Correspondence
Amlodipine in Chronic Heart Failure
N Engl J Med 1997; 336:1023-1024April 3, 1997
- Article
To the Editor:
When the findings of a clinical trial are diametrically the opposite of those anticipated, a reevaluation of the original premises of the study is appropriate. Packer et al. (Oct. 10 issue)1 reported that amlodipine reduced mortality in a subgroup of patients with “nonischemic dilated cardiomyopathy.” No satisfactory explanation was provided for this unexpected result.
The use of the phrase “nonischemic dilated cardiomyopathy” suggests that the investigators considered that condition to be almost synonymous with idiopathic dilated cardiomyopathy, in which the coronary angiogram is normal. The proportion of patients in the trial classified as having “nonischemic dilated cardiomyopathy” was 37 percent. That is a high figure as compared with the proportion of such patients in other, similar trials, such as the Studies of Left Ventricular Dysfunction (18 percent),2 and is much higher than the prevalence in the population. In the Framingham Heart Study,3 11.2 percent of the men and 16.8 percent of the women had heart failure not due to hypertension, coronary heart disease, or rheumatic fever. Patients in the Prospective Randomized Amlodipine Survival Evaluation (PRAISE) Study were classified as having “nonischemic dilated cardiomyopathy” on the basis of a coronary angiogram if available, a history of angina, or a previous myocardial infarction, although the numbers of patients classified according to each of these criteria are not provided. Many patients in this subgroup will have had three-vessel coronary heart disease that was undiagnosed by the investigators. Benton et al. reported that 30 percent of patients with a diagnosis of dilated cardiomyopathy had stenosis greater than 50 percent in at least one coronary artery.4 Figulla et al. found that 34 percent of patients had extensive coronary heart disease.5 In PRAISE, the proportion will be higher because of the method of classification. It is precisely this subgroup of patients — those with a low ejection fraction (0.21 in PRAISE) and severe coronary heart disease in the absence of overt infarction and of typical angina — who would be expected to benefit from a drug with anti-ischemic properties. The authors argue that misclassification would weaken the ability to detect an effect in this subgroup. On the contrary, the system of classification may have identified the particular group of patients with coronary heart disease who derive benefit from amlodipine, despite those patients' being muddled up with patients having idiopathic dilated cardiomyopathy, who may or may not benefit from amlodipine. This explanation is simple, plausible, and clinically relevant. The authors may be able to provide further information, or coronary angiography should be undertaken in a future trial.
5 ReferencesPhilip A. Poole-Wilson, M.D.
Imperial College School of Medicine, London SW3 6LY, United Kingdom1
Packer M ,O'Connor CM ,Ghali JK , et al. Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Engl J Med 1996;335:1107-1114
Full Text | Web of Science | Medline2
The SOLVD Investigators
Full Text | Web of Science | Medline3
Kannel WB ,Belanger AJ . Epidemiology of heart failure. Am Heart J 1991;121:951-957
CrossRef | Web of Science | Medline4
Benton RE ,Coughlin SS ,Tefft MC . Predictors of coronary angiography in patients with idiopathic dilated cardiomyopathy: the Washington, DC Dilated Cardiomyopathy Study. J Clin Epidemiol 1994;47:501-511
CrossRef | Web of Science | Medline5
Figulla HR ,Kellermann AB ,Stille-Siegener M ,Heim A ,Kreuzer H . Significance of coronary angiography, left heart catheterization, and endomyocardial biopsy for the diagnosis of idiopathic dilated cardiomyopathy. Am Heart J 1992;124:1251-1257
CrossRef | Web of Science | Medline
To the Editor:
It is surprising to find in the report of a well-conducted clinical trial that positive and negative effects of treatment are described in two different ways. Packer et al. describe the reduction in the primary end points (the combined risk of mortality from all causes and cardiovascular morbidity) and the secondary end point (mortality from all causes) using the difference in relative risk, which enhances the positive result. On the other hand, they describe the increased incidence of adverse reactions, such as pulmonary edema, using the difference in absolute risk, which minimizes the difference.1 The reduction in the incidence of total fatal and nonfatal events from 37 to 28 percent is reported as a 31 percent reduction (95 percent confidence interval, 2 to 51 percent) and not as a 9 percent absolute reduction. However, the statistically significant increase in the incidence of pulmonary edema from 10 to 15 percent is dismissed as an absolute increase of 5 percent. Adopting the same standard used to describe event reduction, the authors should have stated that pulmonary edema was increased by 50 percent. It is well known that physicians' perceptions of drug efficacy are influenced by the way data are presented.2,3 Recently, we also demonstrated that the completeness of information can influence physicians' decisions to prescribe a certain drug.4
4 ReferencesMarco Bobbio, M.D.
Ospedale Molinette, 10126 Torino, Italy1
Laupacis A ,Sackett DL ,Roberts RS . An assessment of clinically useful measures of the consequences of treatment. N Engl J Med 1988;318:1728-1733
Full Text | Web of Science | Medline2
Naylor CD ,Chen E ,Strauss B . Measured enthusiasm: does the method of reporting trial results alter perceptions of therapeutic effectiveness? Ann Intern Med 1992;117:916-921
Web of Science | Medline3
Bucher HC ,Weinbacher M ,Gyr K . Influence of method of reporting study results on decision of physicians to prescribe drugs to lower cholesterol concentration. BMJ 1994;309:761-764
CrossRef | Web of Science | Medline4
Bobbio M ,Demichelis B ,Giustetto G . Completeness of reporting trial results: effect on physicians' willingness to prescribe. Lancet 1994;343:1209-1211
CrossRef | Web of Science | Medline
To the Editor:
In their study of amlodipine in patients with severe chronic heart failure, Packer et al. have provided clinicians with valuable information. However, I would like to emphasize that their conclusion, that “this trial establishes the safety of amlodipine for the treatment of angina or hypertension in patients with advanced left ventricular dysfunction,” is valid only for patients treated with angiotensin-converting–enzyme (ACE) inhibitors. I believe this is important because in previous trials that found increased mortality with diltiazem, ACE inhibitors were not part of the routine medical regimen.1,2 Therefore, a possible hypothesis is that amlodipine and diltiazem are both safe for patients also treated with ACE inhibitors and that the previous finding of increased mortality with diltiazem was due to the absence of treatment with ACE inhibitors. The corollary of this is that amlodipine in the absence of ACE inhibitors may increase mortality in a manner similar to diltiazem. Given that primary care physicians who treat the majority of patients with heart failure have low utilization rates for ACE inhibitors,3,4 it is my concern that those physicians, in response to the well-publicized results of the PRAISE trial, may use amlodipine without ACE inhibitors in patients with heart failure — a practice that has not been shown to be safe and that may increase mortality.
4 ReferencesJohn J. Allan, M.D.
University of Iowa, Iowa City, IA 522461
The Multicenter Diltiazem Postinfarction Trial Research Group
Full Text | Web of Science | Medline2
Goldstein RE, Boccuzzi SJ, Cruess D, Nattel S, Adverse Experience Committee, Multicenter Diltiazem Postinfarction Research Group
Web of Science | Medline3
O'Connell JB ,Bristow MR . Economic impact of heart failure in the United States: time for a different approach. J Heart Lung Transplant 1994;13:S107-S112
Web of Science | Medline4
Rajfer SI . Perspectives of the pharmaceutical industry on the development of new drugs for heart failure. J Am Coll Cardiol 1993;22:Suppl A:198A-200A
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: The principal conclusion of the PRAISE study was that amlodipine could be safely administered to patients with advanced heart failure. Such a finding would appear to distinguish amlodipine from other calcium-channel blockers, which have been reported to increase cardiovascular risk.1-3 Dr. Allan suggests that the findings of the PRAISE trial may be related not to any special feature of amlodipine but to the frequent use of ACE inhibitors in our study, which may have protected patients from the deleterious effects of calcium-channel blockers. It is true that many trials showing an adverse effect of calcium-channel blockers in patients with heart failure were carried out before ACE inhibitors came into widespread use,1,2 but recent studies have reported adverse effects of calcium-channel blockers in heart failure even in patients receiving ACE inhibitors.3
We recognize that some of the patients in our nonischemic group may have had ischemic heart disease. The inclusion of these misclassified patients, however, would be expected to dilute any effect that amlodipine might have in patients with normal coronary arteries. Dr. Poole-Wilson offers the surprising suggestion that the treatment effect seen in the nonischemic group was not related to an effect in patients with normal coronary arteries but was due to an effect in the misclassified patients. We would disagree with his suggestion for two reasons. First, it is difficult to understand why a history of angina or infarction would negate any benefit that amlodipine might have in patients with coronary artery disease. Second, if we assume that one third of our nonischemic patients had coronary artery disease and that these patients were entirely responsible for the treatment differences we observed, we would need to postulate that amlodipine almost completely prevented deaths among these misclassified patients.
Finally, Dr. Bobbio suggests that we used two different approaches to describe the effects of amlodipine in heart failure, but this is not the case. Data on treatment effects were expressed as both absolute and relative differences. Regardless of the approach, pulmonary edema was reported as an adverse reaction more frequently with amlodipine. However, unlike the primary and secondary end points in the trial, adverse events were reported entirely at the discretion of the investigator and were not adjudicated. Many reports of pulmonary edema in the PRAISE trial were triggered by a radiographic report rather than by a clinical event. The majority of patients with “pulmonary edema” had no pulmonary rales, and many were not hospitalized. Thus, we must be cautious in interpreting spontaneously reported, nonadjudicated data.
3 ReferencesMilton Packer, M.D.
Columbia University College of Physicians & Surgeons, New York, NY 10032Christopher M. O'Connor, M.D.
Duke University Medical Center, Durham, NC 27710David L. DeMets, Ph.D.
University of Wisconsin Medical School, Madison, WI 537061
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;82:1954-1961
CrossRef | Web of Science | Medline2
Goldstein RE, Boccuzzi SJ, Cruess D, Nattel S, Adverse Experience Committee, Multicenter Diltiazem Postinfarction Research Group
Web of Science | Medline3
Littler WA ,Sheridan DJ . Placebo controlled trial of felodipine in patients with mild to moderate heart failure. Br Heart J 1995;73:428-433
CrossRef | Web of Science | Medline
- Citing Articles (3)
Citing Articles
1
Lofty L. Basta. (2003) Routine Implantation of Cardioverter/Defibrillator Devices in Patients Aged 75 Years and Older With Prior Myocardial Infarction and Left Ventricular Ejection Fraction <30: Antagonist Viewpoint. The American Journal of Geriatric Cardiology 12:6, 363-365
CrossRef2
Ferenc Follath, John G.F Cleland, Werner Klein, Richard Murphy. (1998) Etiology and response to drug treatment in heart failure. Journal of the American College of Cardiology 32:5, 1167-1172
CrossRef3
John GF Cleland, Karl Swedberg, Philip A Poole-Wilson. (1998) Successes and failures of current treatment of heart failure. The Lancet 352, SI19-SI28
CrossRef
