(Hypertension. 1996;27:317-318.)
© 1996 American Heart Association, Inc.
Antihypertensive Therapy: Safety and Efficacy of Drugs and Publications
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Periodically, in the history of antihypertensive therapeutics, there have been minor tempests that have significantly affected the utilization of entire classes of agents. The first storm struck with the case study report that suggested reserpine and its related compounds were associated with increased risk of carcinoma of the breast.1 Despite its subsequent disproval of this association, the use of these agents was dramatically reduced in favor of newer agents.
The second storm was initiated by subanalysis of the MRFIT study,2 from which it was inferred that in a subset of hypertensive patients (those with evidence of electrocardiographic abnormality) diuretic treatment may have been harmful rather than beneficial. Fuel was added to this fire from consecutive meta-analysis of available multicenter antihypertensive drug trials, in which diuretic- or beta-adrenergic receptor blocker-based therapy failed to reduce coronary events to a statistically significant extent. Even when in a further meta-analysis3 a statistically significant reduction was finally attained (P<.01), it was emphasized that, while a predicted 40 percent reduction in stroke was achieved, the significant 14 percent reduction in coronary morbidity and mortality was definitely lower than the predicted 20 to 25 percent reduction.
The results of these publications was an avalanche of speculative talks, articles, and editorials that suggested an adverse effect of diuretics that, either by raising serum lipid levels or by lowering serum potassium, led to a so-called "failure to prevent myocardial infarction." A subsequent meta-analysis included additional studies which employed lower diuretic doses and reported a reduction in cardiac events satisfying the predicted 25 percent effect.4 However, despite this confirmation of predicted outcomes through rigorous randomized trials, case-control studies5 6 continued to hint that either large doses of thiazides or the absence of a potassium sparing agent in diuretic combinations may be responsible for an increased rate of sudden cardiac deaths. But, clearly, sudden cardiac death is not synonymous with myocardial infarction although both may be attributed to coronary heart disease deaths. As a consequence of this, in analogy with what had previously happened with reserpine, the use of diuretics was markedly reduced in favor of newer classes of agents.
Now, a third storm has developed in the therapeutic hypertension "ocean": another case study report7 and a non-randomized cohort study have impugned the use of calcium antagonists in hypertension. The case-control study7 suffers from the same disadvantages as the reserpine report; as remarked by Mayes et al8 : "in the absence of rigorous scientific principles, case-control studies depend on arbitrary decisions by the investigator... , in such circumstances, conflicts, contradictions, and controversies will be inevitable and abundant." And, indeed another case-control study published in 1995,9 though not equally well publicized, reached exactly opposite conclusions and claimed that calcium antagonists were significantly less associated with myocardial infarction than traditional antihypertensive therapy based on diuretics and beta-blockers. The non-randomized cohort study10 also questioning the safety of calcium antagonists in hypertension suffers not only from the lack of randomization, but also from small numbers and excessive subset analysis. A third report, a meta-analytic study,11 was presented as supportive of the two other reports; however, it refers to patients with coronary heart disease, not to patients with hypertension; and also suffers from lumping studies performed with different aims and data from short-term and long-term studies using short-acting formulations of calcium antagonists. As expected, publication of these papers has developed into a controversy, with editorials, debates, round tables and, unfortunately, press conferences and press releases pro and against the use of calcium antagonists. In addition to confusing practicing physicians, the general public (through a controversy attracted by-media) have been unduly alarmed.12
In response to this recent controversy, the editors of Hypertension and the Journal of Hypertension have agreed to jointly publish this editorial in their respective journals. The purpose of this editorial is not directed to suppress further scientific communications on this subject. Rather, it is aimed at: stimulating appropriate studies and the publication of their results; calling for some academic restraint in the organization and in participation in oral debates, press conferences and written commentaries; and putting into perspective the excitation that has now pervaded citizen groups calling for scientifically unjustified withdrawals of drugs.
It is not the purpose of this joint editorial to take sides or favor one thesis over another. The answer will come in due course from data obtained by solid scientific methods. We should wait for solid retrospective studies and a well-designed prospective study, that employ time-respected rigorous scientific methods, such as those based on randomization, to the rational practice of medicine.
Of course, we must understand and appreciate the role of the various national regulatory bodies that approve pharmacological compounds for commercial and therapeutic use. These standards require the demonstration of safety and efficacy of drugs. In the case of antihypertensive drugs, efficacy relates to the demonstration of a significant antihypertensive action, and safety requires the demonstration that the side effects that accompany the use of all therapy is free from serious morbidity and, of course, mortality. These requirements have never included reduction of cardiovascular morbidity and mortality as tested in prospective, placebo-controlled or active-agent controlled trial. To date, most of the randomized trials of antihypertensive therapies that have demonstrated a reduction in cardiovascular morbidity and mortality have used, at some stage, diuretics and beta-blockers, and this is why the Joint National Committee's Fifth Report has termed these two classes as "preferred".13 Even the more liberal guidelines of the World Health Organization/International Society of Hypertension indicate that diuretics and beta-blockers are among those antihypertensive agents with more clearly proven benefit based on mortality-morbidity studies.14 But let us remember that no class of antihypertensive agents has demonstrated a reduction in risk for the development of hypertension–related end-stage renal disease or left ventricular hypertrophy and their consequences.
Accordingly, our respective journals formulate the following recommendations (and, as far as they are concerned they will implement them): 1. A moratorium should be maintained on further editorials and debates on this subject unless new and firm scientific evidence is included. 2. Completion and publication of further additional peer-reviewed prospectively designed studies based on randomized or appropriately designed retrospective analyses of randomized studies should be encouraged. 3. Appropriate, thorough and rigorous statistical review of all prospective and retrospective epidemiologic and therapeutic studies should be applied by journal editors to all submitted papers. 4. All authors reporting the results of therapeutic trials should detail in the discussion sections of their reports the shortcomings of their studies in addition to the purported findings. 5. Journal editors should resist the temptation of publishing papers that do not reach the usual standard required for publication only because the controversy they are likely to raise promises multiple citation in the scientific press (and consequent benefit in impact factor) and amplification in the lay press. 6. Until any scientific communication is published in scientific journals, a moratorium on the prior release of its content to the lay media must be strictly kept. Of course, the public's well-being is of primary concern; but in most cases it will be better preserved by prior peer reviewed scientific scrutiny of data. 7. Finally, controversy should be welcomed, as it is only through controversy that science advances; however, controversy should be based on sound scientific evidence. Moreover, arguments should be judged according to their scientific value, and conclusions drawn with a confidence (and addressed to an audience) in proportion to the soundness of the evidence available.
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Footnotes |
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(For joint and simultaneous publication in Hypertension and the Journal of Hypertension.)
Send response to: Edward D. Frohlich, M.D., Vice President for Academic Affairs, Alton Ochsner Medical Foundation, 1516 Jefferson Highway, New Orleans, LA 70121. Telephone: 504/842-3700. Fax: 504/842-3258.
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References |
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TopIntroductionReferences |
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4. Thijs L, Fagard R, Lijnen P, Staesseng J, VanHoof R, Amery A. A meta analysis of outcomes trials in elderly hypertensives. J Hypertens. 1992;10:1102-1109.
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