockers) may be most appropriately assessed by clinical measures of disease progression rather than by functional measures of exercise capacity.

In conclusion, our findings indicate that the administration of carvedilol to patients with moderate to severe heart failure can ameliorate the symptoms, diminish the disability, and reduce the morbidity associated with this disorder. These benefits were apparent across a wide range of measures, both in patients with and those without coronary artery disease and in those who remained symptomatic despite therapy with digitalis, diuretics, and an ACE inhibitor. However, the favorable effects of carvedilol in the present study were observed primarily when measures of efficacy were used that closely resemble those used in clinical practice, whereas methods of assessment developed for use in clinical trials were less able to distinguish a treatment effect. This finding has important implications for the design of future clinical trials.

	Acknowledgments

 
This study was supported by a grant from SmithKline Beecham Pharmaceuticals, King of Prussia, Pa, and Boehringer Mannheim Therapeutics, Mannheim, Germany.

	Footnotes

 
*The members of the PRECISE Study Group are listed in the "Appendix." PRECISE refers to Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise.

	Appendix

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The following centers constituted the PRECISE Study Group.

Baltimore, Md (Johns Hopkins University Hospital): E. Kasper, A.M. Feldman; (Union Memorial Hospital): H. Meilman; (Metropolitan Medical Associates): D. Goldscher; (University of Maryland): S.S. Gottlieb, M.L. Fisher, C. Krichten. Boston, Mass (Boston City Hospital): R.H. Falk, N. Battinelli; (Brigham and Women's Hospital): W.S. Colucci, W. Carlson, E. Loh; (Massachusetts General Hospital): G.W. Dec; (New England Medical Center): J.E. Udelson, M.A. Konstam, J.J. Smith, K.M. Curtin, L.M. Keane. Bronx, NY (Albert Einstein College of Medicine): T.H. LeJemtel, M. Jones. Cleveland, Ohio (Cleveland Clinic): R. Hobbs, K. James. Columbus, Ohio (Ohio State University Hospital): R.J. Cody, P.F. Binkley, G.J. Haas, M. Jones. East Meadow, NY (Nassau County Medical Center): E. Brown, I. Freeman. Elmhurst, NY (Elmhurst Hospital Center): N. Kantrowitz. Falls Church, Va (INOVA Health System): J. Kiernan, J. O'Brien, P. Carson. Grosse Pointe, Mich (Pierson Clinic): V. Kinhal, A.D. Goldberg. Mineola, NY (Cardiovascular Medical Associates): M. Goodman; (Winthrop University Hospital): R. Steingart. Nashville, Tenn (Vanderbilt University Medical Center): J.R. Wilson, T.-K. Yeoh. New Haven, Conn (Yale University School of Medicine); F. Lee. New York, NY (Columbia-Presbyterian Medical Center): J. Sackner-Bernstein, G.W. Neuberg, N. Medina, M. Yushak, D. Ahern, M. Packer; (Mount Sinai Medical Center): M. Kukin, J. Kalman, C. Buchholz, O. Ocampo, M. Steinmetz; (St Luke's/Roosevelt Medical Center): M. Klapholz, D. Toma. Northport, NY (Veterans Affairs Medical Center): G. Mallis, J. Fleischman-Eaton. Philadelphia, Pa (Temple University Hospital): I. Pina. Pittsburgh, Pa (Presbyterian University Hospital): B. Uretsky, S. Murali, T. Tokarczyk, Y. Cannon, S. Loftus; (Western Pennsylvania Hospital): A. Gradman, B. Sharma. Richmond, Va (Medical College of Virginia): G.W. Vetrovec. Rochester, NY (University of Rochester Medical Center): C.-S. Liang, J.M. Delehanty, M. Lotosky, H. Elam. Sellersville, Pa (Buxmont Cardiology Associates): M. Greenspan, P.R. Hermany, J.P. Moyer, M.N. Stram, D.N. Flowers. Summit, NJ (Overlook Hospital): J.J. Gregory, T. Kimball. Washington, DC (Georgetown University Hospital): D. Pearle. Worchester, Mass (University of Massachusetts Medical Center): L. Heller.

Received July 17, 1996; revision received October 7, 1996; accepted October 7, 1996.

	References

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1. Waagstein F, Bristow MR, Swedberg K, Camerini F, Fowler MB, Silver MA, Gilbert EM, Johnson MR, Goss FG, Hjalmarson A, for the Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Lancet.. 1993;342:1441-1446.[Medline] [Order article via Infotrieve]
   
2. CIBIS Investigators and Committees. A randomized trial of ß-blockade in heart failure: the Cardiac Insufficiency Bisoprolol Study (CIBIS). Circulation.. 1994;90:1765-1773.[Abstract/Free Full Text]
   
3. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, Shusterman NH, for the US Carvedilol Heart Failure Study Group. Effect of carvedilol on morbidity and mortality in chronic heart failure. N Engl J Med.. 1996;334:1349-1355.[Abstract/Free Full Text]
   
4. Dougherty RN, MacMahon S, Sharpe N. Beta-blockers in heart failure: promising or proved? J Am Coll Cardiol.. 1994;23:814-821.[Abstract]
   
5. Currie PJ, Kelly MJ, McKenzie A, Harper RW, Lim YL, Federman J, Anderson ST, Pitt A. Oral beta-adrenergic blockade with metoprolol in chronic severe dilated cardiomyopathy. J Am Coll Cardiol.. 1984;3:203-209.[Abstract]
   
6. Ikram H, Fitzpatrick D. Double-blind trial of chronic oral beta blockade in congestive cardiomyopathy. Lancet.. 1981;2:490-493.[Medline] [Order article via Infotrieve]
   
7. Lipicky RJ, Packer M. Role of surrogate endpoints in the evaluation of drugs for heart failure. J Am Coll Cardiol.. 1993;22:179A-184A.
   
8. Sable DL, Brammell HL, Sheehan MW, Nies AS, Gerber J, Horwitz LD. Attenuation of exercise conditioning by beta-adrenergic blockade. Circulation.. 1982;65:679-684.[Free Full Text]
   
9. Marsh RC, Hiatt WR, Brammell HL, Horwitz LD. Attenuation of exercise conditioning by low dose beta adrenergic receptor blockade. J Am Coll Cardiol.. 1983;2:551-556.[Abstract]
   
10. Goldsmith R, Krum H, Sackner-Bernstein J, Schwartz B, Neuberg GW, Penn J, Kukin ML, Packer M. Do changes in exercise tolerance reflect the clinical response to therapy in patients with heart failure? Implications for the design of clinical trials. Circulation. 1992;86(suppl I):I-513. Abstract.
    
11. Ruffolo RR, Gelai M, Heible JP, Willette RN, Nichols AJ. The pharmacology of carvedilol. Eur J Clin Pharmacol. 1990;38(suppl 2):S82-S88.
    
12. Yue T-L, Cheng H-Y, Lysko PG, McKenna PJ, Feuerstein R, Gin JL, Lysko KA, Davis LL, Feuerstein G. Carvedilol, a new vasodilator and beta-adrenoceptor antagonist, is an antioxidant and free radical scavenger. J Pharmacol Exp Ther.. 1992;263:92-98.[Abstract/Free Full Text]
    
13. Olsen SL, Gilbert EM, Renlund DG, Taylor DO, Yanowitz FD, Bristow MR. Carvedilol improves left ventricular function and symptoms in chronic heart failure: a double-blind randomized study. J Am Coll Cardiol.. 1995;25:1225-1231.
    
14. Metra M, Nardi M, Giubbini R, Dei Cas L. Effects of short- and long-term carvedilol administration on rest and exercise hemodynamic variables, exercise capacity and clinical conditions in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol.. 1994;24:1678-1687.
    
15. Krum H, Sackner-Bernstein JD, Goldsmith R, Kukin ML, Schwartz B, Penn J, Medina N, Yushak M, Horn E, Katz SD, Levin HL, Neuberg GW, DeLong G, Packer M. Double-blind, placebo-controlled study of the long-term efficacy of carvedilol in severe chronic heart failure. Circulation.. 1995;92:1499-1506.[Abstract/Free Full Text]
    
16. Rector TS, Kubo SH, Cohn JN. Patients self-assessment of their congestive heart failure, pt 2: content, reliability and validity of a new measure, the Minnesota Living With Heart Failure Questionnaire. Heart Failure.. 1987;3:198-209.
    
17. Guyatt GH, Sullivan MJ, Thompson PJ, Fallen EL, Pugsley SO, Taylor DW, Berman LB. The six-minute walk: a new measure of exercise capacity in patients with chronic heart failure. Can Med Assoc J.. 1985;132:919-923.[Abstract]
    
18. Sparrow J, Parameshar J, Poole-Wilson PA. Assessment of functional capacity in chronic heart failure: time-limited exercise on a self-powered treadmill. Br Heart J.. 1994;71:391-394.[Abstract/Free Full Text]
    
19. Hart DJ, Katz SD, Lee SH, Ahern D, DeLong G, Whelan J, Packer M, Goldsmith RG. Characterization of the 9-minute self-powered treadmill walk, a new submaximal exercise test in patients with heart failure. J Am Coll Cardiol.. 1994;23:384A. Abstract.
    
20. Packer M, Gheorghiade M, Young JB, Smith LK, Costantini PJ, Adams KF, Cody RJ, Gourley LA, Jolly MK, for the RADIANCE Study. Withdrawal of digoxin in patients with chronic heart failure treated with converting-enzyme inhibitors. N Engl J Med.. 1993;329:1-7.[Abstract/Free Full Text]
    
21. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst.. 1959;22:719-748.
    
22. Fisher ML, Gottlieb SS, Plotnick GD, Greenberg NL, Patten RD, Bennett SK, Hamilton BP. Beneficial effects of metoprolol in heart failure associated with coronary artery disease: a randomized trial. J Am Coll Cardiol.. 1994;23:943-950.
    
23. Yushak M, Medina N, Krum H, Sackner-Bernstein J, Goldsmith RL, Kukin ML, Schwartz B, Penn J, Packer M. Utility of direct symptom assessment in measuring the efficacy of therapy in chronic heart failure: evaluation in a controlled trial of beta-blockade. J Am Coll Cardiol.. 1994;23:383A. Abstract.
    
24. Packer M. How should we judge the efficacy of drug therapy in patients with chronic congestive heart failure? The insights of six blind men. J Am Coll Cardiol.. 1987;9:433-438.[Medline] [Order article via Infotrieve]
    
25. Richardson A, Bayliss J, Scriven A, Parameshwar J, Poole-Wilson PA, Sutton GC. Double-blind comparison of captopril alone against frusemide plus amiloride in mild heart failure. Lancet.. 1987;2:709-711.[Medline] [Order article via Infotrieve]
    
26. Gundersen T, Swedberg K, Amtorp O, Remes J, Nilsson B. Absence of effect on exercise capacity of 12-weeks treatment with ramipril in patients with moderate congestive heart failure. Eur Heart J.. 1994;15:1659-1665.[Abstract/Free Full Text]
    
27. McGrath BP, Arnolda L, Matthews PG, Jackson B, Jennings G, Kiat H, Johnston CI. Controlled trial of enalapril in congestive cardiac failure. Br Heart J.. 1985;54:405-414.[Abstract/Free Full Text]
    
28. Elkayam U, Amin J, Mehra A, Vasquez J, Weber L, Rahimtoola SH. A prospective randomized, double-blind crossover study to compare the efficacy and safety of chronic nifedipine therapy to isosorbide dinitrate and their combination in the treatment of chronic congestive heart failure. Circulation.. 1990;82:1954-1962.[Abstract/Free Full Text]
    
29. DiBianco R, Shabetai R, Kostuk W, Moran J, Schlant RC, Wright R. A comparison of oral milrinone, digoxin, and their combination in the treatment of patients with chronic heart failure. N Engl J Med.. 1989;320:677-683.[Abstract]
    
30. Parker JO, for the Ibopamine Study Group. The effects of oral ibopamine in patients with mild heart failure: a double-blind placebo controlled comparison to furosemide. Int J Cardiol.. 1993;40:221-227.[Medline] [Order article via Infotrieve]
    
31. Bristow MR, O'Connell JB, Gilbert EM, French WJ, Leatherman G, Kantrowitz NE, Orie J, Smucker ML, Marshall G, Kelly P, Deitchman D, Anderson JL, for the Bucindolol Investigators. Dose response of chronic ß-blocker treatment in heart failure from either idiopathic dilated cardiomyopathy or ischemic cardiomyopathy. Circulation.. 1994;89:1632-1642.[Abstract/Free Full Text]
    
32. Bristow MR, Gilbert EM, Abraham WT, Adams KF, Fowler MB, Hershberger R, Kubo SH, Narahara KA, Ingersoll H, for the MOCHA Investigators. Multicenter oral carvedilol heart failure assessment (MOCHA): a six-month dose-response evaluation in class II-IV patients. Circulation. 1995;92(suppl I):I-142. Abstract.
    
33. Woodley SL, Gilbert EM, Anderson JL, O'Connell JB, Deitchman D, Yanowitz FG, Mealey PC, Volkman K, Renlund DG, Menlove R, Bristow MR. Beta-blockade with bucindolol in heart failure caused by ischemic versus idiopathic dilated cardiomyopathy. Circulation.. 1991;84:2426-2441.[Abstract/Free Full Text]
    
34. Australia-New Zealand Heart Failure Research Collaborative Group. Effects of carvedilol, a vasodilator–beta-blocker, in patients with congestive heart failure due to ischemic heart disease. Circulation.. 1995;92:212-218.[Abstract/Free Full Text]
    
35. Eichhorn EJ, Heesch CM, Barnett JH, Alvarez LG, Fass SM, Grayburn PA, Hatfield BA, Marcoux LG, Malloy CR. Effect of metoprolol on myocardial function and energetics in patients with nonischemic dilated cardiomyopathy: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol.. 1994;24:1310-1320.
    
36. Wisenbaugh T, Katz I, Davis J, Essop R, Skoularigis J, Middlemost S, Rothlisberger C, Skudicky D, Sareli P. Long term (3 month) effects of a new beta-blocker (nebivolol) on cardiac performance in dilated cardiomyopathy. J Am Coll Cardiol.. 1993;21:1094-1100.
    
37. Engelmeier RS, O'Connell JB, Walsh R, Rad N, Scanlon PJ, Gunnar RM. Improvement in symptoms and exercise tolerance by metoprolol in patients with dilated cardiomyopathy: a double-blind, randomized, placebo-controlled trial. Circulation.. 1985;72:536-546.[Abstract/Free Full Text]
    
38. Bristow MR, Anderson FL, Port JD, Skerl L, Hershberger RE, Larrabee P, O'Connell JB, Renlund DG, Volkman K, Murray J, Feldman AM. Differences in beta-adrenergic neuroeffector mechanisms in ischemic versus idiopathic dilated cardiomyopathy. Circulation.. 1991;84:1024-1039.[Abstract/Free Full Text]
    
39. Gilbert EM, Olsen SL, Mealey P, Volkman K, Larabee P, Bristow MR. Is ß-receptor up-regulation necessary for improved left ventricular function in dilated cardiomyopathy? Circulation. 1991;84(suppl II):II-469. Abstract.
    
40. Packer M. The placebo effect in heart failure. Am Heart J.. 1990;120:1579-1582.[Medline] [Order article via Infotrieve]
    
41. Yates JC, Beamish RE, Dhalla NS. Ventricular dysfunction and necrosis produced by adrenochrome metabolites of epinephrine: relation to pathogenesis of catecholamine cardiomyopathy. Am Heart J.. 1981;102:210-221.[Medline] [Order article via Infotrieve]
    
42. Mann DL, Kent RL, Parsons B, Cooper G. Adrenergic effects of the biology of the adult mammalian cardiocyte. Circulation.. 1992;85:790-804.[Abstract/Free Full Text]
    
43. Wilmore JH, Ewy GA, Freund BJ, Hartzell AA, Jilka SM, Joyner MJ, Todd CA, Kinzer SM, Pepin EB. Cardiorespiratory alterations consequent to endurance exercise training during chronic beta-adrenergic blockade with atenolol and propranolol. Am J Cardiol.. 1985;55:142D-148D.[Medline] [Order article via Infotrieve]
    
44. Newton GE, Parker JD. ß₁ vs nonselective ß-blockade in human congestive heart failure: acute effects on cardiac sympathetic activity. Circulation. 1995;92(suppl I):I-395. Abstract.
    
45. Gilbert EM, Olsen SL, Renlund DG, Bristow MR. Beta-adrenergic receptor regulation and left ventricular function in idiopathic dilated cardiomyopathy. Am J Cardiol.. 1993;71:23C-29C.[Medline] [Order article via Infotrieve]
    
46. Bristow MR, Olsen S, Gilbert EM, Larrabee PA, Volkman AK, Mealey PC, Ferguson D, While M, Renlund DG, O'Connell JB. ß-Blockade with carvedilol selectively lowers cardiac adrenergic drive in the failing human heart. J Am Coll Cardiol.. 1992;19:146A. Abstract.
    
47. Kaiser P, Hylander B, Eliasson K, Kaijser L. Effect of beta₁-selective and nonselective beta blockade on blood pressure relative to physical performance in men with systemic hypertension. Am J Cardiol.. 1985;55:79D-84D.[Medline] [Order article via Infotrieve]
    
48. Gullestad L, Birkeland K, Nordby G, Larsen S, Kjekshus J. Effects of selective ß₂-adrenoceptor blockade on serum potassium and exercise performance in normal men. Br J Clin Pharmacol.. 1991;32:201-207.[Medline] [Order article via Infotrieve]
    
49. Dhalla AK, Singh N, Singal PK. Antioxidant therapy associated with the reversal of oxidative stress delays the pathogenesis of heart failure. Circulation. 1994;90(suppl I):I-491. Abstract.
    
50. Bril A, Slivjak M, DiMartino MJ, Feuerstein GZ, Linee P, Poyser RH, Ruffolo RR Jr, Smith EF III. Cardioprotective effects of carvedilol, a novel beta adrenoceptor antagonist with vasodilating properties, in anaesthetized minipigs: comparison with propranolol. Cardiovasc Res.. 1992;26:518-525.[Medline] [Order article via Infotrieve]
    

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