- Email: [email protected]
Effectiveness of carvedilol alone versus carvedilol + pimobendan for severe congestive heart failure∗
Effectiveness of Carvedilol Alone Versus Carvedilol ⴙ Pimobendan for Severe Congestive Heart Failure Tsutomu Yoshikawa, MD, Akiyasu Baba, MD, Masahiro Suzuki, MD, Hitoshi Yokozuka, MD, Yutaka Okada, MD, Keiichi Nagami, MD, Tetsuo Takahashi, MD, Hideo Mitamura, MD, and Satoshi Ogawa, MD, for the Keio Interhospital Cardiology Study (KICS) Group* imobendan is a new inotropic agent with phosphodiesterase-inhibiting and calcium-sensitizing P effects that increase contractility with minimal increase in oxygen consumption.1–5 We hypothesized that short-term administration of pimobendan in the early phase of -blocker therapy would be beneficial in alleviating exacerbation of congestive heart failure (CHF) resulting in withdrawal for patients with severe CHF. The present study investigated the effects of short-term coadministration of pimobendan during introduction of carvedilol therapy on the clinical outcome, left ventricular contractile function, and neurohormone and cytokine levels compared with conventional carvedilol therapy in a randomized fashion in patients with severe CHF. •••
For the present study patients with New York Heart Association (NYHA) class III/IV symptomatic CHF who had multiple episodes of decompensated heart failure and a left ventricular ejection fraction of ⬍40% on radionuclide ventriculography or contrast ventriculography were enrolled. They were treated with conventional medical treatment including digitalis glycosides, diuretics, and angiotensin-converting enzyme (ACE) inhibitors. Exclusion criteria included a heart rate of ⬍50 beats/min, systolic blood pressure of ⬍90 mm Hg, significant bradyarrhythmias or atrioventricular block, serum creatinine of ⬎3.0 mg/dl, and the presence of stenotic valvular heart disease, alcohol abuse, active myocarditis, or hypertrophic obstructive cardiomyopathy. Plasma creatinine phosphokinase level determination and scintigraphic assessment were performed to exclude myocarditis in the absence of biopsy samples. The study protocol was approved by an institutional review committee, and informed consent was obtained from all patients who participated in the study. Thirty patients were randomly assigned to the conventional -blocker group or the combination group. The conventional group received carvedilol 2.5 mg/ day, titrated up to 20 mg/day over 12 weeks. The combination group received pimobendan 2.5 mg/day From the Cardiology Division, Department of Medicine, Keio University School of Medicine, Tokyo, Japan. Dr. Yoshikawa’s address is: Cardiology Division, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan 160 – 8582. E-mail: [email protected]. Manuscript received September 17, 1999; revised manuscript received and accepted December 17, 1999. *Members in the KICS study are listed in the Appendix. ©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 85 June 15, 2000
for at least 1 month besides carvedilol. Pimobendan was withdrawn while carvedilol was continued to complete 12 weeks of treatment in both groups. Before administration of a  blocker, NYHA functional class, heart rate, and blood pressure were determined, and serially repeated at 4 and 12 weeks of treatment with the  blocker. Chest x-ray, 12-lead electrocardiography, ultrasonic echocardiography, 24hour Holter monitoring, and radionuclide ventriculography were performed before and after 12 weeks treatment with a  blocker. Plasma neurohormones including norepinephrine, epinephrine, dopamine, renin, angiotensin II, aldosterone, arginine-vasopressin, atrial natriuretic peptide, brain natriuretic peptide, endothelin-1, adrenomedullin, tumor necrosis factor-␣, interleukin-6, and interferon-␥ were determined before and after 4 weeks of treatment with the  blocker. Determination of plasma neurohormone levels at 4 weeks was performed under the coadministration of pimobendan in the combination group. The primary end point was defined as worsening of CHF requiring hospitalization, intravenous inotropic agents, and withdrawal of the  blocker or cardiac death during the 12 weeks of treatment. If symptoms stabilized after withdrawal, patients were allowed to cross over to the other protocol. The secondary end point was the state of left ventricular function after 12 weeks of treatment with the  blocker. Differences between groups were assessed using nonpaired 2-tailed t test. A difference in the incidence of withdrawal between groups was analyzed using the chi-square test. Changes within a group were assessed using paired t test. Differences in plasma neurohormones and cytokine changes after introduction of therapy between groups were assessed by analysis of variance followed by Fisher’s least significant difference method. Statistical significance was set at p ⬍0.05. Table I lists baseline characteristics of the study groups. There were no differences in age, duration of illness, occurrence of persistent atrial fibrillation, or left ventricular dimensions on echocardiography. Female gender was more common in the combination group than in the conventional group. The left ventricular ejection fraction measured with radionuclide ventriculography tended to be lower in the combination group than in the conventional group, although statistically insignificant. The conventional group comprised NYHA class III patients exclusively, whereas the combination group comprised 14 patients with NYHA class III and 1 patient with NYHA class 0002-9149/00/$–see front matter PII S0002-9149(00)00803-1
1495
tor-␣ and interferon-␥ were not detectable in most patients. Carvedilol Carvedilol ⫹ Pimobendan Heart rate similarly decreased af(n ⫽ 15) (n ⫽ 15) ter 12 weeks treatment in both the conventional group (from 82 ⫾ 13 to Age (yrs) 58 ⫾ 13 60 ⫾ 11 Men/women 14/1 9/6* 67 ⫾ 11 beats/min, p ⬍0.05) and the NYHA class (III/IV) 15/0 14/1 combination group (from 85 ⫾ 16 to Nonischemic/ischemic 13/2 10/5 72 ⫾ 6 beats/min, p ⬍0.05). CoadAtrial fibrillation 27% 20% ministration of pimobendan during Duration of illness (mo) 57 ⫾ 62 55 ⫾ 53 End-diastolic dimension (cm) 6.5 ⫾ 1.0 6.8 ⫾ 1.0 introduction of -blocker therapy End-systolic dimension (cm) 5.8 ⫾ 1.1 6.0 ⫾ 1.0 ranged from 4 to 12 weeks (mean Ejection fraction (%)† 21 ⫾ 8 16 ⫾ 8 5 ⫾ 2). Three patients were withPulmonary wedge pressure (mm Hg) 14 ⫾ 6 15 ⫾ 8 2 drawn from treatment due to worsCardiac index (L/min/m ) 2.4 ⫾ 0.5 2.3 ⫾ 0.8 ening of CHF during the 12 weeks of End-diastolic volume (ml/m2) 179 ⫾ 35 157 ⫾ 60 Ejection fraction (%)‡ 23 ⫾ 10 28 ⫾ 13 treatment with the  blocker in the Coronary angiography 73% 80% conventional -blocker group. Two Endomyocardial biopsy 33% 33% of them were withdrawn during the *p ⬍0.05. first 4 weeks of treatment. One of † Measured with radionuclide ventriculography. them experienced severe pump fail‡ Measured with contrast left ventriculography, which does not necessarily reflect that of study entry. ure after 20 days of treatment, resulting in multiorgan failure and death. The other patient was withdrawn because of exacerbated CHF after 7 days of treatment, TABLE II Medications Concomitantly Used During but the condition stabilized under intensive medical Study Period management. The patient was crossed over to the Carvedilol ⫹ combination group, and heart failure never worsened Carvedilol Pimobendan during the subsequent 12 weeks. In the remaining (n ⫽ 15) (n ⫽ 15) patient, crossover to the other protocol was not done Digitalis glycosides 60% 60% because of patient’s refusal. One patient was lost to Diuretics 93% 80% follow-up during the first 4 weeks of treatment. In the ACE inhibitors 80% 80% combination group, no patient experienced worsening Calcium channel blockers 13% 33% of CHF during the 12 weeks of treatment. The primary Nitrates 20% 40% Anticoagulants 47% 47% end point defined as withdrawal from the protocol due Antiplatelets 47% 33% to worsening of CHF or cardiac death during the first Antiarrhythmics 33% 20% 12 weeks of treatment tended to be lower in the combination group than in the conventional group (0% vs 21%, p ⫽ 0.058). IV. There was no difference in the etiology between The end-diastolic dimension did not change in the 2 groups, although ischemic etiology tended to be either group during the 12 weeks of treatment (conmore common in the combination group. There was ventional group, from 6.6 ⫾ 1.1 to 6.5 ⫾ 1.1 cm; no difference in cardiac catheterization parameters combination group, from 7.0 ⫾ 1.1 to 6.8 ⫾ 1.2 cm). including pulmonary capillary wedge pressure, cardiac output, left ventricular end-diastolic volume, and However, end-systolic dimension decreased in both ejection fraction. Coronary angiography was per- the conventional (from 5.9 ⫾ 1.2 to 5.3 ⫾ 1.2 cm) and formed in 73% and 80% of patients, respectively. combination (from 6.2 ⫾ 1.1 to 5.6 ⫾ 1.0 cm) groups. Endomyocardial biopsy was performed in approxi- Left ventricular ejection fraction, as measured by radionuclide ventriculography, increased in both groups mately one third of the patients. Table II lists medications concomitantly adminis- (conventional group, from 22 ⫾ 8% to 28 ⫾ 10%; tered during the study period. Digitalis glycosides combination group, from 17 ⫾ 12% to 27 ⫾ 16%). Plasma endothelin-1 levels decreased from 3.81 ⫾ were given to 60% of patients in both groups. Diuret1.22 to 3.09 ⫾ 0.85 pg/ml in the combination group (p ics were given to ⬎80%, and ACE inhibitors to 80% of patients. Four patients in each group could not ⬍0.05), but there was no significant change in the tolerate ACE inhibitors because of adverse reactions conventional group (from 3.18 ⫾ 1.08 to 2.84 ⫾ 1.15 including cough and hypotension. There was no dif- pg/ml). Plasma interleukin-6 levels decreased from ference in the percentage of patients administered 3.9 ⫾ 3.2 to 2.2 ⫾ 1.4 pg/ml in the combination group (p ⬍0.05), but no change was observed in the conother medications. Table III shows the plasma concentration of vari- ventional group (from 3.5 ⫾ 2.9 to 7.7 ⫾ 12.4 pg/ml). ous neurohormones and cytokines at baseline. Plasma There were no significant changes in plasma norepinorepinephrine tended to be higher in the combination nephrine, epinephrine, dopamine, renin, angiotensin group than in the conventional group, although statis- II, arginine-vasopressin, atrial natriuretic peptide, tically insignificant. There was no difference in other brain natriuretic peptide, or adrenomedullin levels. neurohormones and cytokines. Tumor necrosis fac- However, plasma aldosterone level tended to decrease TABLE I Baseline Characteristics of Study Group
1496 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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TABLE III Neurohormones and Cytokines Carvedilol Norepinephrine (pg/ml) Epinephrine (pg/ml) Dopamine (pg/ml) Renin (pg/ml) Angiotensin II (pg/ml) Aldosterone (pg/ml) Arginine-vasopressin (pg/ml) Atrial natriuretic peptide (pg/ml) Brain natriuretic peptide (pg/ml) Endothelin-1 (pg/ml) Adrenomedullin (fmol/ml) Interleukin-6 (pg/ml)
567 37 19 143 37 136 3.6 151 533 3.51 19.5 5.6
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
Carvedilol ⫹ Pimobendan
397 26 16 159 63 86 3.9 126 477 1.42 11.3 6.4
in the combination group (173 ⫾ 167 to 119 ⫾ 86 pg/ml), but not in the conventional group. •••
Beta-blocker therapy is now an established regimen in addition to the standard triple therapies including digitalis glycosides, diuretics, and ACE inhibitors for patients with CHF.6 –10 Use of  blockers is well tolerated by patients with mild to moderate CHF, but not by a considerable number of patients with severe CHF.11–13 There is a dose-related decrease in mortality and improvement in left ventricular function in patients treated with  blockers.14,15 However, it is difficult to up-titrate in patients with severe CHF in practical medicine. One of the remaining problems is how to introduce -blocker therapy successfully in such patients without causing worsening of CHF. Only 1 study described the addition of an inotropic agent to a  blocker in patients with severe CHF. Shakar et al16 added enoximone, a phosphodiesterase inhibitor, to classic -blocker metoprolol, in 30 patients with NYHA class IV CHF for an average 9 months. Eighty percent of the patients tolerated treatment with metoprolol. Forty-eight percent of the patients were weaned off enoximone over the long term. Left ventricular ejection fraction increased, the NYHA functional class improved, and hospital admissions tended to decrease during therapy. The 1-year survival rate was assumed to be higher for the study group than for the placebo-treated patients with NYHA functional class IV disease in the Prospective Randomized Milrinone Survival Evaluation trial and enalapril-treated patients in the Cooperative North Scandinavian Enalapril Survival Study. However, there were several limitations in the study of Shakar et al: (1) It was a nonrandomized, retrospective study in the absence of control group. (2) Metoprolol was used as a  blocker instead of a third-generation  blocker. (3) There was an absence of neurohormonal data. (4) They administered enoximone for adjunctive therapy. We examined the effects of short-term administration of the inotropic agent pimobendan as -blocker therapy in combination with carvedilol for patients with severe CHF of either ischemic or nonischemic etiology, and found that withdrawal due to worsening of CHF tended to be lower in the combination group than in the conventional group.
727 38 23 37 29 166 2.8 140 460 3.68 29.3 3.7
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
365 44 16 63 30 163 2.3 86 414 1.22 23.0 3.3
Left ventricular function improved in a similar degree in both groups. Plasma endothelin-1 and interleukin-6 levels decreased in the combination group, but not in the conventional group. This mode of therapy may become a new alternative of treatment for patients with severe CHF.
APPENDIX
Members participating in the present study: Tsutomu Yoshikawa, MD, Keiichi Fukuda, MD, PhD, Hideo Mitamura, MD, Satoshi Ogawa, MD, Cardiology Division, Department of Medicine, Keio University School of Medicine, Tokyo; Akiyasu Baba, MD, Kawasaki Ida Municipal Hospital, Kawasaki; Masahiro Suzuki, MD, National Saitama Hospital, Wako; Hitoshi Yokozuka, MD, Ashikaga Red Cross Hospital, Ashikaga; Yutaka Okada, MD, Tokyo Metropolitan Ohtsuka Hospital, Tokyo; Keiichi Nagami, MD, Keiyu Hospital, Yokohama; Koji Negishi, MD and Tetsuo Takahashi, MD, Yokohama Municipal Hospital, Yokohama; Susumu Nakagawa, MD, Saiseikai Central Hospital, Tokyo; Fumiaki Nishimura, MD and Shisei Yoh, MD, National Hospital Tokyo Medical Center, Tokyo; Akira Murayama, MD, Urawa Municipal Hospital, Urawa.
1. Fujino K, Sperelakis N, Solaro RJ. Sensitization of dog and guinea pig heart
myofilaments to Ca2⫹ activation and the inotropic effect of pimobendan: comparison with milrinone. Circ Res 1988;63:911–922. 2. Hasenfuss G, Holubarsch C, Heiss HW, Just H. Influence of UDCG-115 on hemodynamics and myocardial energetics in patients with idiopathic dilated cardiomyopathy. Am Heart J 1989;118:512–519. 3. Bo¨hm M, Morano I, Pieske B, Ruegg JC, Wankerl M, Zimmermann R, Erdmann E. Contribution of cAMP-phosphodiesterase inhibition and sensitization of the contractile proteins for calcium to the inotropic effect of pimobendan in the failing human myocardium. Circ Res 1991;68:689 –701. 4. Remme WJ, Kruijssen DA, van Hoogenhuyze DC, Krauss XH, Bartels GL, Storm CJ, de Leeuw PW. Hemodynamic, neurohumoral, and myocardial energetic effects of pimobendan, a novel calcium-sensitizing compound, in patients with mild to moderate heart failure. J Cardiovasc Pharmacol 1994;24:730 –739. 5. Pagel PS, Hettrick DA, Wartlier DC. Comparison of the effects of levosimendan, pimobendan, and milrinone on canine left ventricular-arterial coupling and mechanical efficiency. Basic Res Cardiol 1996;91:296 –307. 6. The Metoprolol in Dilated Cardiomyopathy Trial Study Group. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Lancet 1993;342: 1441–1446. 7. The Cardiac Insufficiency Bisoprolol Study Investigators. A randomized trial of -blockade in heart failure: the cardiac insufficiency bisoprolol study (CIBIS). Circulation 1994;90:1765–1773. 8. The US Carvedilol Heart Failure Study Group. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996;334:1349 –1355. 9. The Cardiac Insufficiency Bisoprolol Study Investigators. The Cardiac Insufficiency Bisoprolol Study (CIBIS-II). Lancet 1999;353:9 –13. 10. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2110 –7. 11. Krum H, Sackner-Bernstein JD, Goldsmith RL, Kukin ML, Schwartz B, Penn J, Medina N, Yushak M, Horn E, Katz SP, Levin HR, Neuberg GW, DeLong G, Packer M. Double-blind, placebo-controlled study of the long-term efficacy of carvedilol in patients with severe chronic heart failure. Circulation 1995;92: 1499 –1506. 12. The US Carvedilol Heart Failure Study Group. Safety and efficacy of carvedilol in severe heart failure. J Cardiac Failure 1997;3:173–179. 13. Macdonald PS, Keogh AM, Aboyoun CL, Lund M, Amor R, McCaffrey DJ. Tolerability and efficacy of carvedilol in patients with New York Heart Association class IV heart failure. J Am Coll Cardiol 1999;33:924 –931. 14. Bristow MR, O’Connell JB, Gilbert EM, French WJ, Leatherman G, Kantrowitz NE, Orie J, Smucker M, Marshall G, Kelly P, Deitchman D, Anderson J. Dose-response of chronic -blocker treatment in heart failure from either idiopathic or ischemic cardiomyopathy. Circulation 1994;89:1632–1642. 15. Bristow MR, Gilbert EM, Abraham WT, Adams KF, Fowler MB, Hershberger R, Kubo SH, Narahara KA, Ingersoll H, Krueger S, Young S, Shusterman N. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. Circulation 1996;94:2807–2816. 16. Shakar SF, Abraham WT, Gilbert EM, Robertson AD, Lowes BD, Zisman LS, Fergusson DA, Bristow MR. Combined oral positive inotropic and betablocker therapy for treatment of refractory class IV heart failure. J Am Coll Cardiol 1998;31:1336 –1340.
BRIEF REPORTS
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For the present study patients with New York Heart Association (NYHA) class III/IV symptomatic CHF who had multiple episodes of decompensated heart failure and a left ventricular ejection fraction of ⬍40% on radionuclide ventriculography or contrast ventriculography were enrolled. They were treated with conventional medical treatment including digitalis glycosides, diuretics, and angiotensin-converting enzyme (ACE) inhibitors. Exclusion criteria included a heart rate of ⬍50 beats/min, systolic blood pressure of ⬍90 mm Hg, significant bradyarrhythmias or atrioventricular block, serum creatinine of ⬎3.0 mg/dl, and the presence of stenotic valvular heart disease, alcohol abuse, active myocarditis, or hypertrophic obstructive cardiomyopathy. Plasma creatinine phosphokinase level determination and scintigraphic assessment were performed to exclude myocarditis in the absence of biopsy samples. The study protocol was approved by an institutional review committee, and informed consent was obtained from all patients who participated in the study. Thirty patients were randomly assigned to the conventional -blocker group or the combination group. The conventional group received carvedilol 2.5 mg/ day, titrated up to 20 mg/day over 12 weeks. The combination group received pimobendan 2.5 mg/day From the Cardiology Division, Department of Medicine, Keio University School of Medicine, Tokyo, Japan. Dr. Yoshikawa’s address is: Cardiology Division, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan 160 – 8582. E-mail: [email protected]. Manuscript received September 17, 1999; revised manuscript received and accepted December 17, 1999. *Members in the KICS study are listed in the Appendix. ©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 85 June 15, 2000
for at least 1 month besides carvedilol. Pimobendan was withdrawn while carvedilol was continued to complete 12 weeks of treatment in both groups. Before administration of a  blocker, NYHA functional class, heart rate, and blood pressure were determined, and serially repeated at 4 and 12 weeks of treatment with the  blocker. Chest x-ray, 12-lead electrocardiography, ultrasonic echocardiography, 24hour Holter monitoring, and radionuclide ventriculography were performed before and after 12 weeks treatment with a  blocker. Plasma neurohormones including norepinephrine, epinephrine, dopamine, renin, angiotensin II, aldosterone, arginine-vasopressin, atrial natriuretic peptide, brain natriuretic peptide, endothelin-1, adrenomedullin, tumor necrosis factor-␣, interleukin-6, and interferon-␥ were determined before and after 4 weeks of treatment with the  blocker. Determination of plasma neurohormone levels at 4 weeks was performed under the coadministration of pimobendan in the combination group. The primary end point was defined as worsening of CHF requiring hospitalization, intravenous inotropic agents, and withdrawal of the  blocker or cardiac death during the 12 weeks of treatment. If symptoms stabilized after withdrawal, patients were allowed to cross over to the other protocol. The secondary end point was the state of left ventricular function after 12 weeks of treatment with the  blocker. Differences between groups were assessed using nonpaired 2-tailed t test. A difference in the incidence of withdrawal between groups was analyzed using the chi-square test. Changes within a group were assessed using paired t test. Differences in plasma neurohormones and cytokine changes after introduction of therapy between groups were assessed by analysis of variance followed by Fisher’s least significant difference method. Statistical significance was set at p ⬍0.05. Table I lists baseline characteristics of the study groups. There were no differences in age, duration of illness, occurrence of persistent atrial fibrillation, or left ventricular dimensions on echocardiography. Female gender was more common in the combination group than in the conventional group. The left ventricular ejection fraction measured with radionuclide ventriculography tended to be lower in the combination group than in the conventional group, although statistically insignificant. The conventional group comprised NYHA class III patients exclusively, whereas the combination group comprised 14 patients with NYHA class III and 1 patient with NYHA class 0002-9149/00/$–see front matter PII S0002-9149(00)00803-1
1495
tor-␣ and interferon-␥ were not detectable in most patients. Carvedilol Carvedilol ⫹ Pimobendan Heart rate similarly decreased af(n ⫽ 15) (n ⫽ 15) ter 12 weeks treatment in both the conventional group (from 82 ⫾ 13 to Age (yrs) 58 ⫾ 13 60 ⫾ 11 Men/women 14/1 9/6* 67 ⫾ 11 beats/min, p ⬍0.05) and the NYHA class (III/IV) 15/0 14/1 combination group (from 85 ⫾ 16 to Nonischemic/ischemic 13/2 10/5 72 ⫾ 6 beats/min, p ⬍0.05). CoadAtrial fibrillation 27% 20% ministration of pimobendan during Duration of illness (mo) 57 ⫾ 62 55 ⫾ 53 End-diastolic dimension (cm) 6.5 ⫾ 1.0 6.8 ⫾ 1.0 introduction of -blocker therapy End-systolic dimension (cm) 5.8 ⫾ 1.1 6.0 ⫾ 1.0 ranged from 4 to 12 weeks (mean Ejection fraction (%)† 21 ⫾ 8 16 ⫾ 8 5 ⫾ 2). Three patients were withPulmonary wedge pressure (mm Hg) 14 ⫾ 6 15 ⫾ 8 2 drawn from treatment due to worsCardiac index (L/min/m ) 2.4 ⫾ 0.5 2.3 ⫾ 0.8 ening of CHF during the 12 weeks of End-diastolic volume (ml/m2) 179 ⫾ 35 157 ⫾ 60 Ejection fraction (%)‡ 23 ⫾ 10 28 ⫾ 13 treatment with the  blocker in the Coronary angiography 73% 80% conventional -blocker group. Two Endomyocardial biopsy 33% 33% of them were withdrawn during the *p ⬍0.05. first 4 weeks of treatment. One of † Measured with radionuclide ventriculography. them experienced severe pump fail‡ Measured with contrast left ventriculography, which does not necessarily reflect that of study entry. ure after 20 days of treatment, resulting in multiorgan failure and death. The other patient was withdrawn because of exacerbated CHF after 7 days of treatment, TABLE II Medications Concomitantly Used During but the condition stabilized under intensive medical Study Period management. The patient was crossed over to the Carvedilol ⫹ combination group, and heart failure never worsened Carvedilol Pimobendan during the subsequent 12 weeks. In the remaining (n ⫽ 15) (n ⫽ 15) patient, crossover to the other protocol was not done Digitalis glycosides 60% 60% because of patient’s refusal. One patient was lost to Diuretics 93% 80% follow-up during the first 4 weeks of treatment. In the ACE inhibitors 80% 80% combination group, no patient experienced worsening Calcium channel blockers 13% 33% of CHF during the 12 weeks of treatment. The primary Nitrates 20% 40% Anticoagulants 47% 47% end point defined as withdrawal from the protocol due Antiplatelets 47% 33% to worsening of CHF or cardiac death during the first Antiarrhythmics 33% 20% 12 weeks of treatment tended to be lower in the combination group than in the conventional group (0% vs 21%, p ⫽ 0.058). IV. There was no difference in the etiology between The end-diastolic dimension did not change in the 2 groups, although ischemic etiology tended to be either group during the 12 weeks of treatment (conmore common in the combination group. There was ventional group, from 6.6 ⫾ 1.1 to 6.5 ⫾ 1.1 cm; no difference in cardiac catheterization parameters combination group, from 7.0 ⫾ 1.1 to 6.8 ⫾ 1.2 cm). including pulmonary capillary wedge pressure, cardiac output, left ventricular end-diastolic volume, and However, end-systolic dimension decreased in both ejection fraction. Coronary angiography was per- the conventional (from 5.9 ⫾ 1.2 to 5.3 ⫾ 1.2 cm) and formed in 73% and 80% of patients, respectively. combination (from 6.2 ⫾ 1.1 to 5.6 ⫾ 1.0 cm) groups. Endomyocardial biopsy was performed in approxi- Left ventricular ejection fraction, as measured by radionuclide ventriculography, increased in both groups mately one third of the patients. Table II lists medications concomitantly adminis- (conventional group, from 22 ⫾ 8% to 28 ⫾ 10%; tered during the study period. Digitalis glycosides combination group, from 17 ⫾ 12% to 27 ⫾ 16%). Plasma endothelin-1 levels decreased from 3.81 ⫾ were given to 60% of patients in both groups. Diuret1.22 to 3.09 ⫾ 0.85 pg/ml in the combination group (p ics were given to ⬎80%, and ACE inhibitors to 80% of patients. Four patients in each group could not ⬍0.05), but there was no significant change in the tolerate ACE inhibitors because of adverse reactions conventional group (from 3.18 ⫾ 1.08 to 2.84 ⫾ 1.15 including cough and hypotension. There was no dif- pg/ml). Plasma interleukin-6 levels decreased from ference in the percentage of patients administered 3.9 ⫾ 3.2 to 2.2 ⫾ 1.4 pg/ml in the combination group (p ⬍0.05), but no change was observed in the conother medications. Table III shows the plasma concentration of vari- ventional group (from 3.5 ⫾ 2.9 to 7.7 ⫾ 12.4 pg/ml). ous neurohormones and cytokines at baseline. Plasma There were no significant changes in plasma norepinorepinephrine tended to be higher in the combination nephrine, epinephrine, dopamine, renin, angiotensin group than in the conventional group, although statis- II, arginine-vasopressin, atrial natriuretic peptide, tically insignificant. There was no difference in other brain natriuretic peptide, or adrenomedullin levels. neurohormones and cytokines. Tumor necrosis fac- However, plasma aldosterone level tended to decrease TABLE I Baseline Characteristics of Study Group
1496 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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TABLE III Neurohormones and Cytokines Carvedilol Norepinephrine (pg/ml) Epinephrine (pg/ml) Dopamine (pg/ml) Renin (pg/ml) Angiotensin II (pg/ml) Aldosterone (pg/ml) Arginine-vasopressin (pg/ml) Atrial natriuretic peptide (pg/ml) Brain natriuretic peptide (pg/ml) Endothelin-1 (pg/ml) Adrenomedullin (fmol/ml) Interleukin-6 (pg/ml)
567 37 19 143 37 136 3.6 151 533 3.51 19.5 5.6
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
Carvedilol ⫹ Pimobendan
397 26 16 159 63 86 3.9 126 477 1.42 11.3 6.4
in the combination group (173 ⫾ 167 to 119 ⫾ 86 pg/ml), but not in the conventional group. •••
Beta-blocker therapy is now an established regimen in addition to the standard triple therapies including digitalis glycosides, diuretics, and ACE inhibitors for patients with CHF.6 –10 Use of  blockers is well tolerated by patients with mild to moderate CHF, but not by a considerable number of patients with severe CHF.11–13 There is a dose-related decrease in mortality and improvement in left ventricular function in patients treated with  blockers.14,15 However, it is difficult to up-titrate in patients with severe CHF in practical medicine. One of the remaining problems is how to introduce -blocker therapy successfully in such patients without causing worsening of CHF. Only 1 study described the addition of an inotropic agent to a  blocker in patients with severe CHF. Shakar et al16 added enoximone, a phosphodiesterase inhibitor, to classic -blocker metoprolol, in 30 patients with NYHA class IV CHF for an average 9 months. Eighty percent of the patients tolerated treatment with metoprolol. Forty-eight percent of the patients were weaned off enoximone over the long term. Left ventricular ejection fraction increased, the NYHA functional class improved, and hospital admissions tended to decrease during therapy. The 1-year survival rate was assumed to be higher for the study group than for the placebo-treated patients with NYHA functional class IV disease in the Prospective Randomized Milrinone Survival Evaluation trial and enalapril-treated patients in the Cooperative North Scandinavian Enalapril Survival Study. However, there were several limitations in the study of Shakar et al: (1) It was a nonrandomized, retrospective study in the absence of control group. (2) Metoprolol was used as a  blocker instead of a third-generation  blocker. (3) There was an absence of neurohormonal data. (4) They administered enoximone for adjunctive therapy. We examined the effects of short-term administration of the inotropic agent pimobendan as -blocker therapy in combination with carvedilol for patients with severe CHF of either ischemic or nonischemic etiology, and found that withdrawal due to worsening of CHF tended to be lower in the combination group than in the conventional group.
727 38 23 37 29 166 2.8 140 460 3.68 29.3 3.7
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
365 44 16 63 30 163 2.3 86 414 1.22 23.0 3.3
Left ventricular function improved in a similar degree in both groups. Plasma endothelin-1 and interleukin-6 levels decreased in the combination group, but not in the conventional group. This mode of therapy may become a new alternative of treatment for patients with severe CHF.
APPENDIX
Members participating in the present study: Tsutomu Yoshikawa, MD, Keiichi Fukuda, MD, PhD, Hideo Mitamura, MD, Satoshi Ogawa, MD, Cardiology Division, Department of Medicine, Keio University School of Medicine, Tokyo; Akiyasu Baba, MD, Kawasaki Ida Municipal Hospital, Kawasaki; Masahiro Suzuki, MD, National Saitama Hospital, Wako; Hitoshi Yokozuka, MD, Ashikaga Red Cross Hospital, Ashikaga; Yutaka Okada, MD, Tokyo Metropolitan Ohtsuka Hospital, Tokyo; Keiichi Nagami, MD, Keiyu Hospital, Yokohama; Koji Negishi, MD and Tetsuo Takahashi, MD, Yokohama Municipal Hospital, Yokohama; Susumu Nakagawa, MD, Saiseikai Central Hospital, Tokyo; Fumiaki Nishimura, MD and Shisei Yoh, MD, National Hospital Tokyo Medical Center, Tokyo; Akira Murayama, MD, Urawa Municipal Hospital, Urawa.
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