Antihypertensive Agents and Cardiovascular Risk:
Toward a Balanced Perspective

William E. Boden, MD

Within the past year, several studies have purportedly identified an increased risk of adverse cardiac events and/or mortality among patients taking certain antihypertensive medications.(Slide 9) Although calcium channel blockers were the initial focus of this controversy, the debate expanded recently to include beta blockers and nonpotassium-sparing diuretics. Reports in the lay media have provoked anxiety and fear among many patients, who have besieged their physicians with questions concerning the implications of the findings. In some cases, patients have independently decided to discontinue therapy, exposing themselves to the well-known risks associated with untreated hypertension.

To counsel patients effectively and make informed therapeutic decisions, physicians must look beyond sweeping conclusions regarding the supposed dangers of some antihypertensive drugs. The need for a more balanced perspective warrants a closer examination of both the data and the methodologies used to produce these results.

Risk of First MI in Hypertensive Patients
 Concern over the safety of calcium channel blockers in hypertensive patients was sparked by a case-control study presented in early 1995 at the American Heart Association (AHA) 35th Annual Conference on Cardiovascular Disease Epidemiology and Prevention. This study, funded by the National Heart, Lung, and Blood Institute (NHLBI), found that the rate of myocardial infarction (MI) was higher in hypertensive patients taking a calcium channel blocker than in those taking a diuretic or beta blocker. A press release issued by the investigators' institution stated that calcium channel blockers may increase the risk of MI by as much as 60%. As these findings were reported (and, in some cases, misinterpreted) by the lay press, large numbers of patients contacted the NHLBI, AHA, U.S. Food and Drug Administration, and their physicians.1 The data triggered concern not just among patients treated with calcium channel blockers, but among those treated with other antihypertensive drugs as well.2 Patients taking calcium channel blockers for indications other than hypertension (eg, angina) were likewise concerned that they might be at increased risk. The atmosphere of alarm prompted some patients to stop taking their medications.1 In a published commentary, the director of the NHLBI pointed out that misinterpretation of the "60% risk" statistic was the basis for much of the panic.1 Some reports failed to explain that this figure was an estimate of increased relative risk, not absolute risk. Attempting to put the findings in perspective, the NHLBI issued a statement cautioning that such a case-control study "although useful, cannot provide definitive information on the effectiveness and long-term safety of a class of drugs." The statement also emphasized that the immediate risk of MI would be low for a patient taking a calcium channel blocker, even if the data were confirmed.

This response temporarily quelled the controversy, until the debate resurfaced with the publication of the formal peer-reviewed study by Psaty et al in August 1995.3 The article detailed findings from a population-based, case-control study involving patients with pharmacologically treated hypertension who were enrolled in a health maintenance organization almost a decade earlier. The 623 cases comprised patients who had suffered a first fatal or nonfatal MI between 1986 and 1993 (for women) or between 1989 and 1993 (for men). A total of 2,032 controls were matched to cases on the basis of age, sex, and calendar year. Data were collected via retrospective reviews of medical and pharmacy records.(Slide 10)

An analysis of 335 cases and 1,395 controls who were initially free of cardiovascular disease showed that the adjusted risk ratio for the occurrence of MI was increased by approximately 60% among patients taking calcium channel blockers (with or without diuretics), compared with diuretics alone (Figure 1).3(Slide 11) The risk ratio for calcium channel blockers was 1.62, with 95% confidence intervals (CI) of 1.11 to 2.34 (P=0.01). The relative risk was adjusted for age, sex, calendar year, smoking, diabetes, pretreatment systolic blood pressure, duration of hypertension, physical activity, and education. The level of risk showed a significant association with increasing doses of calcium channel blockers, both alone and in combination with diuretics (P<0.01).

A second analysis focused on 384 cases and 1,108 controls who were taking either a calcium channel blocker or a beta blocker.3 In patients with or without cardiovascular disease, the adjusted risk of MI was increased by approximately 60% with calcium channel blockers as opposed to beta blockers (risk ratio = 1.57; 95% CI, 1.21 to 2.04; P<0.001). The adjusted risk ratios were not significantly different for nifedipine (1.31; 95% CI, 0.85 to 2.01; P=0.22), diltiazem (1.63; 95% CI, 1.06 to 2.50; P=0.03), and verapamil (1.61; 95% CI, 1.19 to 2.17; P<0.01). High doses of beta blockers were associated with a reduced risk of MI, whereas high doses of calcium channel blockers were associated with increased risk.(Slide 12)

The overall conclusion was that short-acting calcium channel blockers (the predominant type of formulation available during the period examined by this study) were associated with an increased risk of MI in hypertensive patients, particularly when used in high doses.3 The investigators offered several potential explanations and speculations for the findings they reported: negative inotropic effects, proarrhythmic effects, prohemorrhagic effects, proischemic effects from the coronary steal phenomenon, and (for short-acting dihydropyridines) a reflex increase in sympathetic activity, theoretically leading to plaque rupture. The authors observed also that the requirement for multiple daily doses of short-acting agents may have led to poorer compliance and inadequate blood pressure control. They noted that additional studies will be required to address the question of whether long-acting formulations will have beneficial or adverse effects on cardiovascular risk.

Psaty et al allowed that the case-control design, as an observational study, is subject to several limitations.3 Of primary concern is the potential for bias introduced by the self-selection of antihypertensive therapy on the part of physicians and patients. One might postulate that, during the time period covered by the study, the accepted clinical practice may have been to use calcium channel blockers (rather than beta blockers) for hypertensive patients with left ventricular dysfunction, heart failure, or other comorbidity. If the patients in the calcium channel blocker group were, on the whole, sicker, they would have been predisposed to higher event rates. A case-control study cannot factor out the impact of such selection bias. In addition, the authors cited the possibility that higher doses of calcium channel blockers may simply have been a marker for more severe hypertension in this study.(Slide 13)

A commentary by Buring et al took a closer look at the study methodology and conclusions.2 These authors pointed to selection bias as "the greatest limitation of this and other case-control studies." Their article noted that the patients who received calcium channel blockers were likely to have been "systematically different" from those taking other drugs, and even a well-designed case-control study could not eliminate all potentially confounding variables. Furthermore, the patients studied by Psaty et al were not taking the newer, longer-acting calcium channel blockers that are more commonly used nowadays.

In light of these problems, Buring et al suggested that the findings may be hypothesis-generating and potentially important from a research perspective, but were non-definitive from the viewpoint of health care providers or hypertensive patients.2 The next appropriate step would be to conduct prospective, randomized, controlled trials aimed at testing the hypothesis raised by Psaty and coworkers. The commentators stressed that such trials would have to enroll large numbers of patients in light of the fact that the 95% CI was wide in the 623 patients studied by Psaty et al, and the lower boundary represented only a 10% increase in risk with short-acting calcium channel blockers. "Even if the hypothesis raised by Psaty and colleagues turns out to be true, the known risks of uncontrolled hypertension are far greater than the postulated but unproved hazards of calcium channel blockers," they added.

Hopefully, more useful information on current therapies will emerge from ongoing studies, including the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) sponsored by the NHLBI. This randomized trial, incorporating the use of newer, longer-acting calcium channel blockers, seeks to enroll more than 40,000 patients at 400 centers across the United States. The results will not be available until after the year 2000, unless clear risks or benefits become apparent before the conclusion of the trial.

Risk of Mortality with Calcium Channel Blockers in CHD Patients
 In September 1995, the safety of calcium channel blockers was again called into question with the publication of a study by Furberg et al.4 These investigators conducted a metaanalysis of 16 randomized, controlled, secondary-prevention trials in which patients with coronary heart disease (CHD) - either previous MI or stable or unstable angina - were treated with short-acting nifedipine.(Slide 14) Nifedipine was associated with a significant increase in the total mortality rate (risk ratio, 1.16; 95% CI, 1.01 to 1.33), and higher dosages were significantly associated with greater risk (P=0.01). At dosages of 30 to 50 mg/day, the mortality risk was similar in controls and patients. However, the degree of risk increased somewhat at a dosage of 60 mg/day and nearly tripled at 80 mg/day (Figure 2).(Slide 15) In view of the fact that two of the four trials using 60 mg/day were stopped prematurely (because of a trend toward early increased mortality in one trial5 and a doubling of the reinfarction rate in the other6), the authors suggested that the adverse impact of the 60 mg dose on mortality may have been underestimated.

To explore potential mechanisms by which nifedipine might increase the risk of mortality, Furberg et al reviewed clinical trials of all types of calcium antagonists.4 Similar to Psaty et al, these authors speculated that the increased risk might be related to a proischemic effect, negative inotropic effect, proarrhythmic effect, prohemorrhagic effect, or marked hypotension.

Furberg et al suggested that short-acting dihydropyridines other than nifedipine may also increase the risk of mortality.4 On the other hand, they allowed that extrapolation of the findings to slow-release dihydropyridines and nondihydropyridines "represents a greater leap." If intermittent reflex increases in sympathetic activity associated with short-acting formulations were responsible for an increased risk of mortality, then long-acting preparations may be "entirely safe," they stated. However, if the coronary steal phenomenon associated with vasodilatation were responsible for increased risk, "the long-acting formulations, by increasing patient compliance, may be even more dangerous than the short-acting formulations." The authors stressed that such issues could be addressed only through properly designed clinical trials. Nonetheless, the investigators expressed the opinion that the findings could be appropriately extrapolated to populations other than CHD patients.4 They suggested that the data provide a basis for avoiding the use of short-acting nifedipine (and possibly other short-acting dihydropyridines) in hypertensive as well as CHD patients, unless and until more definitive safety data become available.

The report by Furberg et al was accompanied by three editorials that questioned the validity of the methodology and conclusions.7-9 The commentators pointed out that the CIs for mortality at nifedipine dosages of 30 to 60 mg/day were not significant, so the entire case for increased risk could be demonstrated only in dosages of 80 mg/day7,8; this was the only dosage level for which the CIs did not cross unity. Curiously, Furberg et al somewhat arbitrarily chose to use 2-week data rather than 6-month data from two of the four studies that included dosages of 80 mg/day.10,11 Had they used 6-month data, no significant adverse treatment effect would have been apparent.7,8 Accordingly, use of the earlier time point may have introduced an element of bias to the results the authors reported.8

Also of concern is the fact that the analysis of the 80 mg/day dosage included data from the International Nifedipine Trial on Antiatherosclerotic Therapy.12 One editorial charged that it was misleading to pool data from this study (in which only one third of patients had prior MI and two thirds had mild effort angina) with other studies of patients in the early post-MI phase or with unstable angina.7 The metaanalysis should have been confined to trials conducted in homogeneous populations which had similar risks.7,8 Another factor complicating interpretation of the findings is that control groups received placebo in some studies and beta blockers in others.8(Slide 16)

Several of the mechanisms proposed for the purported adverse effect on mortality remain a matter of debate. For instance, commentators pointed out that a proarrhythmic mechanism is unlikely in view of evidence showing that many calcium channel blockers have an antiarrhythmic effect.7,8 The observers also noted that a negative inotropic effect is actually one of the properties responsible for the beneficial effects of beta blockers in ischemic heart disease.7 Of perhaps greater interest is the potential for profound hypotension, repetitive neurohormonal stimulation, accelerated heart rate, and coronary steal with short-acting nifedipine.7

Risk of Mortality with Nondihydropyridine Agents
 Observers have emphasized that, even if the findings regarding short-acting nifedipine are correct, the allegations cannot be extrapolated to all calcium channel blockers - either other short-acting agents or newer, long-acting formulations.7 Even though calcium channel blockers are not currently used routinely in the post-MI population, it is important to note that older randomized, prospective studies found potential benefit in certain subsets of patients treated with nondihydropyridines (ie, verapamil and diltiazem). Unlike the dihydropyridines, which increase heart rate, the nondihydropyridines lower heart rate and may thereby manifest different clinical effects.9 The second Danish Verapamil Infarction Trial (DAVIT II) found a beneficial effect in patients without heart failure - specifically, a significant reduction in 18-month rates of mortality (hazard ratio, 0.64; 95% CI, 0.44 to 0.94; P=0.02) and major events, ie, death or reinfarction (hazard ratio, 0.70; 95% CI, 0.44 to 0.94; P=0.01).13 In the Diltiazem Reinfarction Study, the reinfarction rate was reduced significantly among patients with non-Q-wave MI (51.2% reduction; 90% CI, 7% to 67%; P=0.03).14 The Multicenter Diltiazem Postinfarction Trial (MDPIT) found that the rate of cardiac events (death or reinfarction) was reduced in patients without pulmonary congestion (hazard ratio, 0.77; 95% CI, 0.61 to 0.98),15 as well as those without left ventricular dysfunction.16 The reduction in the cardiac event rate was most evident in patients with a history of hypertension who did not have pulmonary congestion.17

In a recent post-hoc study, our group examined the effect of the heart rate-lowering calcium channel blockers (diltiazem and verapamil) on long-term cardiac death and nonfatal reinfarction rates following non-Q-wave MI.18 Our analysis was based on pooled data from 936 patients enrolled in MDPIT15 and DAVIT II.13 Although this type of study, as with any retrospective investigation, is subject to certain methodologic limitations, the strength of our analysis centers on the fact that it includes a homogeneous patient population who received relatively homogeneous drugs that do not increase heart rate. As shown in Table 1, we found that the overall weighted event rate was 11.2% in the patients treated with calcium channel blockers vs 17.0% in controls. Therefore, diltiazem and verapamil produced a significant, 35% relative reduction in the rate of cardiac death or nonfatal reinfarction during 12 to 18 months of follow-up (P=0.0068). In view of the fact that approximately 750,000 patients present with non-Q-wave MI each year, we pointed out that approximately 43,000 cardiac events might be prevented annually through the use of diltiazem or verapamil.(Slide17)

In subsequent work yet to be published, we analyzed pooled data from both DAVIT I19 (which did not dichotomize infarcts by electrocardiographic subtype) and DAVIT II,13 as well as MDPIT.15 We again found that the heart rate-lowering calcium channel blockers (verapamil and diltiazem) were associated with significant reductions in the rate of cardiac death or reinfarction. A further analysis showed that event rates were significantly reduced in hypertensive patients, whereas little effect was seen in normotensive patients.

As suggested in one of the commentaries on the findings of Furberg et al, a prudent response to these data would be to continue using calcium channel blockers for approved indications.7 Care should be taken to avoid hypotension, and prescribing physicians should carefully evaluate the risk:benefit ratio if these drugs are used in settings in which they are relatively contraindicated, such as in the early post-MI period.

Risk of Sudden Cardiac Death with Beta Blockers and Diuretics
 In the latest development, a case-control study published in October 1995 found that the risk of sudden cardiac death was increased in hypertensive patients treated with beta blockers or nonpotassium-sparing diuretics as opposed to potassium-sparing diuretics (Table 2).20 Interestingly, the degree of risk with nonpotassium-sparing diuretics was ameliorated by the addition of beta blocker therapy.(Slide 18)(Slide 19)

The authors concluded that the higher risk of sudden cardiac death may offset part of the mortality benefit of these drugs in hypertensive patients.20 They also suggested that further attention be given to the difference between the moderate cardioprotective effect of beta blockers in patients taking nonpotassium-sparing diuretics, compared with the increased risk associated with beta blockers in patients not taking nonpotassium-sparing diuretics.

This report illustrates how case-control investigations, which are not designed to detect small differences between therapeutic interventions, can give rise to perplexing results, which may reflect the vagaries of study methodology rather than sound, evidence-based clinical experience. As in the case-control study by Psaty et al, the data from Hoes et al were likewise subject to selection bias. Indeed, the authors themselves pointed out that "although specific classes of antihypertensive drugs have several important indications and contraindications, a large gray area exists in which the choice of drug therapy depends more on the beliefs of the physician than on the actual condition of the hypertensive patient."20 They added, "Thus, many patients who are similar in most respects are treated differently." The investigators attempted to control for the possibility that the choice of antihypertensive drug therapy was influenced by conditions that might affect the risk of sudden cardiac death; however, no case-control study can completely factor out such bias. This investigation may serve as a reminder that case-control studies can provide a means of formulating hypotheses for further investigation, but the answers to such questions can be obtained only through properly controlled, prospective, randomized trials.(Slide 20)

Conclusions
 The reports by Psaty et al and Furberg et al are important in that they have called attention to possible deleterious effects of short-acting calcium channel blockers. However, retrospective data from such case-control studies or metaanalyses should not be used as the basis for making definitive therapeutic recommendations. The only data that can withstand rigorous scientific scrutiny are those obtained in prospective, randomized, controlled clinical trials, such as will be forthcoming from the ongoing ALLHAT study.

Furthermore, no justification can be found for extrapolating data on short-acting nifedipine to long-acting dihydropyridine or nondihydropyridine calcium channel blockers. Conclusions regarding the impact of these latter agents on cardiovascular risk must await the results of prospective, randomized, controlled studies currently underway. At present, the body of scientific evidence provides no sound basis for physicians to discontinue therapy in hypertensive patients who are being treated with long-acting calcium channel blockers, particularly those that lower heart rate.(Slide 21)

References

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[Introduction | Pharmacology | Elderly Hypertensives
Information/Questions | Table of Contents ]

[Introduction | Pharmacology | Elderly Hypertensives
Information/Questions | Table of Contents ]