Prospective study of calcium channel blocker use, cardiovascular disease, and total mortality among hypertensive women.
Michels KB, Rosner BA, Manson JE, Stampfer MJ, Walker AM, Willett WC, Hennekins CH. Circulation.1998;97:1540-1558. [abstact not available]
What have we learned from the calcium channel blocker controversy? (Editorial)
Califf RM and Kramer JM. Circulation. 1998; 97: 1529-1531.
This paper begins with the authors reviewing the perspective from which they pursued their work. "In some but not all observational studies, both case-control and cohort, patients prescribed calcium channel blockers for hypertension had higher risks of cardiovascular diseases and mortality than those prescribed other antihypertensive medications. In a large case-controlled study of hypertensives initially free of cardiovascular disease, those who suffered an MI were significantly more likely to have been treated with calcium channel blockers (primarily short-acting formulations) than hypertensives who did not suffer an MI (covariate-adjusted risk adjusted risk ratio, 1.62; 95%CI, 1.11 to 2.34). In two other case-control studies, no increased risk was seen for hypertensive patients on calcium channel blockers. In a recent case-control study, 27 hypertensive patients who received short-acting calcium channel blockers had a higher risk of cardiovascular events than patients on the long-acting formulation."
Furthermore, in another cohort study involving nifedipine in which there were fewer deaths than in a group treated with beta-blockers, there was also no apparent association with increased risk for cardiovascular events for other calcium channel blockers (verapamil or diltiazem) or for ACE inhibitors relative to beta-blockers.
After conducting a thorough assessment of the data obtained from a large and ongoing cohort study in women established in 1976, the authors emphasize the value of randomized, targeted clinical trials comparing the efficacies and adverse effects of the various antihypertensive drugs, as compared to the less focused approaches seen with larger, demographically-based studies. They conclude by stating the following: "Because short-acting calcium channel blockers have largely been supplanted by long-acting formulations in clinical practice today, clinical trials that are currently under way are randomizing long-acting calcium channel blockers against other antihypertensive agents, including the first-line drugs, diuretics and beta-blockers. Whether short-acting calcium channel blockers have harmful effects compared with other antihypertensive agents may never be completely resolved."
The editorial written by Califf and Kramer in response to this article provides, in my opinion, a useful perspective on how, after all the research leading to marketed drugs like the currently available calcium channel blockers, we could be in a position of questioning their value, and even harm, in the patient populations receiving them. Once this broad group of drugs was created, they were approved for clinical use on the basis of their ability to lower blood pressure and improve treadmill exercise time - two surrogate measures considered to be predictive of improved clinical outcomes with regard to MI, stroke and death. The authors point out that although hundreds of small, carefully executed, randomized trials of calcium channel blockers were conducted, many of them - including those with negative results - were never reported in the medical literature. Most of the studies performed, the authors add, involved uncomplicated patients and would therefore not be likely to discover the full range of possible outcomes, or provide information on the influence of relatively common comorbidities.
Drug labeling based on these studies was carefully restricted to reflect the fact that clinical research had effectively overlooked the majority of patients that constitute most community practices. Nonetheless, from the very beginning, "thought leading" clinicians undertook to extrapolate findings from small, selected studies to the "real world" of cardiovascular disease. Only after a significant post-marketing period did it appear that there may be problems associated with calcium channel blockers - specifically nifedipine and MI. Despite studies suggesting harmful effects and growing concern among regulatory authorities, calcium channel blockers continued to be prescribed. Once fully disclosed by a formal, definitive report which concluded that substantial mortality and morbidity could result from calcium channel blocker use in the general population, however, the public was understandably confounded and disturbed after having been treated with drugs said to be of significant benefit.
The authors state: "A critical question with implications far beyond the specific use of calcium channel blockers is why well-intentioned physicians continue to prescribe a class of drug to thousands of patients every year in the absence of a clear understanding of their effects on the health of the patients for whom they are prescribed." The article by Michels et al reflects the complexity of the data from which determinations of "goodness" or "badness" are made. Furthermore, the point is made that such determinations will not likely occur from observational studies, but rather by the completion of appropriate ongoing comparative studies.
Another question raised by the editorial relates to why we have definitive clinical outcome information about therapies in some conditions (e.g. MI), while we do not have comparable information in other important therapeutic areas, including diabetes, obesity, asthma, and depression. It is noted that when studies require true clinical outcome data, the results can be very useful. Conversely, when studies are limited to relatively simple physiologic surrogate measures, the results can be misleading. Indeed, if the regulatory process does not require true clinical outcome information before a drug may be marketed, two common misconceptions typically occur: (1) the belief that federal research funding agencies, i.e., NIH or AHCPR, will provide needed supplemental research support to ensure the benefits and safety of new therapies; and (2) that physicians and their patients will somehow discern any detrimental effects of the new therapy. Unfortunately, the government cannot afford to conduct such necessary research, and physician practices are usually too small or insufficiently discerning to provide such vigilance.
Given the (appropriate) profit motive of the medical products industry, Califf and Kramer state: "If regulatory groups do not require long-term clinical outcome data in the broad population of patients in whom the treatment is likely to be used, industry is faced with a choice between performing definitive and expensive clinical outcome studies and doing less expensive, small, complicated studies addressing surrogates or mechanisms." This begs the question as to why the regulatory authorities would not demand definitive evidence about whether a drug increases the risk of mortality or stroke when prescribed for hypertension and angina. The point made here is that regulatory authorities tend to address historical standards, set by legislative bodies, for determining safety and efficacy, and they are charged with creating labeling which reflects the data presented to them in the drug application process. The fact is that the complexities of the patient populations who will likely be treated with a given drug, coupled with the influence of comorbid conditions and other variables, commonly leaves a large gap between the evaluation, labeling and practice.
This article and the thoughtful editorial emphasize the growing importance of practicing physicians to actively participate in the clinical research process. In earlier times this might have proven difficult, but improved clinical trial methodology is at hand which can enable rapid, efficient enrollment of patients, providing sufficiently large sample sizes to permit useful assessment of outcomes, in contrast to simple physiologic surrogate markers of efficacy. Further, the idea that clinical research lies exclusively in the domain of the "academic" physician needs to be reconsidered. First, physicians participating in clinical research become more aware of the limitations of the therapies they prescribe - a very helpful impetus for providing sensible and safer patient care. Additionally, with more practitioners participating in useful, larger scale clinical trials, the cost of conducting clinical trials would decrease, thereby benefiting industry, patients and practitioners alike. In the process, those drugs and treatments which do not add meaningful value can be thoughtfully culled, thereby further decreasing cost and improving quality of care.
Finally, the editorial reminds us that patients expect their doctors to know whether the therapy they recommend and use will be helpful or harmful. It is no longer acceptable to think that the methodology for determining these differences is not available - it is. "Given our current knowledge of the fallacy of surrogate outcome measures and the difficulty of interpreting confounded observational analyses, it is imperative for practitioners to become producers of the evidence for evidence-based medicine and not just consumers of the evidence. In the case of calcium channel blockers, many years and thousands of patients later we still do not know which problem, overuse or underuse, we have created."
Hopefully, the message of active participation of healthcare practitioners in the development of new drugs, devices and therapies is clear. We must all feel a sense of commitment to this important process if we are to realize the kind of appropriate information warranted for the care of patients and the rational use of resources in the future. Methodologies and technology are now available to make that participation relatively painless for the willing participant.
