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| |  Bayer Response to Increased Mortality Risk Reported in JAMA LEVERKUSEN, Germany, Aug. 24, 1995 -- In response to recent reports suggesting an increased risk of mortality for patients taking calcium channel blockers (CCBs) -- a retrospective case controlled study by Dr. Bruce Psaty in this week's Journal of the American Medical Association and a presentation by Dr. Curt Furberg at the European Society of Cardiology meeting being held this week in Amsterdam -- Bayer AG issued the following statement: Bayer AG cares greatly about the safety of any of its products. Any report concerning safety is taken very seriously and is investigated very thoroughly, to ensure that patients well-being is not compromised. Bayer AG, in accord with many cardiovascular experts, asserts that these recent reports on calcium channel blockers have no bearing on clinical practice. Reporting these unvalidated, preliminary results by the lay media may cause patients to stop taking their medications, placing them at much greater risk for complications, such as heart attacks and stroke. Millions of patients over the past two decades have found calcium antagonists to be an indispensable therapy in the fight against heart disease. The safety and efficacy of calcium channel blockers have been established in numerous well designed clinical trials. In addition, several large prospective clinical studies in hypertension are in progress, such as ALLHAT, INSIGHT, HOT, PREVENT, AASK, to continue to document the safety of these drugs and explore their added benefits. Epidemiological studies such as Psaty's are useful to generate a working hypothesis, they are not suitable to prove a working hypothesis. Only prospective randomized controlled trials are suitable to prove the efficacy and safety of drugs. In a case control study, a case is only valid if it matches its control. Common practice, however, provides evidence that the use of calcium channel blockers in a managed care environment is related to the severity of the disease, and that the outcome, as compared to diuretics for example, reflects the natural course of the disease rather than the specific effect of the drug. A randomization in a clinical trial is the only sure way to overcome relevant differences in baseline characteristics that may have impact on the outcome (for reference see press release of the AMA/Brigham and Women's Hospital, Boston, Mass.). The aim of Dr. Furberg's previous presentations on this topic has been to attribute a dose-related increased risk in mortality to nifedipine for patients suffering from coronary heart disease. His analysis is based on 16 publications, twelve of which were aimed to investigate the effects of nifedipine under various conditions in acute or threatened myocardial infarction; three others were aimed to investigate the efficacy of nifedipine in unstable angina pectoris; and one was an experimental study in atherosclerosis (INTACT). An independent analysis included two further studies (Haberer et. al. and Cyran et. al.), which were not taken into consideration, although providing important information on nifedipine in unstable angina pectoris. Thus, his selection of publications is not easy to understand. The INTACT study was not performed in patients suffering from unstable or stable angina pectoris (only 30% of the patients had stable angina pectoris) and was not aimed at assessing the efficacy of nifedipine in post MI patients. It is unclear on what basis it is included. Only two of the 16 studies were designed to investigate the effect of nifedipine on the secondary prevention of myocardial infarction and could therefore possibly answer the question raised by Dr. Furberg. By mixing up different indications, he obtained a misleading dose- response relationship for the 80mg daily dosage of nifedipine, however he failed to demonstrate a higher risk for the 100mg daily dosage. There is no statistical proof of any dose-response relationship, since for the 100mg dosage the relative risk returned to normal according to previous presentations of Dr. Furberg. In conclusion, the analysis performed by Dr. Furberg is an analysis of selected publications that were published in the last 5 to 13 years. Re-analysis of the different indications does not provide any evidence of a statistically significant increased risk so that it must be assumed that either the analysis was performed incorrectly or the figures used by Dr. Furberg do not match with the figures in the original publications. The results of this publication are well known to the medical community and have already been incorporated in clinical practice. Drs. Furberg and Psaty analyzed data on short acting nifedipine that should be discussed in the scientific community and should be evaluated in the context of all available data and in the context of the improvement of drug delivery for nifedipine. Bayer AG welcomes scientific debate and supports research. In fact, it is conducting several trials, including INSIGHT involving 6,600 patients. However, Bayer is deeply concerned about scientific debates being carried out in the lay press instead in the peer-reviewed scientific journals. The modern, long acting calcium channel blockers are important first line therapy to millions of patients with heart disease. The scientific documentation of their safety and efficacy is probably the most extensive of any therapeutic agent and continues to grow. Bayer AG is a research based health care company with global operations, based in Leverkusen, Germany. Professor Paul G. Hugenholtz, M.D., Ph.D., h.c., FESC, FACC, Professor of Cardiology Emeritus at University Rotterdam (NL) with a life-long experience with calcium antagonists since they came out in 1967. I attended the "Hot Line" session of recent epidemiology evidence on 23 August at the XVIIth annual meeting of the European Society of Cardiology where more than 12,000 specialists have gathered, among them prominent U.S. and international experts. During that session, which was devoted to the latest evidence on the use of modern, third-generation calcium channel blockers, four papers were presented. Three of them dealing with the ongoing research on the long-term efficacy of these compounds in cardiovascular diseases, during which the emphasis was placed on the safety of these calcium antagonists. The introductory presentation of Dr. Curt Furberg, however, dealt with a review of past experiences with the earlier generation calcium antagonists. Dr. Furberg emphasized that a review of old clinical trials had shown certain unwanted side effects. In addition, he believed that such retrospective analysis should provide caution in the prescription of these drugs. During the ensuing debate, it became rapidly evident that the several hundred cardiologists in attendance disagreed with his opinions for a number of reasons; these were: -- Insufficient documentation -- Data on drugs and dosages that weren't current -- Confused presentation of different syndromes as if they all carried similar risk At the same time, two papers were released in American medical trade press, which while not presented, were circulated at an abbreviated form at the "Hot Line" session press conference held today. Here the same hypothesis was presented as if proven by facts, causing consternation and confusion among the press corps. I believe this type of communication to the general public, when the scientific evidence has not yet been properly provided and presented in an unbiased manner, is an irresponsible act which does not help the patient, the disease, or the medical profession. Currently, major evidence for safety of drugs prescribed throughout the world exist and long-term studies to investigate whether symptom relief and functional improvement of the cardiovascular system is associated with decreased mortality in the long run, are underway. It would seem that this presentation should have lead to scientific discussion between experts, and that it is entirely premature to communicate incomplete and tendentious data to the general public. Franz H. Messerli, M.D., F.A.C.C., F.A.C.P., Professor of Medicine, Ochsner Clinic I would like to emphasize that calcium antagonists have been used for the treatment of cardiovascular disorders such as essential hypertension and coronary heart disorders for more than a quarter of a century. During these times, calcium antagonists have been shown to relieve chest pain from angina pectoris and to lower blood pressure and to be well tolerated. The fact that they do not adversely affect plasma cholesterol, blood sugar, or other metabolic parameters makes them particularly attractive for the long-term treatment of high blood pressure. Recently, a report of a retrospective case controlled study as well as of a meta-analysis have cast doubts on the safety of this class of drugs. The retrospective case controlled study suggested that hypertensive patients who were treated with three short-acting calcium antagonists in high doses (verapamil, diltiazem, and nifedipine) had an excessive rate of myocardial infarction when compared to patients who were treated with a diuretic. This study has been published today in JAMA. The accompanying editorial from the Harvard group puts the data into their proper context. Allow me to quote verbatim: "It would be particularly tragic if the large benefits of antihypertensive drug therapy are lost as a result of stopping medication because of an as yet unsubstantiated fear of increased risk of myocardial infarction. Even if the hypothesis raised by Psaty and colleagues turns out to be true, the known risks of uncontrolled hypertension are far greater than the postulated but unproven hazards of calcium channel blockers." To simplify matters I have outlined some of the concerns arising from this study. The meta-analysis of Furberg and collaborators purporting to show a dose related increase in mortality with nifedipine will be published in Circulation on September 1st. I had the privilege of being able to scrutinize these data and, together with Dr. Opie, to write an accompanying editorial. I don't mind to tell you that we found the data to be less than convincing. Both of these studies were using short-acting calcium antagonists only, none of which were indicated for the treatment of hypertension. Clearly, not all calcium antagonists are created equal and distinct differences from one molecule to the other have been demonstrated in patients with congestive heart failure or in those who have suffered an acute myocardial infarction. Numerous recently reported studies have attested to the safety and efficacy of the newer long-acting calcium antagonists in patients with a wide spectrum of heart disease. One may argue that the fact that, i.e., amlodipine diminishes morbidity and mortality in patients with congestive heart failure from dilated cardiomyopathy does not mean that amlodipine is safe in the treatment of hypertension. However, several ongoing trials with a wide variety of calcium antagonists will provide within the next few years morbidity data in patients with high blood pressure. Until these results are available, we can be confident that lowering of blood pressure and bringing relief in patients with symptomatic angina can be achieved safely and efficiently with the presently available long-acting calcium antagonists. In a nutshell, what can one expect when a short-acting drug is used at an inappropriate dose regimen to treat a condition for which it is not indicated? -- A poor therapeutic result. What did Psaty and collaborates get? -- A poor therapeutic result. What does this prove? -- This does not prove that calcium antagonists are cardiotoxic, but that poor practice of medicine will result in poor outcome! CONTACT: Don Hyman, 203-498-6545, or Dr. Franz-Josef Bohle, 49-214-30-30-10, both of Bayer
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