The results of a meta-analysis of the major hypertension trials using calcium channel blockers (CCBs) as initial or baseline therapy in essential hypertension was recently presented at the European Society of Hypertension meetings and subsequently published in the Lancet. This analysis of over 27,000 patients seems to illustrate an increased incidence of myocardial infarction (MI) and congestive heart failure (CHF) as compared to patients treated with other anti-hypertensive medications. The widespread dissemination of this data in both the medical literature and the lay press has led to great confusion on the part of both patients and physicians as to the appropriateness of using CCBs in the treatment of hypertension. This article will carefully examine not only the results of this meta-analysis, but of other recently published morbidity and mortality studies.

Background and Significance
     In 1997, the Sixth Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) revised their recommendations for initial pharmacological therapy of hypertension. In the absence of compelling or specific indications for another agent, JNC VI recommends diuretics and beta-blockers as initial therapy. This recommendation is based upon the fact that the vast majority of the original studies showing a reduction in cardiovascular events with anti-hypertensive treatment used these older medications. The results of these studies were impressive; as compared to placebo, the risk of myocardial infarction was decreased approximately 15-20%, the risk of stroke was decreased approximately 35-40%, and the risk of CHF was decreased approximately 40-45%.
     Newer anti-hypertensive agents (ACE-Inhibitors, CCBs, Alpha Blockers, and Angiotensin Receptor Blockers [ARBs]) have been shown to decrease blood pressure as effectively as diuretics and beta-blockers. But, until recently there has been very little long-term morbidity and mortality data. Despite the JNC VI recommendations, ACE-Inhibitors and CCBs have become the most frequently prescribed anti-hypertensive medications (Figure 1). Approximately 12 million people in the United States take CCBs, so concerns about the safety and efficacy of these medications have far reaching implications.

     The recent Lancet article is not the first publication to question the safety and efficacy of CCBs. In 1996, Dr. Furberg and colleagues published a meta-analysis which indicated that CCBs might increase the risk of myocardial infarction. In the 1996 analysis, it appeared that the majority of the negative effect was due to the use of short-acting, especially dihydropyridine, CCBs. This finding led to recommendations that short-acting dihydropyridine CCBs (like nifedipine) should not be utilized as initial therapy (if at all). Subsequent to this analysis, most physicians felt that the longer acting CCBs were probably safe. However, the recent analysis in Lancet includes predominantly long-acting agents.

The Lancet Meta-Analysis (Pahor et al)
     In light of the debate over the comparative safety and efficacy of CCBs, Pahor et al conducted a meta-analysis of the available literature. The criteria for studies to be included in this meta-analysis are shown in Table 1. The initial search identified 2406 articles; however, only nine trials met entry criteria. The abbreviated titles of the included trials are also given in Table 1.

Other Recent Morbidity and Mortality Endpoint Trials Using CCBs

Systolic Hypertension in Europe (SYST-EUR)
     Prior to the publication of JNC VI, there was one randomized placebo-controlled trial using CCBs which was sufficiently powered and of sufficient duration to examine the effect on “hard” clinical endpoints (Stroke, MI, CHF, and CV Death). This trial, known as Syst-Eur, enrolled elderly patients with isolated systolic hypertension who were randomized to the long-acting dihydropyridine CCB, nitrendipine, or placebo. As shown in Figure 2, elderly patients randomized to the CCB had significant reductions in all cardiovascular endpoints; these reductions were of such magnitude that the study had to be discontinued early after a follow-up period of over two years.

Verapamil in Hypertension and Atherosclerosis Study (VHAS)
     In VHAS, 1414 mild to moderately hypertensive patients were randomized to the long-acting non-dihydropyridine CCB, Verapamil SR, or the diuretic, chlorthalidone. After approximately two years of follow-up there was no significant difference in the incidence of any cardiovascular endpoint. There was however a trend towards decreased incidence of stroke, but increased incidence of CHF in the verapamil treated group.

Swedish Trial in Older Persons-2 (STOP-2)
     In STOP-2, “older” medications (diuretics and beta-blockers) were compared to “newer” medications (ace-inhibitors and CCBs) in 4410 elderly patients with mild to moderate hypertension. Over five years of follow-up, there was no difference in the incidence of major cardiovascular events between the “older” or “newer” medications. Interestingly though, a subsequent analysis indicated that patients treated with ace-inhibitors had a somewhat lower incidence of MI or CHF than those treated with a CCB.

Nordic Diltiazem Study NORDIL
     In NORDIL, 10,881 patients with diastolic blood pressure >100 mmHg were randomized to a regimen based on a long-acting non-dihydropyridine CCB or a regimen based on diuretics/beta-blockers. At the conclusion of the study, there was no difference in the incidence of the primary endpoint, a composite of all stroke, myocardial infarction, and other cardiovascular events (Table 3). Secondary analysis indicated that there was a significant decrease in the incidence of stroke, but a non-significant increase in MI and CHF in the CCB group.

International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment INSIGHT
     The INSIGHT protocol randomized 6321 patients with mild to moderate hypertension with at least one other risk factor to a long acting dihydropyridine CCB or a diuretic. The results of this trial indicated that there was no significant difference in the incidence of the primary outcome, a combined endpoint of cardiovascular death, myocardial infarction, heart failure, or stroke (Table 4). However, there was a slightly higher incidence of the secondary endpoints fatal MI and CHF in the CCB treated group.

Studies Comparing CCBs and ACE-Inhibitors in Diabetics
     The presence of diabetes mellitus (at least with proteinuria) is considered a compelling indication for the initial use of Ace-Inhibitors by JNC-VI. There have been three recent trials which have compared the use of CCBs to ace-inhibitors in diabetic patients. Each of these trials: the Fosinopril vs Amlodipine Cardiovascular Events Trial (FACET), the Appropriate Blood Pressure Control Control in Diabetes (ABCD), and the African American Study of Kidney Disease and Hypertension (AASK) had slightly different inclusion criteria and methodology. But, each of these trials indicated that ace-inhibitors were superior in reducing cardiovascular and renal endpoints. Many physicians have interpreted these findings to indicate that CCBs are not beneficial, or in fact harmful, for diabetic patients. This is not likely to be the case; rather these data indicate the great benefit of ace-inhibition in diabetic patients. There is nothing in these trials to suggest that CCBs are not appropriate “add-on” therapy in diabetic patients.

Significance of the Findings
      In each of the randomized prospective trials included in the Lancet meta-analysis and outlined above, CCBs appear to be at least equivalent to diuretics and beta-blockers in decreasing the incidence of the primary endpoints for these trials (usually all cardiovascular events). It is important to realize that these studies were specifically designed and powered to determine the effect on this combined endpoint. This is very strong evidence that CCBs are both effective and safe as initial treatment in mild to moderate essential hypertension (either isolated or mixed systolic/diastolic).
      However, when secondary endpoints are closely examined either in individual trials or in the meta-analysis, it appears that the primary benefit to CCBs was seen in reductions in the incidence of stroke, and there was a slight increase in the incidence of MI and CHF. This is potentially worrisome for the large numbers of patients who take CCBs and the physicians who prescribe them. Yet, under the rules of evidence-based medicine, it is important to realize that meta and secondary analyses do not carry the same relative weight as the primary results of individual trials.
      Meta-analyses include many different types of trials with vastly differing methodology, and they can be prone to selection bias where only carefully selected trials are included. It should be noted that a different meta-analysis, authored by Neal, MacMahon, and Chapman and known as the Blood Pressure Lowering Treatment Trialists’ Collaboration, employed different eligibility criteria for studies to be included and came to a different conclusion. In this meta-analysis (Trialists’ Collaboration), treatment with a CCB led to a statistically significant 13% decrease in the incidence of stroke, and there were no significant differences in the incidence rates of MI, CHF, mortality, and All CV Events.
      In general, the best use of secondary and meta-analyses is to identify potential new hypotheses to be tested in subsequent randomized controlled trials. Fortunately, two additional trials examining the use of CCBs as initial anti-hypertensive therapy are due to be published in the next three years. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) is a randomized trial designed to test the hypothesis that a “newer” anti-hypertensive regimen (dihydropyridine CCB +/- ace-inhibitor) is more effective than an older regimen (diuretics +/- beta-blocker). Approximately 19,000 patients with hypertension and at least three other cardiovascular risk factors will be enrolled. Results are expected in 2004.
      The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a randomized trial sponsored by the U.S. National Institutes of Health (NIH). It is designed to test the hypothesis that the combined incidence of fatal CV events and non-fatal MI differs between patients randomized to a diuretic-based regimen and those assigned to three other treatment arms (dihydropyridine CCB, ace-inhibitor, alpha-blocker). The protocol calls for enrollment of 40.000 hypertensive patients with at least one other CV risk factor.
      Final results of ALLHAT are due to be reported in 2003; however, the investigators periodically review the accumulating results to determine if it is ethical to continue the trial. In early 2000, the alpha-blocker arm was discontinued when it appeared that there was an increase in the incidence of CHF and no apparent benefit in reducing other endpoints. Although the interim results of the other arms were not released, both the ace-inhibitor and CCB arms were allowed to continue as planned.
      Both ASCOT and ALLHAT are large-scale, long-term trials which should be powered to effectively answer the concern presented by this meta-analysis. Based on the conflicting data presented here, it may not be prudent for physicians to change their prescribing habits prior to the publication of these trials’ results. Without knowing the results of these trials, it does appear that calcium channel blockers are appropriate as first line therapy for elderly patients (especially those with isolated systolic hypertension); however, in younger patients there remains concern that CCBs may not be as effective in preventing myocardial infarction and CHF as other agents.
      Although we all eagerly await the results of ALLHAT, in many ways the question posed by this trial is becoming less important. Recommendations for hypertension management are beginning to call for increasingly aggressive blood pressure goals. There is also a growing realization that in the majority of cases it takes two, three, four, or more medications used in combination to reach these aggressive goals. Even in patients with mild hypertension, low-dose combination therapy may be able to achieve greater efficacy with lower side-effects than monotherapy. As the emphasis on combination therapy increases, the choice of initial drug may become less important.

References

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Davis BR, Cutler JA, Gordon DJ, et al. Rationale and design for the antihypertensive and lipid lowering treatment to prevent heart attack trial (ALLHAT). Am J Hypertens 1996;9:342-360.

Furberg CD, Psaty BM. Calcium antagonists: not appropriate as first-line antihypertensive agents. Am J Hypertens 1996;9:122-125.

Hansson L, Hedner T, Lund-Johansen P, et al. Randomised trial of effects of calcium antagonists compared with diuretics and ß-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study. Lancet 2000; 356: 359-65.

Hansson L, Lindholm LH, Ekborn T, et al. Randomized trial of old and new antihypertensive drugs in elderly patients. Cardiovascular morbidity and mortality in the swedish trial in older patients with hypertension-2 (STOP-2) study. Lancet 1999;354:1751-1756.

Neal B, MacMahon S, Chapman N. Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of ace-inhibitors, calcium antagonists, and other blood pressure lowering drugs: results of prospectively designed overviews of randomized trials. Lancet 2000; 356: 1955-1964.

Pahor M, Psaty BM, Alderman MH, et al. Health outcomes associated with calcium antagonists compared with other first-line anti-hypertensive therapies: a meta-analysis of randomized controlled trials. Lancet 2000; 356; 1949-1954.

Rosei EA, Dal Palu C, Leonetti G, Magnani B, Pessina A, Zanchetti A. Clinical results of the Verapamil in Hypertension and Atherosclerosis Study. J Hypertens 1997; 15: 1337-44.

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