Double-blind, placebo-controlled study of the long-term efficacy of carvedilol in patients with severe chronic heart failure

H. Krum, J. D. Sackner-Bernstein, R. L. Goldsmith, M. L. Kukin, B. Schwartz, J. Penn, N. Medina, M. Yushak, E. Horn, S. D. Katz, H. R. Levin, G. W. Neuberg, G. DeLong, M. Packer

Research output: Contribution to journalArticle

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Abstract

Background: Clinical trials have shown that β-adrenergic blocking drugs are effective and well tolerated in patients with mild to moderate heart failure, but the utility and safety of these drugs in patients with advanced disease have not been evaluated. Methods and Results: We enrolled 56 patients with severe chronic heart failure into a double-blind, placebo-controlled study of the vasodilating β-blocker carvedilol. All patients had advanced heart failure, as evidenced by a mean left ventricular ejection fraction of 0.16±0.01 and a mean maximal oxygen consumption of 13.6±0.6 mL · kg-1 · min-1 despite digitalis, diuretics, and an angiotensin-converting enzyme inhibitor (if tolerated). After a 3-week, open-label, up-titration period, 49 of the 56 patients were assigned (in a double-blind fashion using a 2:1 randomization) to receive either carvedilol (25 mg BID, n=33) or matching placebo (n=16) for 14 weeks, while background therapy remained constant. Hemodynamic and functional variables were measured at the start and end of the study. Compared with the placebo group, patients in the carvedilol group showed improved cardiac performance, as reflected by an increase in left ventricular ejection fraction (P=.005) and stroke volume index (P=.010) and a decrease in pulmonary wedge pressure, mean right atrial pressure, and systemic vascular resistance (P=.003, .002, and .017, respectively). In addition, compared with placebo, patients treated with carvedilol benefited clinically, as shown by an improvement in symptom scores (P=.002), functional class (P=.013), and submaximal exercise tolerance (P=.006). The combined risk of death, worsening heart failure, and life-threatening ventricular tachyarrhythmia was lower in the carvedilol group than in the placebo group (P=.028), but carvedilol-treated patients had more dizziness and advanced heart block. Conclusions: Carvedilol produces clinical and hemodynamic improvement in patients who have severe heart failure despite treatment with angiotensin-converting enzyme inhibitors.

Original languageEnglish (US)
Pages (from-to)1499-1506
Number of pages8
JournalCirculation
Volume92
Issue number6
StatePublished - 1995

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Heart Failure
Placebos
Stroke Volume
Angiotensin-Converting Enzyme Inhibitors
Hemodynamics
carvedilol
Pulmonary Wedge Pressure
Heart Block
Atrial Pressure
Exercise Tolerance
Digitalis
Dizziness
Random Allocation
Diuretics
Tachycardia
Oxygen Consumption
Vascular Resistance
Adrenergic Agents
Clinical Trials
Safety

Keywords

  • carvedilol
  • heart failure
  • receptors, adrenergic, beta

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Krum, H., Sackner-Bernstein, J. D., Goldsmith, R. L., Kukin, M. L., Schwartz, B., Penn, J., ... Packer, M. (1995). Double-blind, placebo-controlled study of the long-term efficacy of carvedilol in patients with severe chronic heart failure. Circulation, 92(6), 1499-1506.

Double-blind, placebo-controlled study of the long-term efficacy of carvedilol in patients with severe chronic heart failure. / Krum, H.; Sackner-Bernstein, J. D.; Goldsmith, R. L.; Kukin, M. L.; Schwartz, B.; Penn, J.; Medina, N.; Yushak, M.; Horn, E.; Katz, S. D.; Levin, H. R.; Neuberg, G. W.; DeLong, G.; Packer, M.

In: Circulation, Vol. 92, No. 6, 1995, p. 1499-1506.

Research output: Contribution to journalArticle

Krum, H, Sackner-Bernstein, JD, Goldsmith, RL, Kukin, ML, Schwartz, B, Penn, J, Medina, N, Yushak, M, Horn, E, Katz, SD, Levin, HR, Neuberg, GW, DeLong, G & Packer, M 1995, 'Double-blind, placebo-controlled study of the long-term efficacy of carvedilol in patients with severe chronic heart failure', Circulation, vol. 92, no. 6, pp. 1499-1506.
Krum H, Sackner-Bernstein JD, Goldsmith RL, Kukin ML, Schwartz B, Penn J et al. Double-blind, placebo-controlled study of the long-term efficacy of carvedilol in patients with severe chronic heart failure. Circulation. 1995;92(6):1499-1506.
Krum, H. ; Sackner-Bernstein, J. D. ; Goldsmith, R. L. ; Kukin, M. L. ; Schwartz, B. ; Penn, J. ; Medina, N. ; Yushak, M. ; Horn, E. ; Katz, S. D. ; Levin, H. R. ; Neuberg, G. W. ; DeLong, G. ; Packer, M. / Double-blind, placebo-controlled study of the long-term efficacy of carvedilol in patients with severe chronic heart failure. In: Circulation. 1995 ; Vol. 92, No. 6. pp. 1499-1506.
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AU - Krum, H.

AU - Sackner-Bernstein, J. D.

AU - Goldsmith, R. L.

AU - Kukin, M. L.

AU - Schwartz, B.

AU - Penn, J.

AU - Medina, N.

AU - Yushak, M.

AU - Horn, E.

AU - Katz, S. D.

AU - Levin, H. R.

AU - Neuberg, G. W.

AU - DeLong, G.

AU - Packer, M.

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N2 - Background: Clinical trials have shown that β-adrenergic blocking drugs are effective and well tolerated in patients with mild to moderate heart failure, but the utility and safety of these drugs in patients with advanced disease have not been evaluated. Methods and Results: We enrolled 56 patients with severe chronic heart failure into a double-blind, placebo-controlled study of the vasodilating β-blocker carvedilol. All patients had advanced heart failure, as evidenced by a mean left ventricular ejection fraction of 0.16±0.01 and a mean maximal oxygen consumption of 13.6±0.6 mL · kg-1 · min-1 despite digitalis, diuretics, and an angiotensin-converting enzyme inhibitor (if tolerated). After a 3-week, open-label, up-titration period, 49 of the 56 patients were assigned (in a double-blind fashion using a 2:1 randomization) to receive either carvedilol (25 mg BID, n=33) or matching placebo (n=16) for 14 weeks, while background therapy remained constant. Hemodynamic and functional variables were measured at the start and end of the study. Compared with the placebo group, patients in the carvedilol group showed improved cardiac performance, as reflected by an increase in left ventricular ejection fraction (P=.005) and stroke volume index (P=.010) and a decrease in pulmonary wedge pressure, mean right atrial pressure, and systemic vascular resistance (P=.003, .002, and .017, respectively). In addition, compared with placebo, patients treated with carvedilol benefited clinically, as shown by an improvement in symptom scores (P=.002), functional class (P=.013), and submaximal exercise tolerance (P=.006). The combined risk of death, worsening heart failure, and life-threatening ventricular tachyarrhythmia was lower in the carvedilol group than in the placebo group (P=.028), but carvedilol-treated patients had more dizziness and advanced heart block. Conclusions: Carvedilol produces clinical and hemodynamic improvement in patients who have severe heart failure despite treatment with angiotensin-converting enzyme inhibitors.

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