Editorials

The Calcium Channel Antagonist Controversy



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Am Fam Physician. 1998 Apr 1;57(7):1484-1492.

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After their introduction in the mid-1980s, the calcium channel antagonists became an increasingly popular first choice for the treatment of hypertension. Patients liked them for various reasons: they are effective and easy to take (a once-daily regimen); they do not cause side effects, such as drowsiness and impotence, which are common with the older antihypertensive medications; and treatment with these agents does not require frequent visits to the physician. Physicians liked them, too: they are effective and do not interact with most drugs used concurrently by hypertensive patients; they do not cause metabolic alterations requiring frequent blood tests; and they are safe—or were thought to be safe, until about three years ago, when a number of reports cast doubt on their safety.

The article by Straka and colleagues1 in this issue is a critical appraisal of many of the studies published on this topic since 1995. It is a well-balanced review, highlighting the main findings of each trial as well as the flaws in the design of the trials that have led to the current controversy.

A lot more controversy is yet to come. On the one hand, prospective trials comparing long-acting dihydropyridines with angiotensin-converting enzyme (ACE) inhibitors in various populations showed superiority of the ACE inhibitor. These trials are the Fosinopril Amlodipine Cardiovascular Events Trial (FACET),2 the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS)3 and the Appropriate Blood Pressure Control in Diabetes (ABCD) Trial comparing nisoldipine (Sular) with enalapril (Vasotec) in patients with type 2 (non– insulin-dependent) diabetes.4 Some trials had to be interrupted prematurely because of excessive incidence of cardiovascular events in the calcium channel antagonist arm. In the ABCD trial, patients treated with nisoldipine experienced fatal and nonfatal myocardial infarction at a rate 9.5 times higher than patients receiving enalapril.

On the other hand, the recently released Sixth Report of the Joint National Commission (JNC VI)5 of the National Institutes of Health (NIH) recommends as first-line therapy not only the diuretics and beta blockers as before6 but also the long-acting dihydropyridines for isolated systolic hypertension in the elderly. This surprising recommendation is based on a single study comparing nitrendipine with placebo in such patients (the Systolic Hypertension in Europe [SYST-EUR] Trial),7 which found a statistically significant reduction in strokes and a nonsignificant reduction in all cardiovascular events and overall mortality in patients receiving nitrendipine. Assuming that these effects can be extrapolated to all long-acting dihydropyridines, the data indicate that treatment with a calcium channel antagonist of this class is better than no treatment. This should at least alleviate concerns about a possible ill-defined deleterious effect of calcium channel antagonists, but does not alter the notion that other antihypertensive medications may be superior in terms of protection from end-organ damage.

This, of course, is the crucial issue in deciding what should be the first choice for the vast majority of asymptomatic “healthy” patients with hypertension (i.e., which class or classes of drugs offer the greatest potential for protection from stroke, heart disease and renal disease) with the minimum infringement on the quality of life. A number of large trials, including the Anti-hypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),8 sponsored by the NIH, were designed specifically to compare the long-term outcomes with various antihypertensive drugs in the general population and in selected subpopulations. Their results, expected mostly after the turn of the century, should provide definitive answers, which is why it has been suggested that the release of the JNC-VI at this time was premature.9

Meantime, what is the practitioner to do? Physicians may continue to prescribe diuretics and beta blockers as first-line drugs because these have proven benefits and retain their role in JNC VI. A nondihydropyridine long-acting calcium channel antagonist may be a first choice in special cases (e.g., patients prone to angina, supraventricular arrhythmias or bronchospasm) as an alternative to beta blockade. Under certain conditions, namely congestive heart failure and diabetes, ACE inhibitors are an ideal first choice because they suppress the reninangiotensin system.10 Definitive guidelines for the use of ACE inhibitors as first-line antihypertensives must await the results of ALLHAT.

For severe hypertension that is resistant to a two-drug regimen, a long-acting dihydropyridine calcium channel antagonist is our choice as a third drug, but it can also be chosen for a two-drug combination with a beta blocker or an ACE inhibitor. We would avoid using a two-drug combination of diuretic and calcium channel antagonist not only because the blood pressure lowering effects of this combination are less than additive but also because most of the adverse outcomes have been reported with such combinations and appear to be particularly detrimental for patients with diabetes-related hypertension.

With the current state of knowledge, we are reluctant to use calcium channel antagonists in patients with congestive heart failure, except as part of a multi-drug combination for coexisting severe resistant hypertension, although this may change if the newly introduced mibefradil (Posicor) proves to be advantageous. And, of course, we keep an open mind and are ready to amend our strategy if new convincing information becomes available.

Dr. Irene Gavras is a clinical professor at Boston University School of Medicine and attending physician at Boston Medical Center. Dr. Haralambos Gavras is a professor of medicine at Boston University School of Medicine, chief of Hypertension and Atherosclerosis at Boston Medical Center and director of a Specialized Center of Research in the Molecular Genetics of Hypertension.

REFERENCES

1. Straka RJ, Swanson AL, Parra D. Calcium channel antagonists, morbidity and mortality: what's the evidence? Am Fam Physician. 1998;57:1551–60.

2. Tatti P, Pahor M, Byington RP, Di Mauro P, Guarisco R, Strollo F. Results of the Fosinopril Amlodipine Cardiovascular Events Trials (FACET) in hypertensive patients with non–insulin dependent diabetes mellitus [Abstract]. Circulation. 1997;96(supple 1):764.

3. Borhani NO, Mercuri M, Borhani PA, Buckalew VM, Canossa-Terris M, Carr AA, et al. Final outcome results of the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS). JAMA. 1996;276:785–91.

4. Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non–insulin-dependent diabetes and hypertension. N Engl J Med. 1998;338:645–52.

5. JNC VI. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of Blood Pressure. Arch Intern Med. 1997;157:2413–46.

6. JNC V. The fifth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1993;153:154–84.

7. Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhager WH, et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet. 1997;350:757–64.

8. Davis BR, Cutler JA, Gordon DJ, Furberg CD, Wright JT Jr, Cushman WC, et al. Rationale and design for the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Am J Hypertens. 1996;9(4 Pt 2):342–60.

9. Furberg CD, Psaty BM. JNC VI: timing is everything. Lancet. 1997;350:1413–4.

10. Gavras H. Angiotensin-converting enzyme inhibition and the heart. Hypertension. 1994;23(6 Pt 2):813–8.


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