September 1, 1995

New analyses regarding the safety of calcium-channel blockers: NHLBI Clinical Alert

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During the late summer and fall, three scientific papers are being published in medical journals reporting new analyses regarding the safety of calcium-channel blocking drugs. Anticipating the release of these data, the National Heart, Lung, and Blood Institute (NHLBI) convened an Ad Hoc Panel on Calcium-Channel Blockers in early June, 1995. Based on the presentations and discussions at this meeting, the Institute has prepared this brief statement to provide a perspective on the new information.

BACKGROUND

The calcium-channel blockers (CCBs), also called calcium entry blockers and calcium antagonists, are a class of vasodilating drugs first introduced into U.S. clinical practice in 1980. The main labeled indications for their use are the treatment of arterial hypertension and of chronic angina pectoris. Their potential effects in preventing, ameliorating, or retarding the progression of other major cardiovascular conditions have also been studied. There are three sub-classes of CCBs that are chemically distinct and have pharmacologic differences: the dihydropyridines (prototype--nifedipine), benzothiazepines (diltiazem), and phenylalkylamines (verapamil). In addition, several CCBs have both short-acting (requiring multiple daily doses) and long-acting (once daily) dosage forms. The latter have been introduced only in recent years.

Concerns about the safety of some CCB drugs first drew attention following the publication of several meta-analyses during 1989-91 (1,2,3). Using statistical methods for pooling results of randomized clinical trials conducted in patients following myocardial infarction (MI) or with stable or unstable angina, these analyses suggested that CCBs of the dihydropyridine sub-class (short-acting nifedipine in all but a few of the long-term trials) increased the risk of mortality (by about 16 percent) and reinfarction (by 19 percent). Non-dihydropyridine CCBs (diltiazem, verapamil) were associated with neither increased nor decreased mortality, but pooled results tended toward lower rates of nonfatal MI.

NEW ANALYSES

A publication in the September 1 issue of "Circulation" (4) extends the meta-analyses just described to address the question of dose-response. In order to do so without attempting to equate doses of different drugs, these analyses were confined to the 16 trials of nifedipine in patients with clinical coronary disease, mostly with acute ischemic syndromes. The trials were divided into six groups according to the dose used in those randomized to nifedipine treatment. A dose-response relationship was observed, and mortality was higher in nifedipine-treated patients compared to placebo in trials that employed a dose of 80 mg daily or greater.

Another study, focused on CCBs in the treatment of hypertension, was published in the August 23/30 issue of the "Journal of the American Medical Association" (5). This is the observational (case-control) study first reported by Psaty et al. at an American Heart Association conference in March, 1995 that was widely discussed in the lay press. As in all observational studies, the choice of drug for each patient was determined by the treating physician based on relevant aspects of the patient's medical condition, likely including risk factors for MI, the cardiovascular (CV) outcome addressed by the study. The investigators attempted to extract information on such confounding factors from the medical records and control for them in their analyses; in retrospective studies there is always some question about the success of such efforts. Two main comparisons were carried out: CCBs versus diuretics in relationship to MI risk in patients free of CV disease according to the medical record; and CCBs versus beta-blockers in patients both without and with diagnosed CV disease (but not a prior MI or heart failure). The results showed a higher risk of MI (by about 60 percent) associated with CCB use compared either with diuretic or with beta-blocker treatment. Further, the higher the CCB dose, the greater the relative risk of MI compared to each of the other drugs. The higher risk of CCBs compared to beta-blockers was seen in patients with and without diagnosed CV disease. When individual CCBs were compared to beta-blockers, the MI risks were higher for each--for nifedipine (by 31 percent), for diltiazem (by 63 percent), and for verapamil (by 61 percent)--but the increased risk was statistically significant only for the latter two drugs. All of the CCBs in this study were in short-acting formulations. Note that the results with diltiazem and verapamil in this population are at odds with those of randomized trials in a post-MI population, a group at high risk for recurrent MI, in which diltiazem and verapamil have had either no effect on events or have shown a favorable trend. The different results could reflect the different populations or could reflect failure to adjust fully for coronary risk factors.

The third new study will be published in the "Journal of the American Geriatrics Society" in November (6). Like the study by Psaty, it is observational in nature, based on records collected for other research purposes. This study was conducted by Pahor, Guralnik, Havlik, and colleagues at the National Institute on Aging in a sample of elderly patients. The analyses focused on risk of mortality in patients prescribed single-drug treatment for hypertension, comparing individual CCBs with beta-blockers. Risk was significantly higher for nifedipine, increased but not significantly so for diltiazem, and not increased for verapamil. Here also, the investigators adjusted for other CV risk factors to the extent possible. Again, all of the CCBs were of the shorter-acting type.

CLINICAL TRIALS IN HYPERTENSION

The last two studies described above are observational and thus subject to all the potential biases of such study designs. Therefore, it is important to consider evidence from randomized controlled trials in hypertensive patients. Unfortunately, the completed trials comparing CCBs to other antihypertensive drugs or to placebo, such as the Treatment of Mild Hypertension Study (7) and the Veterans Administration Monotherapy Trial (8), included only 100-200 patients per treatment group, and therefore were not large enough to reliably detect or exclude a beneficial or harmful effect on MI rate or other CV events. Reported but as-yet- unpublished results from the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS), with about 450 patients in each group, showed (with a small number of total events) a trend toward a higher rate of CV events in the isradapine (a dihydropyridine) compared to the diuretic group (9).

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a large-scale, long-term randomized clinical trial to determine if the rate of coronary heart disease death or nonfatal MI is reduced by antihypertensive treatment with a CCB (amlodipine, an inherently long-acting dihydropyridine), an angiotensin- converting-enzyme inhibitor (lisinopril), or an alpha-1- blocker (doxazosin) compared to a diuretic (chlorthalidone) (10). ALLHAT is sponsored by the NHLBI, in collaboration with the Department of Veterans' Affairs and with support from the pharmaceutical industry. Enrollment of a study population of 40,000 older men and women (approximately half African American) is currently 25 percent complete. Followup is scheduled through the year 2002.

Other large trials involving CCBs are underway in Europe and elsewhere. Only two of these, centered in Scandinavia (11,12), are comparing CCBs to other classes of antihypertensive drugs and have largely enrolled their study populations. One involves shorter-acting dihydropyridine CCBs (11); the other employs diltiazem (12). These trials differ from ALLHAT in other important respects, such as the absence of a double-blind design.

POSSIBLE MECHANISMS OF ADVERSE EFFECTS

There are a number of mechanisms by which CCBs could theoretically increase the risk of adverse CV outcomes in some clinical situations. The shorter-acting drugs can cause reflex sympathetic stimulation, leading to increased myocardial oxygen demand and potentiating arrythmogenesis (13). All CCBs are known to have negative inotropic effects (14). Some CCBs have anti-platelet actions, an effect that has generally been viewed as likely to reduce MI risk. However, this action, together with vasodilatation, could have led to the excess of hemorrhagic complications in a recent trial in cardiac surgery patients (15). Finally, there is evidence for differential arterial vasodilation in the setting of advanced coronary artery disease leading to a redistribution of blood flow to smaller collateral vessels (16).

CONCLUSIONS

Calcium-channel blockers are used in many millions of patients in the United States and other countries. They are effective in relief of certain cardiac disorders--angina pectoris (especially variant angina) and some arrhythmias, and they are effective, well-tolerated agents for blood pressure reduction. Like most drugs, however, CCBs have multiple effects. As such, it is important to establish whether the known benefits are accompanied by significant risks, or conversely whether major morbidity and mortality are reduced. At present, the following conclusions seem prudent and consistent with available information:

1) With recognition of the likely biases of observational studies, the apparent concordance of findings from observational studies of hypertensive patients and randomized trials in primarily acute MI and unstable angina patients suggests that short-acting nifedipine should be used with great caution (if at all), especially at higher doses, in the treatment of hypertension, angina, and MI.

2) Whether this conclusion should be generalized to any other classes of CCBs, to other short-acting dihydropyridines such as isradipine, or to longer-acting dosage forms of nifedipine or other dihydropyridines is unclear. Verapamil and diltiazem were associated with significantly increased MI risk in the University of Washington case-control study in patients with hypertension, but not in other studies, including well-designed clinical trials in patients with MI, a group at high risk of recurrent MI.

3) The results of ongoing and possibly additional large- scale randomized clinical trials in people with hypertension are absolutely essential to the ultimate resolution of these extremely important issues of safety and efficacy. For example, in ALLHAT a risk as large as that seen with CCBs in the study by Psaty et al. could, if present, be detected after only a few years of followup.

4) Practitioners should be reminded that there are drugs with unequivocal survival and other benefits in the post- infarction and hypertensive settings. Certain beta-blockers in post-MI patients (17) are known to reduce mortality and reinfarction; in contrast, controlled trials of adequate size of CCBs have not revealed such a benefit, and there is no reason to use them in the post-infarction setting except to treat symptoms. Similarly, diuretics and beta-blockers have reduced major cardiovascular events and mortality in well-controlled trials in hypertension, while other agents have not been adequately tested, leading "The Fifth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure" to recommend diuretics and beta-blockers as preferred drugs for treating hypertension (18).

5) Uncertainties about the choice of drugs for the treatment of hypertension should not detract from efforts to achieve optimal blood pressure control, because it is clear that lowering blood pressure is an effective strategy for preventing stroke, MI, and other CV sequelae of hypertension.

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REFERENCES

1. Held PH, Yusuf S, Furberg CD. Calcium channel blockers in acute myocardial infarction and unstable angina: an overview. Br Med J. 1989;299:1187-1192.

2. Yusuf S, Held P, Furberg. Update of effects of calcium antagonists in myocardial infarction or angina in light of the second Danish Verapamil Infarction Trial (DAVIT-II) and other recent studies. Am J Cardiol. 1991;67:1295-1297.

3. Glasser SP, Clark PI, Lipicky RJ, Hubbard JM, Yusuf S. Exposing patients with chronic, stable, exertional angina to placebo periods in drug trials. JAMA. 1991;265:1550-1554.

4. Furberg CD, Psaty BM, Meyer JV. Nifedipine: dose- related increase in mortality in patients with coronary heart disease. Circulation. 1995; 92:1326-1331.

5. Psaty BM, Heckbert S, Koepsell T, Siscovick DS, Raghunathan TE, Weiss NS, Rosendaal FR, Lemaitre RN, Smith NL, Wahl PW, Wagner EH, Furberg CD. The risk of myocardial infarction associated with antihypertensive drug therapy. JAMA. 1995;274:620-625.

6. Pahor M, Guralnick JM, Corti MC, Foley DJ, Carbonin P, Havlik RJ. Longterm survival and use of antihypertensive medications in older persons. J Am Geriatr Soc. 1995; (in press).

7. Neaton JD, Grimm RH Jr, Prineas RJ, Stamler J, Grandits GA, Elmer PJ, Cutler JA, Flack JM, Schoenberger JA, McDonald R, Lewis CE, Liebson PR; for the Treatment of Mild Hypertension Study Research Group. Treatment of Mild Hypertension Study: final results. JAMA. 1993;270-713-724.

8. Materson BJ, Reda DJ, Cushman WC, Massie BM, Freis ED, Kochar MS, Hamburger RJ, Fye C, Lakshman R, Gottdiener J, Ramirez EA, Henderson WG; for the DVA Cooperative Study Group on Antihypertensive Agents. Single-drug therapy for hypertension in men: a comparison of six antihypertensive agents with placebo. N Engl J Med. 1993;328:914-921.

9. McClellan K. Unexpected results from MIDAS in atherosclerosis [summary of results presented at the 15th Scientific Meeting of the International Society of Hypertension in Melbourne, Australia, March 1994]. Inpharma Wkly. 1994;932-4.

10. Davis BR, Cutler JA, Gordon DJ, Furberg CD, Wright JT, Cushman WC, Grimm RH, LaRosa J, Whelton PK, Perry HM, Alderman MH, Ford CE, Oparil S, Francis C, Proschan M, Pressel S, Black HR, Hawkins CM; for the ALLHAT Research Group. Rationale and design for the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Am J Hypertension. 1995; (in press).

11. Dahl”f B, Hansson L, Lindholm LH, Schirst‚n B, Wester P-O, Ekbom T, Hedner T, Faire U de. STOP-Hypertension 2: a prospective intervention trial of newer versus older treatment alternatives in old patients with hypertension: Swedish Trial in Old Patients With Hypertension. Blood Press. 1993;2:136-141.

12. The NORDIL Group. The Nordic Diltiazem Study (NORDIL): a prospective intervention trial of calcium antagonist therapy in hypertension. Blood Press. 1993;2:314-321.

13. Ruzicka M, Leenen FHH. Relevance of intermittent increases in sympathetic activity for adverse outcome on short-acting calcium antagonists. In: JH Laragh, BM Breener (eds): Hypertension. Pathophysiology, Diagnosis and Management. New York: Raven Press, 1995; 2815-2825.

14. Francis GS. Calcium channel blockers and congestive heart failure. Circulation. 1991;83:336-338.

15. Wagenknecht LE, Furberg CD, Hammon JW, Legault C, Troost BT. Surgical bleeding: unexpected effect of a calcium antagonist. B Med J. 1995;310:776-777.

16. Egstrup K, Anderson PE. Transient myocardial ischemia during nifedipine therapy in stable angina pectoris, and its relation to coronary collateral flow and comparison with metoprolol. Am J Cardiol. 1993;71:177-183.

17. Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction: an overview of randomized trials. Prog Cardiovasc Dis. 1985;27:335-371.

18. Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. The Fifth Report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure (JNC V). Arch Intern Med. 1993;153:154-183.