Calcium Antagonists in Coronary Artery Disease and Hypertension
1995; Lippincott Williams & Wilkins; Volume: 92; Issue: 5 Linguagem: Inglês
10.1161/01.cir.92.5.1079
ISSN1524-4539
Autores Tópico(s)Heart Rate Variability and Autonomic Control
ResumoHomeCirculationVol. 92, No. 5Calcium Antagonists in Coronary Artery Disease and Hypertension Free AccessResearch ArticleDownload EPUBAboutView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticleDownload EPUBCalcium Antagonists in Coronary Artery Disease and Hypertension Time For Reevaluation? Salim Yusuf Salim YusufSalim Yusuf From the Division of Cardiology, McMaster University, and Cardiovascular Therapeutics and Research Program, Hamilton Civic Hospitals Research Centre, Hamilton General Hospital, Ontario, Canada. Originally published1 Sep 1995https://doi.org/10.1161/01.CIR.92.5.1079Circulation. 1995;92:1079–1082Calcium antagonists have been used in patients with cardiovascular diseases for about 2 decades. Regulatory authorities have approved the use of calcium antagonists in individuals with angina pectoris to relieve chest pain or with hypertension to lower blood pressure. As a class, they are among the most widely used drugs for treatment of cardiovascular conditions. Numerous randomized placebo-controlled studies have demonstrated the value of these agents for relieving symptoms in patients with angina, an action generally associated with increased exercise tolerance in formal exercise testing. However, no study in which a calcium antagonist was used in stable angina pectoris or other clinical manifestations of coronary artery disease has yet to demonstrate convincingly a reduction in morbidity (eg, reinfarction or stroke) or mortality. In part, this gap in our information may be because few large, long-term clinical trials have been designed to test these questions and perhaps because relief of angina per se is a worthwhile goal of therapy in symptomatic patients. However, data accumulated from clinical trials conducted over the last decade have raised concerns as to whether some or all of the calcium antagonists increase morbidity (eg, worsen unstable angina,1 increase heart failure,2 or increase the risk of infarction3 ) and mortality.4 These data on the potential adverse effects of calcium antagonists have been obtained from patients who have a variety of clinical manifestations of coronary artery disease, including stable angina pectoris,5 unstable angina,16 and acute myocardial infarction (MI),7 during long-term use after MI,7 and heart failure.8 Patients who have these various conditions often have several similarities in clinical course and some common underlying pathophysiological abnormalities. Therefore, these data, obtained from a broad group of patients with coronary artery disease, have widespread clinical applicability. Further direct evidence of a potential adverse effect with calcium antagonists comes from a meta-analysis by Glasser et al9 of the trials of calcium antagonists in stable angina registered with the US Food and Drug Administration (FDA) for use in stable angina. These trials were designed primarily to document an improvement in anginal symptoms. Each study individually was too small to provide clear information on mortality or morbidity. However, in an overview of these trials, there was a 63% increase in the odds of adverse outcomes (composite end point of death, MI, ventricular tachycardia, other major arrhythmias, and dropouts for adverse events). Unfavorable effects of calcium antagonists also have been seen in several previous trials of MI and unstable angina patients; in particular, agents of the dihydropyridine class have been associated with an increased risk of death and nonfatal MI.3 In this issue of Circulation, Furberg et al10 demonstrate increasing mortality with increasing doses of nifedipine (an adverse dose-response relation). This provides further evidence that the excess mortality with nifedipine is likely to be causal. Trends toward increased cardiovascular morbidity or mortality also have been observed with other dihydropyridines, such as nicardipine11 or isradipine,12 albeit only small or moderate-sized studies are available. I am not aware of any published large and long-term trial testing the effects of the newer dihydropyridines in preventing major cardiovascular events in patients who have stable coronary disease or angina. However, reliable information on the effects of some of the new dihydropyridines in hypertension or congestive heart failure (CHF) should be available in the next few years because well-designed and larger trials are in progress (see Table). Recent data from the Prospective Randomized Amlodipine Survival Evaluation (PRAISE) study indicated no clear overall mortality benefit or harm from use of dihydropyridines in patients with severe CHF.13 Contrary to the investigators' prior expectations, there appeared to be little effect in the large subgroup of patients who had coronary artery disease and a nominally significant reduction in morbidity and mortality in the minority of patients who did not have coronary artery disease. These investigators appropriately have interpreted their findings as hypothesis-generating and have designed a new study (PRAISE-2) to test their provocative findings.Data from trials of nondihydropyridines have not demonstrated increased mortality or MI rates in patients with coronary artery disease and good left ventricular function.3814 Unlike dihydropyridines, agents such as diltiazem and verapamil do not increase heart rate, and it is possible that important clinical differences may exist between the various subclasses of calcium antagonists. Nevertheless, they share several common pharmacological properties, and convincing evidence of reduced mortality with the use of nondihydropyridine agents such as diltiazem or verapamil in any cardiovascular condition is unavailable. In a recent long-term trial15 of 809 patients with stable angina pectoris comparing verapamil with metoprolol for a period of 3 to 4 years, there were similar numbers of major cardiovascular events. Although this study, one of the largest trials comparing antianginal drugs, indicates similar effects, moderate-sized differences (eg, a 15% relative risk) between verapamil and metoprolol still could be present. However, large differences in major cardiovascular events (eg, a 50% difference in risk) are probably excluded. A meta-analysis of the post-MI trials suggests that diltiazem and verapamil reduce the risk of reinfarction (odds ratio, 0.79; 95% CI, 0.67 to 0.94) but probably not the mortality (odds ratio, 0.95; 95% CI, 0.82 to 1.09) compared with placebo when added to standard therapy.3 This contrasts with the other class of commonly used anti-ischemic agents, β-blockers, for which convincing evidence of decreased rates of both mortality and reinfarction are available from a large body of data.16 At present, calcium antagonists have not been approved by the US FDA or Canadian Health Protection Branch for secondary prevention, their use in MI is dissuaded by official organizations,17 and recent data suggest a decrease in their use in patients after MI.1819A second reason that calcium antagonists are widely used is to lower blood pressure (BP) in patients with hypertension. Epidemiological studies have documented that elevations in BP are associated with increased risk of strokes, MI, CHF, and renal dysfunction.20 Large, randomized trials have demonstrated clearly that diuretics decrease cardiovascular mortality, strokes, heart failure, and renal dysfunction to the extent predicted from epidemiological studies based on differences in BP observed in the randomized trials.21 However, the coronary heart disease risk reduction in these trials was only approximately two thirds of that predicted, which led to concerns that some of the shortfall in potential benefit expected from BP lowering might be due to the adverse metabolic effects of diuretics at the relatively high doses used. Several trials comparing β-blockers with diuretics failed to demonstrate the superiority of β-blockers in preventing major vascular events, indicating that both classes of agents are perhaps equally effective.21 More recently, data from trials in which lower doses of diuretic (eg, 12.5 to 25 mg thiazides per day)22 were used indicate a far lower rate of adverse effects than for the previous regimens (in which doses that were several times higher were used), with similar degrees of BP and stroke reduction and an apparently larger reduction in coronary heart disease rates. Calcium antagonists have been promoted and used with the expectation that they may be superior to diuretics because they do not have an "adverse" metabolic profile. However, this contention has not been tested formally in large trials. Results of two moderate-sized trials with dihydropyridines suggest that these agents may in fact be inferior to diuretics12 or angiotensin-converting enzyme inhibitors23 in preventing morbidity, despite a similar BP reduction. This raises questions as to the appropriateness of regulatory agencies in relying solely on BP lowering as a surrogate outcome. The results of both these trials are available only as an abstract12 or meeting report,23 although these trials were completed some years earlier. Full publication of the results of these trials would be welcomed by the scientific community. In the absence of reliable data from large trials comparing calcium antagonists with diuretics in hypertension, it is reasonable to base decisions on results from these two moderate-sized trials and to extrapolate from the larger trials in coronary artery disease. Although initially the group of patients with coronary artery disease appears to be distinct from those with hypertension, coronary artery disease patients have hypertension, and, conversely, many hypertensive patients have overt or occult coronary artery disease. Therefore, it may be prudent to avoid the use of calcium antagonists as first-line therapy in hypertension unless clear evidence from randomized trials establishes the clinical superiority of these agents. Such a cautious approach is supported by disturbing data from a recent, relatively small case-control study, suggesting an adverse effect in hypertension of calcium antagonists compared with other drugs.24 Although case-control studies are likely to be affected by biases, this result is consistent with the information from randomized trials in coronary artery disease. What then is the current place of calcium antagonists in the management of patients with cardiovascular disease? At present, it is prudent to use drugs from alternative classes of agents as initial treatment for angina or hypertension. For example, it is reasonable to consider the use of nitrates and β-blockers as the initial treatment for relieving angina and to consider use of a calcium antagonist only if symptoms persist, if nitrates and β-blockers are contraindicated or not tolerated, or if revascularization is inappropriate. If a calcium antagonist is used, it would be prudent to use a nondihydropyridine agent such as diltiazem or verapamil. If a patient with angina also has CHF or poor left ventricular function, amlodipine may be a relatively safe alternative. Although the long-acting preparation may have some theoretical advantages, there is no good evidence of a reduction in major vascular events to support their use. Widespread use of calcium antagonists should await the results of the ongoing trials. In patients with hypertension, diuretics or β-blockers initially should be considered the drugs of choice. Such a position is consistent with the guidelines of the Fifth Joint National Committee25 and the Canadian Hypertension Society.26 In patients with left ventricular dysfunction, CHF, or type I diabetics with nephropathy, an angiotensin-converting enzyme inhibitor should be the initial drug of choice. Calcium antagonists should be reserved for use when diuretics, β-blockers, or angiotensin-converting enzyme inhibitors have been used already or are not tolerated or contraindicated and when further BP reduction is necessary. In such circumstances, diltiazem or verapamil may be preferred over a dihydropyridine calcium antagonist. Large trials currently are under way that compare the new calcium antagonists with diuretics. Until such trials demonstrate the clear superiority of calcium antagonists, diuretics should remain the first line of therapy in hypertension. Table 1. Major Ongoing Trials of Calcium Antagonists in Cardiovascular DiseaseTrialAgentsHypothesisProjected No. of PatientsPrimary End PointCommentsHypertensionHOTFelodipine at 5- and 10-mg doses plus ACE-I, BB, or DTest the effects of DBP lowering to ≤90, ≤85, or ≤80 mm Hg18 000CV eventsDBP shows only a small difference between groups (87±7, 85±8, and 83±8 mm Hg at 3 months). This small contrast could limit the ability to show differences.STOPD vs ACE-I vs calcium antagonistsEffects of three classes of agents with the same BP target6600Major CV eventsAdequate power to detect ≥25% difference between classes of agents, which may be unrealistically optimistic.ALLHATD vs amlodipine vs lisinopril vs doxazosinRelative effects of classes of agents with the same BP target40 000CHDHigh power to detect a 16% relative risk difference between arms.INSIGHTNifedipine GITS vs amiloride and hydrochlorthiazideRelative effects of two classes of agents6600CV eventsMay not have adequate power to detect plausible differences.EURO-SYSTNitrendipine+enalapril or hydrochlorthiazideImpact of Ca2+ antagonist–based treatment vs placebo3000StrokesHeart FailureV-HEFT-3Felodipine vs standard treatmentEffect of a direct vasodilator when added to ACE-I, dig, and D600Ex tolerance, LV function, and quality of lifeOnly moderate power to assess clinical outcomes.PRAISE-2Amlodipine vs placeboEffects in patients without CHD1800Mortality and morbidityMACH-1Mabefradil vs placeboNYHA class II to IV and using ACE-I, dig, or D2000MortalityHOT indicates Hypertension Optimal Treatment; ACE-I, angiotensin-converting enzyme inhibitor; BB, β-blocker; D, diuretic; CV, cardiovascular; DBP, diastolic blood pressure; STOP, Swedish Trial in Old Patients with Hypertension; ALLHAT, Antihypertensive and Lipid Lowering Heart Attack Prevention Trial; BP, blood pressure; CHD, coronary heart disease; INSIGHT, International Nifedipine Study, Intervention as a Goal in Hypertension Treatment; GITS, Gastro-intestinal Therapeutic System; EURO-SYST, European Study of Systolic Hypertension; V-HEFT, Veterans Heart Failure Trial; dig, digoxin; PRAISE, Prospective Randomized Amlodipine Survival Evaluation; MACH-1, Mortality Assessment in Congestive Heart Failure; and NYHA, New York Heart Association.FootnotesCorrespondence to Dr Salim Yusuf, Hamilton Civic Hospitals Research Centre, Hamilton General Hospital, 237 Barton St E, Hamilton, Ontario L8L 2X2, Canada. 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