(Circulation. 1996;94:346-352.)
© 1996 American Heart Association, Inc.
Articles |
Diltiazem Improves Cardiac Function and Exercise Capacity in Patients With Idiopathic Dilated Cardiomyopathy
Results of the Diltiazem in Dilated Cardiomyopathy Trial
the Department of Cardiology and Pulmonology, Universitats-Kliniken, Gottingen, Germany (H.R.F., R.S.); the Department of Cardiology, Stadtische Kliniken, Bielefeld, Germany (F.G., J.H.); the Department of Cardiology, Stadtische Kliniken, Kassel, Germany (U.Z.); Medizinische Klinik, Marien Hospital, Wesel, Germany (M.R.); and Abteilung Medizinische Statistik, University of Gottingen (R.H.).
Correspondence to Prof Dr Hans R. Figulla, Abteilung Kardiologie und Pulmonologie, Medizinische Universitatsklinik, Robert-Koch-Str 40, D-37075 Gottingen, Germany.
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Abstract |
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Background Evidence is arising that calcium antagonists in idiopathic dilated cardiomyopathy (IDC) may have beneficial effects on virus-induced cardiopathology, alcohol toxicity, microcirculatory disorders, and impaired calcium cycling, all possibly involved in the pathogenesis of the disease. Thus, the effect of adjunct diltiazem (60 to 90 mg TID) on standard treatment was investigated.
Methods and Results The Diltiazem in Dilated Cardiomyopathy (DiDi) trial was a randomized, double-blind, placebo-controlled, multicenter trial of 186 patients (92 receiving diltiazem, 94 receiving placebo) with IDC diagnosed by coronary angiography, catheterization of the left side of the heart, and a left ventricular ejection fraction of <0.50 (mean, 0.34±0.11). The effect of adjunct diltiazem treatment on transplant listing–free survival, hemodynamics, exercise capacity, and subjective status was investigated. During the 24-month study period, 33 patients dropped out of the study; 153 patients finished the study protocol. Twenty-seven patients died or had a listing for heart transplantation: 16 in the placebo group and 11 in the diltiazem group. The transplant listing–free survival rate was 85% for diltiazem and 80% for placebo recipients (P=.444). After 24 months, only diltiazem significantly increased cardiac index at rest (P=.01) and under a workload (P=.02), systolic and diastolic pressures (P=.003 and P=.004), stroke volume index (P=.003), and stroke work index (P=.000) and decreased both pulmonary artery pressure under workload (P=.007) and heart rate (P=.001). Diltiazem also increased exercise capacity (P=.002) and subjective well-being (P=.01). Adverse reactions were minor and evenly distributed in both groups, except for an increase in the PQ interval in the diltiazem group.
Conclusions In patients with IDC, the adjunct therapy of diltiazem improves cardiac function, exercise capacity, and subjective status without deleterious effects on transplant listing–free survival.
Key Words: calcium channels • heart failure • heart rate • transplantation • trials
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Introduction |
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Human IDC is a heterogeneous disease with variable hemodynamic course.1 The pathogenetic mechanisms involved in the disease initiation and progression are unknown. Genetic disorders of the dystrophin gene,2 virus infection,3 extended alcohol toxicity,4 microcirculation disorders,5 and impaired Ca2+ cycling are common findings in human and various animal models of IDC6 7 in contrast to secondary forms of myocardial dysfunction such as ischemic or pressure- or volume-induced heart failure.
Various first-generation calcium antagonists have been shown not to improve survival, hemodynamics, or clinical complaints in secondary heart failure.8 However, evidence is arising that calcium antagonists may have a beneficial effect in IDC on virus-induced cardiopathology,9 alcohol toxicity,10 microcirculatory disorders,11 12 and impaired calcium cycling.13 14 Some years ago, therefore, we performed a small uncontrolled trial to investigate the long-term effect of the calcium antagonist diltiazem on a subset of IDC patients. That trial demonstrated beneficial effects.15 However, to determine whether the therapeutic use of diltiazem in adjunct to conventional therapy improves transplant indication–free survival, hemodynamics, and well-being in a general group of IDC patients, a placebo-controlled, double-blind, prospective trial was performed, the results of which are presented here.
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Methods |
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Study Design and Entry Criteria
The DiDi trial was a randomized, double-blind, placebo-controlled, multicenter trial created to evaluate the effect of diltiazem in IDC patients who had achieved a state of compensated heart failure by means of conventional heart failure treatment (ACE inhibitors, digitalis, diuretics, or nitrates). The primary end point of this trial was to determine major events such as mortality and the listing for heart transplantation during the 2-year study period. The secondary end point was to determine cardiac function, exercise capacity, and clinical complaints.
To achieve a study power of 80%, we estimated that 184 patients (92 receiving placebo and 92 receiving diltiazem) would be required to demonstrate a significant reduction (
<0.05, two-sided log rank test). The assumption was that the 2-year event rate (mortality and transplant listing) would be reduced from 24% to 8% according to the results of a pilot trial.15
The study was carried out in 11 centers in Germany. The protocol was approved by the Institutional Ethical Review Board of the University Hospital of Gottingen and the Institutional Review boards of each center. All patients gave written, informed consent.
According to the definition of the World Health Organization–International Society and Federation of Cardiology, IDC is a heart muscle disease with predominant impairment of the systolic function of unknown origin.16
Men and women between 18 and 70 years of age were included in the study if IDC had been diagnosed within the last 6 months and LVEF was <0.50, independent of the patient's symptomatic status. Patients were excluded from the trial if they demonstrated one or more of the following parameters: a history of hypertension or hypertension on clinical examination (systolic pressure of >160 mm Hg and/or diastolic pressure of >95 mm Hg measured with the patient in a sitting position at three subsequent examinations); a valvular or congenital heart disease, except for first- or second-degree mitral or tricuspid regurgitation by ventriculography; clinical or histological signs of ongoing myocarditis; concomitant coronary artery disease diagnosed by evidence of any coronary stenosis 
50%; insulin-dependent diabetes mellitus; systemic diseases such as collagenosis, malignancies, thyroid diseases, and pheochromocytoma; pregnancy; severe liver or kidney disease; alcohol or drug dependency; multimorbidity; foreseeable noncompliance with treatment regimens; participation in another trial; previous treatment with any calcium antagonist or ß-blocker agent for more than 3 months; second- or third-degree AV block; or no written, informed consent.
The following diagnostic procedures were performed before entry into the trial: catheterization of the left side of the heart with coronary angiography; pulmonary artery catheterization at rest and under supine ergometry; 24-hour Holter ECG monitoring for the determination of the incidence of ventricular ectopic beats; ECG at rest; 2D echocardiography; clinical examination; standard laboratory tests, including norepinephrine determination in plasma after 30 minutes of rest; and chest roentgenogram for the determination of cardiaothoracic ratio. Facultative procedures were equilibrium-gated blood-pool scintigraphy for the determination of LVEF, LV endomyocardial biopsy, and ergospirometry for the determination of maximal oxygen consumption.
Treatment Protocol
After entry into the trial, patients received the study medication consisting of either placebo or diltiazem tablets in a double-blind fashion. The concomitant medication was prescribed according to patient's needs; however, the patient and his or her physician were informed that prescription of any calcium blocker agent or ß-blocker agent was not allowed. Study medication was provided as 60-mg tablets (Godecke Parke Davis AG). Randomization was performed in blocks of 10 patients for each center.
Treatment began with 30 mg TID on days 1 and 2 and 60 mg TID on days 3 and 4; patients weighing >50 kg also received 90 mg TID on day 5 and afterward. Patients weighing 
50 kg at entry were treated with 60 mg diltiazem TID. Enough medication for 6 months was given to the patients. The trial began in March 1989, and randomization ended after inclusion of 186 patients in May 1992. Follow-up ended in May 1994.
Follow-up Examinations
Follow-up examinations under medication were performed at 6-month intervals for 24 months. The patients were seen in the outpatient clinic of their respective centers. The following procedures were performed every 6 months: ECG at rest; 2D echocardiography; physical examination; standard laboratory tests, including determination of norepinephrine; and a questionnaire, including determination of the Karnofsky scale (eg, 100=normal, no complaints, and no evidence of disease; 70=unable to work, able to live at home, and can care for most personal needs with some assistance; 40=unable to care for personal needs and requires institutional or hospital care; and 0=dead).
At yearly intervals, pulmonary artery catheterization at rest and under supine workload also was performed. Workload consisted of bicycle ergometry in the supine position that was increased by 25 W every 5 minutes until the patient experienced fatigue. Measurements were made between the third and fifth minutes of each increment. In addition, 24-hour Holter monitoring, chest roentgenograms, and facultative measurements such as gated blood-pool scanning and ergospirometry were performed.
The patients remained in the trial for 24 months, after which the study medication was discontinued. All patients were encouraged to avoid alcohol and drug abuse during the study period. Critical events such as death, indication for heart transplantation, deterioration to NYHA functional class IV despite intensified therapy for 1 week, and pacemaker implantation were reported to the study's Steering Committee immediately. The listing for heart transplantation was defined as the point at which patients were put on a heart transplantation waiting list. Heart transplantation was considered to be indicated when the patient's condition became unstable as a result of recurrent heart failure into NYHA class IV or unstable rhythm disturbances in combination with deterioration of LVEF <0.20 and/or the patient's subjective state becoming intolerable. The decision for heart transplantation was made by the center that included the patient in the trial.
The patient's condition was classified by a panel to be improved, unchanged, or deteriorated on the basis of a combination of NYHA classification, Karnofsky scale, and the patient's subjective well-being. All classifications and indications for heart transplantation were made without knowledge of the patients' allocation to treatment regimen; allocation to treatment is still unknown to any physicians involved in the treatment of these patients.
Statistical Analysis
Intergroup comparisons for data on an ordinal scale were done with the Wilcoxon rank sum test from the NPAR1WAY procedure under SAS 6.08. Intraindividual comparisons were done with the Wilcoxon signed rank sum test from SAS 6.08 UNIVARIATE procedure. Data analyses were performed on an intent-to-treat basis for all randomized patients.
For lifetime data, the Peto-Peto-Wilcoxon scores, which correspond to the Kaplan-Meier estimator, were used. Thus, the Peto-Peto-Wilcoxon test from Statistica version 4.5/MS-Windows was used. For these tests, the probability values provided had to be doubled because those given by the program are only one-sided. Calculations for intergroup comparisons of categorical outcomes were done with StatXact 2.1/MS DOS for exact permutation tests or the signed rank test according to Dixon and Mood. CIs for odds ratios were calculated with StatXact 2.1/MS DOS. All probability values were calculated two-sided.
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Results |
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Study Population
From March 1989 to May 1992, 186 patients were enrolled from 11 centers. Four centers enrolled 80% of the patients (150). These centers screened 638 patients; the eligibility rate was 24%. Reasons for exclusion were (in the order of incidence) hypertension, LVEF
0.50, age, noncompliance, refusal to participate, myocarditis, and alcohol abuse. Ninety-four patients were randomized to placebo; 92 received diltiazem treatment.
Table 1
gives the baseline characteristics of the 186 patients. Because of the higher prevalence of IDC in men, the majority of patients were middle-aged men in NYHA class II. The duration of preclinical symptoms or signs was long with a high variance because any prior cardiac complaint or sign such as left bundle branch block was considered a preclinical event. Most patients were treated with ACE inhibitors and digitalis as is the standard treatment protocol in patients with LV dysfunction. Although the incidence of premature ventricular contractions was high during Holter monitoring, only a minority of patients, those with symptomatic palpitations, received antiarrhythmic drug treatment with exclusively class I or III agents (12 patients: 6 receiving placebo and 6 receiving diltiazem). Patients with cardiac syncope or episodes of sustained ventricular tachycardia received implantable cardiac defibrillators (n=3). In patients with LVEF <0.35, anticoagulation with dicumarole (Marcumar) was mandatory.
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Primary End Points
Survival and Heart Transplantation
Follow-up for 24 months was scheduled for all patients. However, 33 patients (13 receiving placebo and 20 receiving diltiazem) did not finish the trial (P=.32) for the following reasons: unwillingness to participate at re-examination appointments (5 placebo and 8 diltiazem patients), including 3 patients who were lost to follow-up (1 placebo and 2 diltiazem patients), and unwillingness to accept study medication and preference of open-labeled therapy (8 placebo and 12 diltiazem patients).
The survival rate after 24 months of the 183 patients whose status was known, regardless of whether they remained in the study, was 80.6% for placebo and 83.3% for diltiazem patients (P=.780; 95% CI, 0.563 to 2.557; Table 2).
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One hundred fifty-three patients remained in the study. Of those, 27 patients reached a primary end point because of either death or indication for heart transplantation (16 placebo and 11 diltiazem patients). Fig 1 shows the Kaplan-Meier event-free survival curves for those patients. Although the transplant listing–free survival was higher in the diltiazem group (85.2%) compared with the placebo group (80.4%), it did not reach statistical significance (P=.444). If patients were subclassified according to NYHA functional class, it could be shown that patients in NYHA classes III and IV had a significantly lower transplant listing–free survival rate compared with NYHA class I and II patients, regardless of the study medication (P=.0016; Fig 2).
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If patients were subclassified according to those with severe (LVEF 0.30) or minor (LVEF >0.30) LV dysfunction at entry, a significant difference in event rate was demonstrated (P=.004). However, the negative inotropic action of diltiazem did not increase the event rate (death or indication for heart transplantation) in the patient group with low LVEFs. Instead, there was a trend for a reduced cardiac event rate in that group (P=.388) compared with patients who received placebo (Fig 3).
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Secondary End Points
Hemodynamics
One hundred twenty-six patients finished the 24-month study period under study medication. In these patients, the long-term hemodynamic course was determined. As Table 3 shows, all hemodynamic parameters except pulmonary artery pressure at rest showed significant improvement in the diltiazem group. Although LVEF improved and the heart became smaller in both groups, these improvements were more pronounced in the diltiazem group. In addition, only the diltiazem group demonstrated a significant increase in cardiac index, stroke volume index, stroke work index, and arterial pressures and a reduction in mean pulmonary artery pressure at comparable workloads and heart rate.
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Although the norepinephrine plasma levels did not change significantly in either group, there was a trend of fewer premature ventricular contractions during the 24-hour Holter monitoring in the diltiazem group. However, the latter had no effect on the incidence of sudden cardiac death (6 patients receiving placebo and 7 receiving diltiazem). The PQ time increased significantly in the diltiazem group. No patients developed a second- or third-degree AV block (Table 3
).
Well-being
Concomitant with the hemodynamic improvements, exercise capacity in the ergometry test was significantly improved in the diltiazem group (Table 3). The latter result, combined with the beneficial hemodynamic effects of diltiazem in IDC, might explain the profound tendency of a reduced need for heart transplant. The Karnofsky scale increased significantly in both groups (P=.000), as did the NYHA functional class (P=.005).
When the changes in Karnofsky scale, NYHA functional class, and patients' subjective well-being were combined and rated as deteriorated, unchanged, or improved, a significant improvement in the diltiazem group (P=.01) was demonstrated (Fig 4).
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Adverse Reactions
Adverse reactions associated with the application of diltiazem or placebo had an incidence of 22%. In the placebo group, 24 patients reported adverse reactions such as dizziness (n=4), impotence (n=2), dry skin (n=2), and other vegetative symptoms (n=16). In the diltiazem group, 16 patients described adverse reactions such as dry skin (n=2), dizziness (n=2), and sleep disturbance (n=2), and 10 patients had various unspecified vegetative symptoms.
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Discussion |
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The pathogenetic mechanisms involved in the initiation and propagation of human IDC are unknown. However, calcium antagonists have been shown to reduce virus-induced cardiopathology9 and myocardial alcohol toxicity,10 both of which might be involved in human IDC. In the cardiomyopathic Syrian hamster, calcium antagonists were shown to prevent vasospasms11 12 ; in other models, they restored impaired calcium cycling.13 14 Thus, from a theoretical point of view, it seems rational to investigate the effect of calcium blockers in human IDC17 because they may specifically affect disease propagation. In this trial, diltiazem was investigated in IDC patients. Diltiazem was used as a calcium antagonist agent because in an acute hemodynamic study in IDC patients, it exhibited a preferable hemodynamic profile: it lowered heart rate and increased LVEF. These simultaneous effects could not be elucidated by nifedipine or verapamil.18 In addition, a pilot longitudinal nonrandomized study with diltiazem in IDC gave promising results.15
In the present study, 183 patients with IDC could be prospectively followed for 2 years (3 patients were lost to follow-up). Only 1 of the 14 patients who died in this trial succumbed to progressive heart failure; the remainder suffered sudden cardiac arrest. Thus, with those who received transplantations (n=9) excluded, unlike in previous studies,19 20 sudden cardiac arrest is the predominant cause of death in IDC patients but is not affected by adjunct diltiazem therapy. Therefore, the primary end points of this trial, reduction of mortality and the necessity for heart transplantation, could not be reached by adjunct diltiazem therapy, although less than half of the patients in the diltiazem group had to be listed for transplantation.
However, the secondary end points of this trial could be reached by diltiazem treatment. Although in both study groups the cardiothoracic ratio and LVEF improved significantly, additional hemodynamic improvement, mainly in the systolic function indexes, was found as a result of adjunct diltiazem treatment. Only diltiazem increased cardiac index, stroke volume, and stroke work and improved patients' endurance on stress tests and their sense of well-being. Thus, the need for heart transplantation was reduced by diltiazem because the listing for heart transplantation in IDC is based primarily on hemodynamic data and patients' well-being. These beneficial effects of diltiazem are contradictory to findings in other studies in ischemic heart failure patients with LV dysfunction. In ischemic heart failure, diltiazem even decreased survival rate, probably because of its negative inotropic mode of action,21 22 as did other calcium antagonists mainly in patients with myocardial infarction.23 In short-term studies in this particular group of patients, the hemodynamics sometimes improved with calcium antagonist treatment, but the patients developed more symptoms. Therefore, therapy with the first generation of calcium antagonists (verapamil, diltiazem, and nifedepine) was not recommended.24
It is the goal of any therapy in patients with heart failure to improve survival, hemodynamics, and symptoms. Unfortunately, these goals are independently related. As shown in this trial, adjunct diltiazem therapy can fulfill two of these three goals.
For the first time, it can be shown that a calcium blocker agent has long-term beneficial effects in patients with LV dysfunction. Therefore, it is likely that diltiazem has some special effects on disease propagation in IDC patients that are different from those experienced by other heart failure patients (see above). Even in patients with pronounced heart failure such as NYHA functional classes III and IV (Fig 2) or patients with an LVEF 0.30, no deterioration by diltiazem could be seen; instead, this subgroup did best under the study medication (Fig 3).
Recently, the results of the Metoprolol in Dilated Cardiomyopathy Trial25 and CIBIS26 were published. As with diltiazem in the present trial, neither metoprolol nor bisoprolol could attain a significant reduction of the transplant listing–free survival rate or overall mortality. In fact, metoprolol slightly increased the mortality rate compared with placebo but significantly reduced the need for heart transplantation, whereas bisoprolol significantly improved survival in the subgroup of 338 patients with cardiac insufficiency other than myocardial infarction. As in the present study, LVEF improved in the placebo and study groups, with a more pronounced improvement in the latter. No patients had to be withdrawn from the trial during the titration period, whereas 4% of the patients in the metoprolol trial had to be withdrawn because of intolerance to metoprolol. In addition, the titration period in the metoprolol or bisoprolol drug regimen is complicated and takes 4 to 6 weeks, whereas it took 5 days in the present study. Thus, the overall dropout rate of 18% in DiDi for a 2-year longitudinal study remained remarkably small (Table 2) compared with 14% for 1 year in the metoprolol trial and 23% to 26% in CIBIS for a mean study period of 1.9 years.25 26 Diltiazem also induced fewer adverse reactions. In summary, like metoprolol and bisoprolol, diltiazem has no effect on primary end points but has pronounced beneficial hemodynamic effects and is easier to apply than metoprolol. Metoprolol and diltiazem both improved the patients' well-being and exercise capacity.
The mechanisms by which metoprolol or diltiazem improves myocardial function are unclear. Both substances have similar modes of action, both reduce heart rate significantly, and thus both could reduce metabolic stress and enhance the recovery of the failing heart.27 In IDC, contractility is maximized at low heart rates.28 Both mechanisms may reduce the propagation of heart failure as a result of the so-called "cardiomyopathy of overload."29
In this trial, it was shown for the first time that a first-generation calcium antagonist has long-term beneficial effects in patients with LV dysfunction. In IDC, diltiazem therapy can fulfill two of the three goals of heart failure therapy, ie, improvement in hemodynamics and well-being without adverse effects on survival. Diltiazem may therefore be recommended for adjunct therapy in IDC patients.
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Appendix |
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Study Board
Hans R. Figulla, MD (chairman), and Reinhard Hilgers, PhD, Medical Faculty, University of Gottingen; and Wolfgang Schneider, MD, Department of Cardiology, Universitatskliniken Frankfurt.
Safety Board
Reinhard Kandolf, PhD, Center for Pathology, University of Tubingen, and Peter Kunkel, MD, Department of Cardiology, Medizinische Klinik, Bamberg.
Investigators and Participating Centers
R. Engberding, MD, and B. Gerecke, MD, Stadtkrankenhaus, Wolfsburg; U. Gleichmann, MD, and D. Baller, MD, Herzzentrum NRW, Bad Oeynhausen; K. Haerten, MD, and M. Raiber, MD, Marien-Hospital, Wesel; M. Kaltenbach, MD, W. Schneider, MD, and M. Scholz, MD, Universitatsklinik Frankfurt; H. Kreuzer, MD, R. Soballa, and H.R. Figulla, MD, Universitatskliniken Gottingen; H. Kuhn, MD, F. Gietzen, MD, and J. Hegselmann, MD, Stadtische Krankenhaus, Bielefeld; K.L. Neuhaus, MD, and U. Zeymer, MD, Stadtische Kliniken, Kassel; N. Reifart, MD, and E. Geiß, MD, Rotes-Kreuz Krankenhaus, Frankfurt; W. Rudolph, MD, and R. Unterberg, MD, Deutsches Herzzentrum, Munchen; M. Schlepper, MD, and V. Mitrovic, MD, Kerckhoff Klinik, Bad Nauheim; and H. Zebe, MD, and S. Sporl-Donch, MD, Furstenhof Klinik, Bad Wildungen.
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Acknowledgments |
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This work was supported by a grant from Godecke Parke Davis AG, Freiburg, Germany. The thoughtful reading of the manuscript by Stepfan Vonhof, MD, Gottingen, Germany, is gratefully acknowledged. The precise secretarial work was done by C. Bunker.
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Selected Abbreviations and Acronyms |
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Footnotes |
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*A complete list of participating investigators and centers is provided in the "Appendix."
Received August 22, 1995; revision received January 19, 1996; accepted January 23, 1996.
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References |
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