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The calcium antagonist controversy: a posthumous commentary1
The Calcium Antagonist Controversy: A Posthumous Commentary Franz H. Messerli,
MD,
and Ehud Grossman,
MD
In 1995, some retrospective reports showed that certain patients treated with short-acting calcium antagonists were at increased risk for myocardial infarction and had a higher mortality rate compared with patients treated with other cardiovascular drugs. Subsequent reports attempted to establish a connection between calcium antagonists and disorders as diverse as malignancy, Parkinsonism, cognitive dysfunction, and suicide. However, other retrospective studies and, more compelling, several prospective studies have reported that calcium antagonists exert a beneficial effect on morbidity and mortality in a variety of cardiovascular disorders such as hypertension, ischemic heart disease after myocardial infarction, and congestive heart failure due to dilated cardiomyopathy. Calcium antagonists are a heteroge-
neous drug class, and distinct differences have been documented between short- and long-acting, as well as between dihydropyridine and nondihydropyridine, agents. Sympathetic activation, which is a risk factor for coronary events, occurs with short-acting agents only and is absent with long-acting calcium antagonists. Recent data make it extremely unlikely that calcium antagonists increase the risk of malignancy by affecting apoptosis or immunosuppression or both. Long-acting calcium antagonists have distinct benefits in patients with hypertension and diabetes and may be more beneficial than other drugs in patients with diabetes and left ventricular hypertrophy. Q1998 by Excerpta Medica, Inc. Am J Cardiol 1998;82:35R–39R
alcium antagonists are widely used as antihypertensive agents, and their use has increased dramatC ically over the last decade. Their wide appeal can be
cium antagonists as a class promote adverse cardiovascular events— deserves further consideration. Recently, a few retrospective studies have been published that attest to the safety of calcium antagonists.6 – 8 Several prospective studies have reported that calcium antagonists exert a beneficial effect on morbidity and mortality in patients with congestive heart failure due to dilated cardiomyopathy, ischemic heart disease after myocardial infarction, and hypertension.9 –13 The evidence for and against calcium antagonists should be weighed solely on its scientific merits. Therefore, several points need to be clarified before one can reach a conclusion.
1
attributed to several features, including their antihypertensive efficacy, metabolic neutrality, and tolerability. If one accepts the surrogate endpoint of lowering blood pressure as the goal of antihypertensive treatment, calcium antagonists could be considered near-ideal agents. However, as with most drug classes, longitudinal studies documenting efficacy in preventing stroke, myocardial infarction, congestive heart failure, or death are sparse. Recent reports show that hypertensive patients treated with short-acting calcium antagonists are at increased risk for myocardial infarction and have a higher mortality rate compared with patients treated with other antihypertensive drugs.2–5 These findings were widely publicized by news media and caused anxiety and even panic among patients, some of whom discontinued the antihypertensive drugs altogether; physicians whose offices were inundated with phone calls were frustrated because of the lack of complete information. Although this panic was unnecessary and unfortunate, the principal question raised by these studies, however imperfect—whether individual calcium antagonists or calFrom the Department of Internal Medicine, Section on Hypertensive Diseases, Ochsner Clinic and Alton Ochsner Medical Foundation, New Orleans, Louisiana; and Internal Medicine D, Chaim Sheba Medical Center, Tel-Hashomer, Israel. Modified from Grossman E, Messerli FH. Calcium antagonists in cardiovascular disease: a necessary controversy but an unnecessary panic. (Editorial.) Am J Med 1997;102:147–149; and from Messerli FH, Grossman E. Do calcium antagonists increase the risk for malignancies? (Editorial.) J Am Coll Cardiol 1998;31:809 – 810. Address for correspondence (reprints are not available): Franz H. Messerli, MD, Ochsner Clinic, 1514 Jefferson Highway, New Orleans, Louisiana 70121. ©1998 by Excerpta Medica, Inc. All rights reserved.
CALCIUM ANTAGONISTS ARE A HETEROGENEOUS CLASS OF DRUG Not all calcium antagonists are created equal; therefore, one cannot assume that all calcium antagonists are equally dangerous or equally beneficial. Psaty et al,3 in a retrospective case-control study, showed a significant increase in the relative risk for myocardial infarction only with verapamil and diltiazem but not with nifedipine. In contrast, Pahor et al,5 in a retrospective cohort study of elderly patients, showed that nifedipine, but not verapamil or diltiazem, was associated with increased mortality risk. Thus, even studies that implicate calcium antagonists as a class for promoting cardiovascular events attest, at a closer look, to the heterogeneity of this effect. Calcium antagonists differ in their molecular structure, their sites and modes of action on the slow calcium channel, and their effects on various other cardiovascular functions. For example, verapamil is less vasoselective, has more negative inotropic effects, and elicits less activation of both the autonomic nervous system and the renin–angiotensin cascade than dihydropyridine calcium antagonists. Verapamil, 0002-9149/98/$19.00 PII S0002-9149(98)00756-5
35R
therefore, may be more appropriate for hypertensive patients with ischemic heart disease, particularly after myocardial infarction.9,10 Conversely, amlodipine, which has little negative inotropic effect, may be beneficial in selected patients with congestive heart failure.11
EFFECTS ARE DOSE-DEPENDENT (SOLA DOSIS FACIT VENENUM) The increased risk for cardiovascular events or mortality with short-acting calcium antagonists was associated only with medium and large doses of these agents.3,4 Neither the case-control study3 nor the metaanalysis4 showed a significant increase in the risk ratio with the low-dose calcium antagonists. Similarly, the risk ratio for mortality was significantly increased only in those who used a large dose of nifedipine in the cohort study.5 In contrast, Reicher-Reiss et al14 showed no increase in morbidity and mortality risk in patients with an acute myocardial infarction who were treated for 1 year with short-acting nifedipine (10 mg 3 times a day). In this study, the 5-year mortality risk of patients who were randomly assigned to nifedipine was exactly the same as that for placebo. These findings are similar to those from a case-control study with thiazide diuretics, in which a larger dose of thiazide was associated with a 3.5-fold increase in the risk for cardiac arrest compared with the lower dose.15 It may not be the drug per se but the dose that determines the risk for cardiovascular events.
LONG-ACTING VERSUS SHORTACTING CALCIUM ANTAGONISTS All retrospective studies that purported to show increased risk with calcium antagonists used the shortacting agents. Short-acting calcium antagonists rapidly attain a plasma concentration that is prone to markedly decrease blood pressure and stimulate the sympathetic nervous system. Although this stimulation is more marked with the first dose, it persists with prolonged therapy of short-acting calcium antagonists (Figure 1).16 A precipitous decrease in blood pressure in association with sympathetic stimulation may decrease coronary blood flow and increase oxygen demand and, thereby, increase the rate of myocardial ischemia, particularly in patients with underlying ischemic heart disease. Another factor to be considered in this context is the activity of the sympathetic nervous system. Increased sympathetic activity is a non–pressure-related coronary risk factor in hypertension. It may directly and indirectly cause the development or maintenance of left ventricular hypertrophy and atherosclerosis and may potentiate cardiac arrhythmias and sudden death.17 Recent studies show that variability in blood pressure, independent of the absolute level, correlates with end-organ damage in hypertensive patients.18,19 Short-acting drugs do not achieve smooth blood pressure control, and their use is associated with major fluctuations in blood pressure. Thus, use of shortacting drugs may fail to attenuate end-organ damage although they decrease blood pressure. The theoretical 36R THE AMERICAN JOURNAL OF CARDIOLOGYT
disadvantages of short-acting calcium antagonists do not apply to long-acting formulations that achieve a more gradual and sustained antihypertensive effect and therefore avoid activating the sympathetic nervous system. For example, distinct differences are observed between short-acting and long-acting nifedipine. Whereas short-acting nifedipine produces an increase in heart rate and circulating catecholamine levels, with the XL formulation, both heart rate and circulating catecholamine levels are unchanged (Figure 2). Alderman et al20 recently documented a 4 – 8-fold lower relative risk ratio of morbidity and mortality in patients taking a long-acting calcium antagonist compared with those taking a short-acting one. A prospective study, the Shanghai Trial of Nifedipine in the Elderly (STONE),12 which compared long-acting nifedipine with placebo in a group of 1,632 elderly hypertensive patients, showed a significant reduction of 59% for all events and of 62% for combined cardiovascular events in the active treatment arm. The Systolic Hypertension in Europe (Syst-Eur) study21 has provided ironclad data attesting to the safety and efficacy of calcium antagonists. In this study, .4,000 elderly patients with isolated systolic hypertension were randomly assigned to a calcium antagonist (nitrendipine) or to placebo. The study was terminated early because of a 42% reduction in the stroke rate in the calcium antagonist arm. The study also revealed highly significant reductions in the rates of cardiac endpoints and cardiovascular events.
IS THE DIABETIC HYPERTENSIVE PATIENT DIFFERENT? A comparison of Syst-Eur with the Systolic Hypertension in the Elderly (SHEP) study shows that there was no difference in the reduction of morbidity and mortality between a diuretic and a calcium antagonist in the subjects without diabetes; a significantly greater benefit was achieved with a calcium antagonist in hypertensive patients with diabetes. In fact, in the 10% of patients in the Syst-Eur trial who had diabetes, the benefits of antihypertensive therapy with a calcium antagonist were much more pronounced than in nondiabetic patients.22 These data, attesting to benefits of long-acting dihydropyridine calcium antagonists in hypertensive patients with diabetes, are not necessarily in conflict with those of the Appropriate Blood Pressure Control in Diabetes (ABCD) study,23 in which in a similar population there was no difference between an angiotensin-converting enzyme (ACE) inhibitor and the long-acting dihydropyridine calcium antagonist in primary outcome (renal function), although admittedly more patients taking the calcium antagonists had myocardial infarctions. However, since a placebo arm was lacking in that study, the absolute reduction in rates of myocardial infarction could not be compared between the 2 treatment groups. One may conclude from these 2 studies that ACE inhibitors have a more favorable effect in the
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NOVEMBER 12, 1998
FIGURE 1. Acute and long-term effects of short-acting calcium antagonists on mean arterial pressure (MAP), heart rate (HR), and norepinephrine (NE).
FIGURE 2. Effects of short and long-acting nifedipine on mean arterial pressure (MAP), heart rate (HR), and norepinephrine (NE).
hypertensive patient with diabetes than do calcium antagonists, but not that calcium antagonists are harmful. Interesting in this regard is a recent study in hypertensive patients with diabetes and left ventricular hypertrophy.24 In a 48-week follow-up, nitrendipine decreased arterial pressure and, in parallel, decreased left ventricular mass. In contrast, despite a similar decrease in arterial pressure, enalapril did not decrease left ventricular mass. This difference is astonishing because ACE inhibitors have been believed to be the most powerful drug class for decreasing left ventricular hypertrophy. The fact that in the hypertensive patient with diabetes the activity of the renin–angiotensin–aldosterone cascade is often low (hyporeninemia/hypoaldosteronism) could, to some extent, account for the relative inefficacy of the ACE inhibitor compared with the calcium antagonist.
DO CALCIUM ANTAGONISTS INCREASE THE RISK FOR MALIGNANCY? Cardiovascular disorders such as hypertension, hyperlipidemia, and arrhythmias often require treatment for years and even decades. Since morbidity and mortality of these disorders (particularly when mild) are relatively low, the benefits from treatment are comparatively small. The British MRC study25 allows us to calculate that almost 1,000 patients need to be exposed to antihypertensive therapy with a diuretic for 1 year to prevent a single stroke. Diuretic drugs are comparatively powerful drugs to prevent stroke, and benefits are easy to demonstrate. In contrast, the effects of b blockers on strokes and the benefits of b blockers and diuretics on coronary artery disease are considerably smaller. This means that numerous patients will be exposed to the adverse effects and cost A SYMPOSIUM: CALCIUM ANTAGONIST CONTROVERSY
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FIGURE 3. Prospective studies reporting malignancy rates in calcium antagonist (CA) users. CI 5 confidence interval; HCTZ 5 hydrochlorothiazide; MIDAS 5 Multicenter Isradipine Diuretic Atherosclerosis Study; Nifedipine SR 5 nifedipine slow release; PRAISE 5 Prospective Randomized Amlodipine Survival Evaluation; STONE 5 Shanghai Trial of Nifedipine in the Elderly; Syst-Eur 5 Systolic Hypertension in Europe.
of these drugs without harvesting real benefit. Given this scenario of small benefits and long-term exposure, any potential risk of malignancy associated with drugs to treat chronic cardiovascular disorders has to be taken very seriously. Chemical agents can increase the risk for malignancy either by being directly carcinogenic or by impeding the immune response or apoptosis, or both. Direct carcinogenicity usually requires many years and even decades of exposure and is specific for certain malignancies only. In contrast, the effects of immunosuppression or inhibition of apoptosis can manifest themselves within a much shorter period and affect a much larger spectrum of malignancies. It is apoptosis that is purported to be affected by calcium antagonists. In this regard, several studies provide some reassurance. In a cohort of .11,000 patients, half of whom were receiving a calcium antagonist, Braun et al26 observed no increase in malignancy rates. Of note, most patients were receiving the shortacting forms of nifedipine, diltiazem, and verapamil— the same drugs that in much smaller studies were implicated in carcinogenicity. Several other studies from powerful data bases also refute the hypothesis that calcium antagonists increase the risk of malignancies. In .4,000 patients in the West of Scotland Cancer Surveillance Unit,27 a retrospective analysis showed no increased malignancy risk. Similarly, a Danish cohort study28 of .17,000 patients showed no excess malignancy risk in those taking a calcium antagonist. In all 4 prospective randomized trials assessing morbidity and mortality, the malignancy risk was lower in patients receiving calcium antagonists than in those receiving either placebo or diuretics (Figure 3).2,11,12,21 Perhaps the most powerful data refuting the hypothesis that calcium antagonists alter apoptosis come from the Mayo Clinic. In 621 posttransplant patients with immunosuppression by cyclosporine, Textor et al29 found no excess malignancy 38R THE AMERICAN JOURNAL OF CARDIOLOGYT
risk in those receiving calcium antagonists (despite comparable immunosuppression) compared with those who were not. Thus, it is extremely unlikely that calcium antagonists increase the risk of malignancy by affecting apoptosis or immunosuppression or both. Although we can be reassured to a great extent by existing data, we must continue to be vigilant with regard to carcinogenicity of all drugs used to treat cardiovascular disorders for years and decades.
CONCLUSIONS Considering the data available in 1998, we believe that short-acting calcium antagonists should no longer be used for treatment of hypertension. The practice of using oral or sublingual nifedipine in a hypertensive emergency or pseudoemergency should be abandoned because it can lead to syncope, myocardial infarction, stroke, and death.30 However, use of a low dose of the long-acting formulations appears to be safe and promising in patients with essential hypertension. Despite the availability of many antihypertensive drugs, only 26% of US patients with hypertension have their condition adequately controlled (blood pressure ,140/90 mm Hg).31 Therefore, long-acting calcium antagonists should continue to be a cornerstone in the treatment strategy. In hypertensive patients with diabetes, blood pressure lowering with calcium antagonists is clearly beneficial and may have a particular advantage in patients with left ventricular hypertrophy. The calcium antagonist controversy was helpful in alerting physicians to the fact that hypertension remains a surrogate endpoint and that not all drugs that decrease blood pressure will, pari passu, decrease morbidity and mortality. A prime example of failure of the so-called surrogate endpoint concept is provided by our recent meta-analysis in hypertension in the elderly: Although b blockers did lower blood
VOL. 82 (9B)
NOVEMBER 12, 1998
pressure, they consistently failed to decrease the rate of myocardial infarction and cardiovascular and allcause mortality.32 This means that numerous elderly hypertensive patients are exposed to adverse effects, inconvenience, and cost of b blockers without harvesting any benefits. The excessive news media coverage of the calcium blocker controversy was inappropriate and led to panic and confusion among patients and frustration among physicians. Perhaps we should remember the first rule of treatment set forth by Sir George Pickering: “Never frighten your patients.”33 1. Leader SG, Mallick R, Briggs NC. Myocardial infarction in newly diagnosed hypertensive Medicaid patients free of coronary heart disease and treated with calcium channel blockers. Am J Med 1997;102:150 –157. 2. Borhani NO, Mercuri M, Borhani PA, Buckalew VM, Canossa-Terris M, Carr AA, Kappagoda T, Rocco MV, Schnaper HW, Sowers JR. Final outcome results of the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS). A randomized controlled trial. JAMA 1996;276:785–791. 3. Psaty BM, Heckbert SR, Koepsell TD, 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 therapies. JAMA 1995;274:620 – 625. 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. Pahor M, Guralnik JM, Corti MC, Foley DJ, Carbonin P, Havlik RJ. Long-term survival and use of antihypertensive medications in older persons. J Am Geriatr Soc 1995;43:1191–1197. 6. Braun S, Boyko V, Behar S, Reicher-Reiss H, Shotan A, Schlesinger Z, Rosenfeld T, Palant A, Friedensohn A, Laniado S, Goldbourt U. Calcium antagonists and mortality in patients with coronary artery disease: a cohort study of 11,575 patients. J Am Coll Cardiol 1996;28:7–11. 7. Aursnes I, Litleskare I, Froyland H, Abdelnoor M. Association between various drugs used for hypertension and risk of acute myocardial infarction. Blood Press 1995;4:157–163. 8. Jick H, Derby LE, Gurewich V, Vasilakis C. The risk of myocardial infarction associated with antihypertensive drug treatment in persons with uncomplicated essential hypertension. Pharmacotherapy 1996;16:321–326. 9. Danish Study Group on Verapamil in Myocardial Infarction. Effect of verapamil on mortality and major events after acute myocardial infarction (The Danish Verapamil Infarction Trial-II [DAVIT II]). Am J Cardiol 1990;66:779 – 785. 10. Multicenter Diltiazem Postinfarction Trial Research Group. The effect of diltiazem on mortality and reinfarction after myocardial infarction. N Engl J Med 1988;319:385–392. 11. Packer M, O’Connor CM, Ghali JK, Pressler ML, Carson PE, Belkin RN, Miller AB, Neuberg GW, Frid D, Wertheimer JH, Cropp AB, DeMets DL, for the Prospective Randomized Amlodipine Survival Evaluation Study Group (PRAISE). Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Engl J Med 1996;335:1107–1114. 12. Gong L, Zhang W, Zhu Y, Zhu J, 11 collaborating centres in the Shanghai area, Kong D, Page´ V, Ghadirian P, LeLorier J, Hamet P. Shanghai Trial of Nifedipine in the Elderly (STONE). J Hypertens 1996;14:1237–1245. 13. The DEFIANT-II Research Group. Doppler flow and echocardiography in functional cardiac insufficiency: assessment of nisoldipine therapy. Results of the DEFIANT-II Study. Eur Heart J 1997;18:31– 40. 14. Reicher-Reiss H, Behar S, Boyko V, Mandelzweig L, Kaplinsky E, Goldbourt U. Long-term mortality follow-up of hospital survivors of a myocardial infarction
randomized to nifedipine in the SPRINT study. Secondary Prevention Reinfarction Israeli Nifedipine Trial. Cardiovasc Drugs Ther 1998;12:171–176. 15. Siscovick DS, Raghunathan TE, Psaty BM, Koepsell TD, Wicklund KG, Lin X, Cobb L, Rautaharju PM, Copass MK, Wagner EH. Diuretic therapy for hypertension and the risk of primary cardiac arrest. N Engl J Med 1994;330: 1852–1857. 16. Grossman E, Messerli FH. Effect of calcium antagonists on plasma, norepinephrine levels, heart rate, and blood pressure. Am J Cardiol 1997;80:1453–1458. 17. Ruzicka M, Leenen FH. Relevance of 24 H blood pressure profile and sympathetic activity for outcome on short versus long-acting 1,4-dihydropyridines. Am J Hypertens 1996;9:86 –94. 18. Parati G, Pomidossi G, Albini F, Malaspina D, Mancia G. Relationship of 24-hour blood pressure mean and variability to severity of target-organ damage in hypertension. J Hypertens 1987;5:93–98. 19. Frattola A, Parati G, Cuspidi C, Albini F, Mancia G. Prognostic value of 24-hour blood pressure variability. J Hypertens 1993;11:1133–1137. 20. Alderman MH, Cohen HW, Roque´ R, Madhavan S. The risk of cardiovascular morbidity and mortality associated with calcium channel blockers in antihypertensive therapy. Lancet 1998; in press. 21. Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhager WH, Bulpitt CJ, de Leeuw PW, Dollery CT, Fletcher AE, Forette F, Leonetti G, Nachev C, O’Brien ET, Rosenfeld J, Rodicio JL, Tuomilehto J, Zanchetti A. 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;350:757–764. 22. Tuomilehto J, Rastenyte D, Birkenha¨ger WH, Staessen JA, Thijs L, Antikainen R, Bulpitt CJ, Fagard R, Fletcher A, Forette F, Goldhaber A, Palantin P, Sarti C, for the Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Cardiovascular prognosis in older diabetic and nondiabetic patients treated or untreated for isolated systolic hypertension. N Engl J Med 1998; in press. 23. 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– 652. 24. Gerritsen TA, Bak AAA, Stolk RP, Jonker JJC, Grobbee DE. Effects of nitrendipine and enalapril on left ventricular mass in patients with non-insulindependent diabetes mellitus and hypertension. J Hypertens 1998;16:689 – 696. 25. MRC Working Party. Medical Research Council trial of treatment of hypertension in older adults: principal results. Br Med J 1985;291:97–104. 26. Braun S, Boyko V, Behar S, Reicher-Reiss H, Laniado S, Kaplinsky E, Goldbourt U. Calcium channel blocking agents and risk of cancer in patients with coronary heart disease. Bezafibrate Infarction Prevention (BIP) Study Research Group. J Am Coll Cardiol 1998;31:804 – 808. 27. Hole DJ, Gillis CR, McCallum IR, McInnes GT, MacKinnon PL, Meredith PA, Murray LS, Robertson JW, Lever AF. Cancer risk of hypertensive patients taking calcium antagonists. J Hypertens 1998;16:119 –124. 28. Olsen JH, Sørensen HT, Frijs S, McLaughlin JK, Steffensen FH, Nielsen GL, Andersen M, Fraumeni JF Jr, Olsen J. Cancer risk in users of calcium channel blockers. Hypertension 1997;29:1091–1094. 29. Textor SC, Taler SJ, Canzanello VJ, Schwartz L, Wiesner RH, Porayko MK, Krom RAF. Cancer after liver transplantation (TX): excess risk associated with calcium channel blocker administration? (Abstr.) Am J Hypertens 1997;10:199A. 30. Grossman E, Messerli EH, Grodzicki T, Kowey P. Should a moratorium be placed on nifedipine capsules in hypertensive emergencies and pseudoemergencies? JAMA 1996;276:1328 –1331. 31. Burt VL, Whelton P, Roccella EJ, Brown C, Cutler JA, Higgins M, Horan MJ, Labarthe D. Prevalence of hypertension in the US adult population. Results from the Third National Health and Nutrition Examination Survey, 1988 –1991. Hypertension 1995;25:305–313. 32. Messerli FH, Grossman E, Goldbourt U. Are b-blockers efficacious as first-line therapy for hypertension in the elderly? A systematic review. JAMA 1998;279:1903–1907. 33. Pickering GA. Part I: Hypertension. Definitions, natural histories, and consequences. In: Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis, and Management. Vol. 1, 2nd ed. New York: Raven Press, 1995:3–21.
A SYMPOSIUM: CALCIUM ANTAGONIST CONTROVERSY
39R
MD,
and Ehud Grossman,
MD
In 1995, some retrospective reports showed that certain patients treated with short-acting calcium antagonists were at increased risk for myocardial infarction and had a higher mortality rate compared with patients treated with other cardiovascular drugs. Subsequent reports attempted to establish a connection between calcium antagonists and disorders as diverse as malignancy, Parkinsonism, cognitive dysfunction, and suicide. However, other retrospective studies and, more compelling, several prospective studies have reported that calcium antagonists exert a beneficial effect on morbidity and mortality in a variety of cardiovascular disorders such as hypertension, ischemic heart disease after myocardial infarction, and congestive heart failure due to dilated cardiomyopathy. Calcium antagonists are a heteroge-
neous drug class, and distinct differences have been documented between short- and long-acting, as well as between dihydropyridine and nondihydropyridine, agents. Sympathetic activation, which is a risk factor for coronary events, occurs with short-acting agents only and is absent with long-acting calcium antagonists. Recent data make it extremely unlikely that calcium antagonists increase the risk of malignancy by affecting apoptosis or immunosuppression or both. Long-acting calcium antagonists have distinct benefits in patients with hypertension and diabetes and may be more beneficial than other drugs in patients with diabetes and left ventricular hypertrophy. Q1998 by Excerpta Medica, Inc. Am J Cardiol 1998;82:35R–39R
alcium antagonists are widely used as antihypertensive agents, and their use has increased dramatC ically over the last decade. Their wide appeal can be
cium antagonists as a class promote adverse cardiovascular events— deserves further consideration. Recently, a few retrospective studies have been published that attest to the safety of calcium antagonists.6 – 8 Several prospective studies have reported that calcium antagonists exert a beneficial effect on morbidity and mortality in patients with congestive heart failure due to dilated cardiomyopathy, ischemic heart disease after myocardial infarction, and hypertension.9 –13 The evidence for and against calcium antagonists should be weighed solely on its scientific merits. Therefore, several points need to be clarified before one can reach a conclusion.
1
attributed to several features, including their antihypertensive efficacy, metabolic neutrality, and tolerability. If one accepts the surrogate endpoint of lowering blood pressure as the goal of antihypertensive treatment, calcium antagonists could be considered near-ideal agents. However, as with most drug classes, longitudinal studies documenting efficacy in preventing stroke, myocardial infarction, congestive heart failure, or death are sparse. Recent reports show that hypertensive patients treated with short-acting calcium antagonists are at increased risk for myocardial infarction and have a higher mortality rate compared with patients treated with other antihypertensive drugs.2–5 These findings were widely publicized by news media and caused anxiety and even panic among patients, some of whom discontinued the antihypertensive drugs altogether; physicians whose offices were inundated with phone calls were frustrated because of the lack of complete information. Although this panic was unnecessary and unfortunate, the principal question raised by these studies, however imperfect—whether individual calcium antagonists or calFrom the Department of Internal Medicine, Section on Hypertensive Diseases, Ochsner Clinic and Alton Ochsner Medical Foundation, New Orleans, Louisiana; and Internal Medicine D, Chaim Sheba Medical Center, Tel-Hashomer, Israel. Modified from Grossman E, Messerli FH. Calcium antagonists in cardiovascular disease: a necessary controversy but an unnecessary panic. (Editorial.) Am J Med 1997;102:147–149; and from Messerli FH, Grossman E. Do calcium antagonists increase the risk for malignancies? (Editorial.) J Am Coll Cardiol 1998;31:809 – 810. Address for correspondence (reprints are not available): Franz H. Messerli, MD, Ochsner Clinic, 1514 Jefferson Highway, New Orleans, Louisiana 70121. ©1998 by Excerpta Medica, Inc. All rights reserved.
CALCIUM ANTAGONISTS ARE A HETEROGENEOUS CLASS OF DRUG Not all calcium antagonists are created equal; therefore, one cannot assume that all calcium antagonists are equally dangerous or equally beneficial. Psaty et al,3 in a retrospective case-control study, showed a significant increase in the relative risk for myocardial infarction only with verapamil and diltiazem but not with nifedipine. In contrast, Pahor et al,5 in a retrospective cohort study of elderly patients, showed that nifedipine, but not verapamil or diltiazem, was associated with increased mortality risk. Thus, even studies that implicate calcium antagonists as a class for promoting cardiovascular events attest, at a closer look, to the heterogeneity of this effect. Calcium antagonists differ in their molecular structure, their sites and modes of action on the slow calcium channel, and their effects on various other cardiovascular functions. For example, verapamil is less vasoselective, has more negative inotropic effects, and elicits less activation of both the autonomic nervous system and the renin–angiotensin cascade than dihydropyridine calcium antagonists. Verapamil, 0002-9149/98/$19.00 PII S0002-9149(98)00756-5
35R
therefore, may be more appropriate for hypertensive patients with ischemic heart disease, particularly after myocardial infarction.9,10 Conversely, amlodipine, which has little negative inotropic effect, may be beneficial in selected patients with congestive heart failure.11
EFFECTS ARE DOSE-DEPENDENT (SOLA DOSIS FACIT VENENUM) The increased risk for cardiovascular events or mortality with short-acting calcium antagonists was associated only with medium and large doses of these agents.3,4 Neither the case-control study3 nor the metaanalysis4 showed a significant increase in the risk ratio with the low-dose calcium antagonists. Similarly, the risk ratio for mortality was significantly increased only in those who used a large dose of nifedipine in the cohort study.5 In contrast, Reicher-Reiss et al14 showed no increase in morbidity and mortality risk in patients with an acute myocardial infarction who were treated for 1 year with short-acting nifedipine (10 mg 3 times a day). In this study, the 5-year mortality risk of patients who were randomly assigned to nifedipine was exactly the same as that for placebo. These findings are similar to those from a case-control study with thiazide diuretics, in which a larger dose of thiazide was associated with a 3.5-fold increase in the risk for cardiac arrest compared with the lower dose.15 It may not be the drug per se but the dose that determines the risk for cardiovascular events.
LONG-ACTING VERSUS SHORTACTING CALCIUM ANTAGONISTS All retrospective studies that purported to show increased risk with calcium antagonists used the shortacting agents. Short-acting calcium antagonists rapidly attain a plasma concentration that is prone to markedly decrease blood pressure and stimulate the sympathetic nervous system. Although this stimulation is more marked with the first dose, it persists with prolonged therapy of short-acting calcium antagonists (Figure 1).16 A precipitous decrease in blood pressure in association with sympathetic stimulation may decrease coronary blood flow and increase oxygen demand and, thereby, increase the rate of myocardial ischemia, particularly in patients with underlying ischemic heart disease. Another factor to be considered in this context is the activity of the sympathetic nervous system. Increased sympathetic activity is a non–pressure-related coronary risk factor in hypertension. It may directly and indirectly cause the development or maintenance of left ventricular hypertrophy and atherosclerosis and may potentiate cardiac arrhythmias and sudden death.17 Recent studies show that variability in blood pressure, independent of the absolute level, correlates with end-organ damage in hypertensive patients.18,19 Short-acting drugs do not achieve smooth blood pressure control, and their use is associated with major fluctuations in blood pressure. Thus, use of shortacting drugs may fail to attenuate end-organ damage although they decrease blood pressure. The theoretical 36R THE AMERICAN JOURNAL OF CARDIOLOGYT
disadvantages of short-acting calcium antagonists do not apply to long-acting formulations that achieve a more gradual and sustained antihypertensive effect and therefore avoid activating the sympathetic nervous system. For example, distinct differences are observed between short-acting and long-acting nifedipine. Whereas short-acting nifedipine produces an increase in heart rate and circulating catecholamine levels, with the XL formulation, both heart rate and circulating catecholamine levels are unchanged (Figure 2). Alderman et al20 recently documented a 4 – 8-fold lower relative risk ratio of morbidity and mortality in patients taking a long-acting calcium antagonist compared with those taking a short-acting one. A prospective study, the Shanghai Trial of Nifedipine in the Elderly (STONE),12 which compared long-acting nifedipine with placebo in a group of 1,632 elderly hypertensive patients, showed a significant reduction of 59% for all events and of 62% for combined cardiovascular events in the active treatment arm. The Systolic Hypertension in Europe (Syst-Eur) study21 has provided ironclad data attesting to the safety and efficacy of calcium antagonists. In this study, .4,000 elderly patients with isolated systolic hypertension were randomly assigned to a calcium antagonist (nitrendipine) or to placebo. The study was terminated early because of a 42% reduction in the stroke rate in the calcium antagonist arm. The study also revealed highly significant reductions in the rates of cardiac endpoints and cardiovascular events.
IS THE DIABETIC HYPERTENSIVE PATIENT DIFFERENT? A comparison of Syst-Eur with the Systolic Hypertension in the Elderly (SHEP) study shows that there was no difference in the reduction of morbidity and mortality between a diuretic and a calcium antagonist in the subjects without diabetes; a significantly greater benefit was achieved with a calcium antagonist in hypertensive patients with diabetes. In fact, in the 10% of patients in the Syst-Eur trial who had diabetes, the benefits of antihypertensive therapy with a calcium antagonist were much more pronounced than in nondiabetic patients.22 These data, attesting to benefits of long-acting dihydropyridine calcium antagonists in hypertensive patients with diabetes, are not necessarily in conflict with those of the Appropriate Blood Pressure Control in Diabetes (ABCD) study,23 in which in a similar population there was no difference between an angiotensin-converting enzyme (ACE) inhibitor and the long-acting dihydropyridine calcium antagonist in primary outcome (renal function), although admittedly more patients taking the calcium antagonists had myocardial infarctions. However, since a placebo arm was lacking in that study, the absolute reduction in rates of myocardial infarction could not be compared between the 2 treatment groups. One may conclude from these 2 studies that ACE inhibitors have a more favorable effect in the
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FIGURE 1. Acute and long-term effects of short-acting calcium antagonists on mean arterial pressure (MAP), heart rate (HR), and norepinephrine (NE).
FIGURE 2. Effects of short and long-acting nifedipine on mean arterial pressure (MAP), heart rate (HR), and norepinephrine (NE).
hypertensive patient with diabetes than do calcium antagonists, but not that calcium antagonists are harmful. Interesting in this regard is a recent study in hypertensive patients with diabetes and left ventricular hypertrophy.24 In a 48-week follow-up, nitrendipine decreased arterial pressure and, in parallel, decreased left ventricular mass. In contrast, despite a similar decrease in arterial pressure, enalapril did not decrease left ventricular mass. This difference is astonishing because ACE inhibitors have been believed to be the most powerful drug class for decreasing left ventricular hypertrophy. The fact that in the hypertensive patient with diabetes the activity of the renin–angiotensin–aldosterone cascade is often low (hyporeninemia/hypoaldosteronism) could, to some extent, account for the relative inefficacy of the ACE inhibitor compared with the calcium antagonist.
DO CALCIUM ANTAGONISTS INCREASE THE RISK FOR MALIGNANCY? Cardiovascular disorders such as hypertension, hyperlipidemia, and arrhythmias often require treatment for years and even decades. Since morbidity and mortality of these disorders (particularly when mild) are relatively low, the benefits from treatment are comparatively small. The British MRC study25 allows us to calculate that almost 1,000 patients need to be exposed to antihypertensive therapy with a diuretic for 1 year to prevent a single stroke. Diuretic drugs are comparatively powerful drugs to prevent stroke, and benefits are easy to demonstrate. In contrast, the effects of b blockers on strokes and the benefits of b blockers and diuretics on coronary artery disease are considerably smaller. This means that numerous patients will be exposed to the adverse effects and cost A SYMPOSIUM: CALCIUM ANTAGONIST CONTROVERSY
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FIGURE 3. Prospective studies reporting malignancy rates in calcium antagonist (CA) users. CI 5 confidence interval; HCTZ 5 hydrochlorothiazide; MIDAS 5 Multicenter Isradipine Diuretic Atherosclerosis Study; Nifedipine SR 5 nifedipine slow release; PRAISE 5 Prospective Randomized Amlodipine Survival Evaluation; STONE 5 Shanghai Trial of Nifedipine in the Elderly; Syst-Eur 5 Systolic Hypertension in Europe.
of these drugs without harvesting real benefit. Given this scenario of small benefits and long-term exposure, any potential risk of malignancy associated with drugs to treat chronic cardiovascular disorders has to be taken very seriously. Chemical agents can increase the risk for malignancy either by being directly carcinogenic or by impeding the immune response or apoptosis, or both. Direct carcinogenicity usually requires many years and even decades of exposure and is specific for certain malignancies only. In contrast, the effects of immunosuppression or inhibition of apoptosis can manifest themselves within a much shorter period and affect a much larger spectrum of malignancies. It is apoptosis that is purported to be affected by calcium antagonists. In this regard, several studies provide some reassurance. In a cohort of .11,000 patients, half of whom were receiving a calcium antagonist, Braun et al26 observed no increase in malignancy rates. Of note, most patients were receiving the shortacting forms of nifedipine, diltiazem, and verapamil— the same drugs that in much smaller studies were implicated in carcinogenicity. Several other studies from powerful data bases also refute the hypothesis that calcium antagonists increase the risk of malignancies. In .4,000 patients in the West of Scotland Cancer Surveillance Unit,27 a retrospective analysis showed no increased malignancy risk. Similarly, a Danish cohort study28 of .17,000 patients showed no excess malignancy risk in those taking a calcium antagonist. In all 4 prospective randomized trials assessing morbidity and mortality, the malignancy risk was lower in patients receiving calcium antagonists than in those receiving either placebo or diuretics (Figure 3).2,11,12,21 Perhaps the most powerful data refuting the hypothesis that calcium antagonists alter apoptosis come from the Mayo Clinic. In 621 posttransplant patients with immunosuppression by cyclosporine, Textor et al29 found no excess malignancy 38R THE AMERICAN JOURNAL OF CARDIOLOGYT
risk in those receiving calcium antagonists (despite comparable immunosuppression) compared with those who were not. Thus, it is extremely unlikely that calcium antagonists increase the risk of malignancy by affecting apoptosis or immunosuppression or both. Although we can be reassured to a great extent by existing data, we must continue to be vigilant with regard to carcinogenicity of all drugs used to treat cardiovascular disorders for years and decades.
CONCLUSIONS Considering the data available in 1998, we believe that short-acting calcium antagonists should no longer be used for treatment of hypertension. The practice of using oral or sublingual nifedipine in a hypertensive emergency or pseudoemergency should be abandoned because it can lead to syncope, myocardial infarction, stroke, and death.30 However, use of a low dose of the long-acting formulations appears to be safe and promising in patients with essential hypertension. Despite the availability of many antihypertensive drugs, only 26% of US patients with hypertension have their condition adequately controlled (blood pressure ,140/90 mm Hg).31 Therefore, long-acting calcium antagonists should continue to be a cornerstone in the treatment strategy. In hypertensive patients with diabetes, blood pressure lowering with calcium antagonists is clearly beneficial and may have a particular advantage in patients with left ventricular hypertrophy. The calcium antagonist controversy was helpful in alerting physicians to the fact that hypertension remains a surrogate endpoint and that not all drugs that decrease blood pressure will, pari passu, decrease morbidity and mortality. A prime example of failure of the so-called surrogate endpoint concept is provided by our recent meta-analysis in hypertension in the elderly: Although b blockers did lower blood
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pressure, they consistently failed to decrease the rate of myocardial infarction and cardiovascular and allcause mortality.32 This means that numerous elderly hypertensive patients are exposed to adverse effects, inconvenience, and cost of b blockers without harvesting any benefits. The excessive news media coverage of the calcium blocker controversy was inappropriate and led to panic and confusion among patients and frustration among physicians. Perhaps we should remember the first rule of treatment set forth by Sir George Pickering: “Never frighten your patients.”33 1. Leader SG, Mallick R, Briggs NC. Myocardial infarction in newly diagnosed hypertensive Medicaid patients free of coronary heart disease and treated with calcium channel blockers. Am J Med 1997;102:150 –157. 2. Borhani NO, Mercuri M, Borhani PA, Buckalew VM, Canossa-Terris M, Carr AA, Kappagoda T, Rocco MV, Schnaper HW, Sowers JR. Final outcome results of the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS). A randomized controlled trial. JAMA 1996;276:785–791. 3. Psaty BM, Heckbert SR, Koepsell TD, 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 therapies. JAMA 1995;274:620 – 625. 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. Pahor M, Guralnik JM, Corti MC, Foley DJ, Carbonin P, Havlik RJ. Long-term survival and use of antihypertensive medications in older persons. J Am Geriatr Soc 1995;43:1191–1197. 6. Braun S, Boyko V, Behar S, Reicher-Reiss H, Shotan A, Schlesinger Z, Rosenfeld T, Palant A, Friedensohn A, Laniado S, Goldbourt U. Calcium antagonists and mortality in patients with coronary artery disease: a cohort study of 11,575 patients. J Am Coll Cardiol 1996;28:7–11. 7. Aursnes I, Litleskare I, Froyland H, Abdelnoor M. Association between various drugs used for hypertension and risk of acute myocardial infarction. Blood Press 1995;4:157–163. 8. Jick H, Derby LE, Gurewich V, Vasilakis C. The risk of myocardial infarction associated with antihypertensive drug treatment in persons with uncomplicated essential hypertension. Pharmacotherapy 1996;16:321–326. 9. Danish Study Group on Verapamil in Myocardial Infarction. Effect of verapamil on mortality and major events after acute myocardial infarction (The Danish Verapamil Infarction Trial-II [DAVIT II]). Am J Cardiol 1990;66:779 – 785. 10. Multicenter Diltiazem Postinfarction Trial Research Group. The effect of diltiazem on mortality and reinfarction after myocardial infarction. N Engl J Med 1988;319:385–392. 11. Packer M, O’Connor CM, Ghali JK, Pressler ML, Carson PE, Belkin RN, Miller AB, Neuberg GW, Frid D, Wertheimer JH, Cropp AB, DeMets DL, for the Prospective Randomized Amlodipine Survival Evaluation Study Group (PRAISE). Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Engl J Med 1996;335:1107–1114. 12. Gong L, Zhang W, Zhu Y, Zhu J, 11 collaborating centres in the Shanghai area, Kong D, Page´ V, Ghadirian P, LeLorier J, Hamet P. Shanghai Trial of Nifedipine in the Elderly (STONE). J Hypertens 1996;14:1237–1245. 13. The DEFIANT-II Research Group. Doppler flow and echocardiography in functional cardiac insufficiency: assessment of nisoldipine therapy. Results of the DEFIANT-II Study. Eur Heart J 1997;18:31– 40. 14. Reicher-Reiss H, Behar S, Boyko V, Mandelzweig L, Kaplinsky E, Goldbourt U. Long-term mortality follow-up of hospital survivors of a myocardial infarction
randomized to nifedipine in the SPRINT study. Secondary Prevention Reinfarction Israeli Nifedipine Trial. Cardiovasc Drugs Ther 1998;12:171–176. 15. Siscovick DS, Raghunathan TE, Psaty BM, Koepsell TD, Wicklund KG, Lin X, Cobb L, Rautaharju PM, Copass MK, Wagner EH. Diuretic therapy for hypertension and the risk of primary cardiac arrest. N Engl J Med 1994;330: 1852–1857. 16. Grossman E, Messerli FH. Effect of calcium antagonists on plasma, norepinephrine levels, heart rate, and blood pressure. Am J Cardiol 1997;80:1453–1458. 17. Ruzicka M, Leenen FH. Relevance of 24 H blood pressure profile and sympathetic activity for outcome on short versus long-acting 1,4-dihydropyridines. Am J Hypertens 1996;9:86 –94. 18. Parati G, Pomidossi G, Albini F, Malaspina D, Mancia G. Relationship of 24-hour blood pressure mean and variability to severity of target-organ damage in hypertension. J Hypertens 1987;5:93–98. 19. Frattola A, Parati G, Cuspidi C, Albini F, Mancia G. Prognostic value of 24-hour blood pressure variability. J Hypertens 1993;11:1133–1137. 20. Alderman MH, Cohen HW, Roque´ R, Madhavan S. The risk of cardiovascular morbidity and mortality associated with calcium channel blockers in antihypertensive therapy. Lancet 1998; in press. 21. Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhager WH, Bulpitt CJ, de Leeuw PW, Dollery CT, Fletcher AE, Forette F, Leonetti G, Nachev C, O’Brien ET, Rosenfeld J, Rodicio JL, Tuomilehto J, Zanchetti A. 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;350:757–764. 22. Tuomilehto J, Rastenyte D, Birkenha¨ger WH, Staessen JA, Thijs L, Antikainen R, Bulpitt CJ, Fagard R, Fletcher A, Forette F, Goldhaber A, Palantin P, Sarti C, for the Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Cardiovascular prognosis in older diabetic and nondiabetic patients treated or untreated for isolated systolic hypertension. N Engl J Med 1998; in press. 23. 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– 652. 24. Gerritsen TA, Bak AAA, Stolk RP, Jonker JJC, Grobbee DE. Effects of nitrendipine and enalapril on left ventricular mass in patients with non-insulindependent diabetes mellitus and hypertension. J Hypertens 1998;16:689 – 696. 25. MRC Working Party. Medical Research Council trial of treatment of hypertension in older adults: principal results. Br Med J 1985;291:97–104. 26. Braun S, Boyko V, Behar S, Reicher-Reiss H, Laniado S, Kaplinsky E, Goldbourt U. Calcium channel blocking agents and risk of cancer in patients with coronary heart disease. Bezafibrate Infarction Prevention (BIP) Study Research Group. J Am Coll Cardiol 1998;31:804 – 808. 27. Hole DJ, Gillis CR, McCallum IR, McInnes GT, MacKinnon PL, Meredith PA, Murray LS, Robertson JW, Lever AF. Cancer risk of hypertensive patients taking calcium antagonists. J Hypertens 1998;16:119 –124. 28. Olsen JH, Sørensen HT, Frijs S, McLaughlin JK, Steffensen FH, Nielsen GL, Andersen M, Fraumeni JF Jr, Olsen J. Cancer risk in users of calcium channel blockers. Hypertension 1997;29:1091–1094. 29. Textor SC, Taler SJ, Canzanello VJ, Schwartz L, Wiesner RH, Porayko MK, Krom RAF. Cancer after liver transplantation (TX): excess risk associated with calcium channel blocker administration? (Abstr.) Am J Hypertens 1997;10:199A. 30. Grossman E, Messerli EH, Grodzicki T, Kowey P. Should a moratorium be placed on nifedipine capsules in hypertensive emergencies and pseudoemergencies? JAMA 1996;276:1328 –1331. 31. Burt VL, Whelton P, Roccella EJ, Brown C, Cutler JA, Higgins M, Horan MJ, Labarthe D. Prevalence of hypertension in the US adult population. Results from the Third National Health and Nutrition Examination Survey, 1988 –1991. Hypertension 1995;25:305–313. 32. Messerli FH, Grossman E, Goldbourt U. Are b-blockers efficacious as first-line therapy for hypertension in the elderly? A systematic review. JAMA 1998;279:1903–1907. 33. Pickering GA. Part I: Hypertension. Definitions, natural histories, and consequences. In: Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis, and Management. Vol. 1, 2nd ed. New York: Raven Press, 1995:3–21.
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