calcium channel blockers and hypertension: evolving perspectives—1996

Cardiovascular Drugs and Therapy 1997;1{):883-891 © Kluwer Academic Publishers. Boston. Printed in U.S.A.

Calcium Evolving

Channel Blockers and Hypertension: Perspectives 1996

Murray Epstein Division of Nephrology, Department of Medicine, University of Miami School of Medicine and the Nephrology Section, VA Medical Center, MiamL Florida, USA

Summary. In recent years, calcium channel blockers (CCBs) have been used extensively in the United States and elsewhere as antihypertensive agents, and their availability has been an important advance in the management of hypertension. As antihypertensive agents, the CCBs thus appear considerably more versatile than most previous vasodilators. The available studies indicate that CCBs are metabolically neutral and do not exacerbate dyslipidemia or impair glucose tolerance. In contrast to diuretics and beta-blockers, CCBs do not appear to alter insulin sensitivity. The CCBs also differ from previous vasodilators because of their favorable accompanying effects on the heart and kidney. Despite the attributes of CCBs enumerated earlier, a number of recent retrospective analyses by Psaty et al. (JAMA 1995;274:620-625) have suggested that CCBs may be detrimental and may promote adverse cardiovascular events. I have recently reviewed the results of Psaty's meta-analysis and report (Arch Intern Med 1995;155: 2150-2156). I have emphasized that it is the rate of drug delivery into the systemic circulation that produces profound effects on the hemodynamic and neurohumoral responses to a dihydropyridine CCB drug. During chronic treatment with dihydropyridines, major fluctuations in blood pressure (rapid onset and offset of antihypertensive effects) during the dosing interval may persist for drugs and formulations that are short acting. In contrast, slow-release formulations of otherwise rapidly absorbed dihydropyridines achieve a more gradual and sustained antihypertensive effect. It is probable that newer CCB formulations that do not provoke intermittent sympathetic activation and do not evoke a cardioacceleratory response would not be expected to promote adverse cardiovascular events.

Cardiovasc Drugs Ther 1997;10:883-891

Key Words. calcium channel blockers (CCBs), dyslipidemia, antihypertensives, renal microcirculation, slow-release CCB formulations

Calcium-channel blockers (CCBs) have assumed a major role in the treatment of patients with a variety of cardiovascular and noncardiovascular disorders, and importantly, hypertension. In recent years, CCBs have been used extensively as antihypertensive agents, and their wide availability has been an important advance in the management of hypertension. The major hemodynamic abnormality present in most patients with essential hypertension is an increase in peripheral resistance. Considerable evidence suggests

that the elevation of peripheral resistance is mediated in part by abnormal transmembrane flux of calcium. To the extent that abnormal calcium flux constitutes a determinant of elevated peripheral resistance, the major mechanism whereby CCBs lower blood pressure (blockade of calcium-mediated electromechanical coupling in contractile tissue produces arteriolar vasodilation) is particularly relevant [1-3]. As a result of reducing total peripheral resistance, systemic blood pressure decreases. In addition to their effects on peripheral blood vessels, the hormonal and renal actions of CCBs have been postulated to contribute to blood pressure lowering [3-5].

Differences Between Calcium Channel Blockers

CCBs are a heterogeneous group of compounds with diverse chemical structures and pharmacologic actions [1]. Presently, eight CCBs are available in the United States; more will be marketed soon. The order in which the three prototypic agents were released into the market was verapamil (Calan®), nifedipine (Pro- cardia®), and diltiazem (Cardizem®). Subsequently, nicardipine (Cardene®), isradipine (Dynacirc®), felodipine (Plendil®), and amlodipine (Norvasc ®) and nisoldipine (Sular ®) were released. Six of the currently marketed agents--nifedipine, nicardipine, isradipine, amlodipine, felodipine, and nisoldipine--are members of the dihydropyridine group of CCBs. All CCBs re- tard the entry of calcium into the cell, be it cardiac muscle, peripheral vascular smooth muscle, or endo- crine, but with differing specificities. Verapamil has considerable in vivo cardiac specificity, whereas diltiazem has less, and the dihydropyridines (e.g., nifedipine, felodipine, amlodipine, isradipine, and nisoldipine) have virtually no in vivo specificity for cardiac calcium channels. In contrast, dihydropyridines are quite specific for vascular smooth muscle, diltiazem less specific, and verapamil least specific [1]. Vera-

Address for correspondence: Murray Epstein, MD, Nephrology Sec- tion, V.A. Medical Center, 1201 Northwest 16 Street, Miami, FL 33125, USA.

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884 Epstein

pamil, diltiazem, and the dihydropyridines probably decrease blood pressure equally well, although maxi- mal doses often may be required for some, such as diltiazem. Verapamil and, to a lesser extent, diltiazem should not be used in patients with left ventricular dysfunction or with any degree of arterioventricular block. Noncardiac side-effect profiles are different for each of the CCBs [3]. Verapamil may produce troublesome constipation, whereas the dihydropyridines may produce headache, flushing, and dependent edema.

Stow-Release Formulations

In the past several years, manufacturers of all of the CCBs have introduced innovative slow-release formulations in order to obviate some of the problems posed by the pharmacokinetics of the agents. These prepara- tions include Procardia XL ® by Pfizer, Cardizem ® CD by Hoechst Marion Roussel, Sular ® by Zeneca Phar- maceuticals, Calan ® SR by G.D. Searle, Isoptin ® SR by Knoll Pharmaceuticals, and more recently Covera ® by G.D. Searle. A sustained-release form of verapamil (Verelan ®) has been made available by Wyeth-Ayerst Laboratories and Lederle Laboratories.

Differences Between Calcium Channel Blockers and other Vasodilators

Drugs that directly reduce peripheral vascular resistance, such as hydralazine, have been used in antihypertensive therapy for many years. Nevertheless, the effectiveness of these agents is often limited by the reactive stimulation of renal and hormonal responses that counteract their antihypertensive actions (Fig. 1). These responses tend to produce tolerance to hydralazine's vasodilating action as well as to cause volume-expansion-induced pseudotolerance to its antihypertensive effects [3].

The precise mechanism(s) whereby CCBs interfere with angiotensin II or alpha-adrenergic-mediated vasoconstriction remains uncertain. Nevertheless, in the presence of CCBs (as indicated in the figure by the interruptions of the arrows) the expected adaptive changes in peripheral vascular resistance, heart rate, cardiac output, and extracellular fluid volume that eventually lead to a reduction in the blood-pressure- lowering response to vasodilators are mitigated or attenuated. An intriguing speculation is the possibility that CCBs might countervail the sodium-retaining renal effects of decreased perfusion and, possibly, of decreased levels of natriuretic hormones [6]. In contrast with other vasodilators, such as hydralazine and mi- noxidil, the slow-release formulations of CCBs blunt the reflex increase in sympathetic activity that typi- cally occurs in association with blood pressure reduction [7]. CCBs may also interfere with the action of

angiotensin II on vascular smooth muscle. Despite the early increase in plasma renin activity (PRA) during CCB therapy, aldosterone levels fail to rise propor- tionally (and occasionally decrease), perhaps because of the role of calcium in hormonal release. Recent evidence indicates that acute administration of CCBs, unlike most other nondiuretic antihypertensive medications, produces a diuresis and natriuresis [6]. Addi- tionally, when CCBs are given long term, they are not sodium retaining [6].

CCBs differ from previous vasodilators because of their favorable accompanying effects on the heart and kidney. As antihypertensive agents, the CCBs thus appear considerably more versatile than previous vasodilators.

Use of Calcium Channel Blockers as Antihypertensive Agents

To date, all of the CCBs have been shown to be simi- larly effective and well-tolerated antihypertensive drugs. Interestingly, CCBs generally have a lesser effect on the blood pressure of normotensive patients. In hypertensive patients, however, there is some evidence that their effect on blood pressure increases with the degree of hypertension. These observations taken together lend support to the notion that these agents act by specifically reversing pathophysiologic perturbations. There are few contraindications to the use of CCBs (as opposed to beta-blockers) as antihypertensive agents--severely depressed left ventricular systolic function (frank congestive heart failure or history thereof), sick sinus syndrome, and arterioventricular conduction disturbances.

As mentioned, several studies have shown that all CCBs have similar antihypertensive properties. Ad- verse or salutary effects thus dictate the choice of a specific agent. For example, the newer dihydropyridines may be preferred in a patient with mild ventricular systolic dysfunction, conduction system disease, or slow heart rate. In contrast, verapamil or diltiazem may be more suitable in a patient with tachycardia. In this regard, a recent study by Zimlichman et al. [8] considered the question of vascular selectivity and concomitant effects on cardiac performance. These investigators evaluated, in a double-blind study, the acute hemodynamic effects of oral nisoldipine in patients with essential hypertension. Hemodynamic measurements, using the impedance cardiography method, were performed before and at hourly inter- vals following the oral administration of the drug/ placebo. Nisoldipine significantly decreased systolic and diastolic blood pressure, with a slight increase in heart rate. Stroke volume did not change significantly following the medication. These findings confirm the notion that nisoldipine is vascular selective and consequently has a substantive blood-pressure-

Calcium Cha~mel Blockers and Hypertension 885

Vasodilation

1 PVR

~ aP

~' SNS activity

Renin-angiotensin aldosterone t activity

Renin perfusion

~ }PVR ~ .

Venoconstriction J " f c o - - - - ~

Natriuretic hormones

Fig. 1. A summary of the mechanisms whereby CCBs attenuate the expected adaptive cha,~es in peripheral vascular resistance (PVR), heart rate, cardiac outpztt, re*~al perfusion, and extracelbtlar fl~id volume that would otherwise eventually lead to a reduction in the initial blood-pressure-lowering response. Symbols indicate countervailing mechanisms that are attenuated by CCBs. (Reproduced with permission from Epstebz [3].)

lowering effect without concomitant negative inotro- pic effects.

M e t a b o l i c E f f e c t s

In view of the fact that hypertension is often associated with metabolic abnormalities, there is increasing concern regarding the metabolic effects of antihypertensive drug therapy and its impact on cardiovascular risk reduction resulting from the treatment of hypertension [9-18]. These concerns have been highlighted by the recent JNC V Guidelines that have recom- mended diuretic and beta-blocker agents for first-line treatment for hypertension [19]. It has become readily apparent that antihypertensive therapy with high doses of thiazide diuretics and beta-blockers is associated with impaired insulin sensitivity and other interrelated metabolic abnormalities. The preliminary report of the British Medical Research Council (MRC) trial disclosed a 12% incidence of glucose intolerance in young people followed up for 5 years of diuretic therapy. Diuretics, at least in high doses, have been associated with potassium and magnesium depletion [20], lipid abnormalities [10,13,15,16], and glucose intolerance [9,15,16,21]. Beta-blocker therapy is associated with impaired insulin sensitivity and release, glucose intolerance, and dyslipidemia [13-16,21-23]. In light of these observations, the metabolic effects of CCBs should be considered in some detail.

Recent studies have indicated that the vasculature is an insulin-sensitive and IGF-I-sensitive tissue [24]. Both hormones regulate both vascular tone and meta-

bolic processes. They modulate vascular tone by stimu- lating endothelial cell production and by regulating vascular cation metabolism. They also regulate glucose metabolism, which may have important implications with respect to vascular tone and vascular growth [24].

The available studies indicate that CCBs are metabolically neutral and do not exacerbate dyslipidemia or impair glucose tolerance. In contrast to diuretics and beta-blockers, CCBs do not appear to alter insulin sensitivity. For example, Shamoon et al. [25] assessed the influence of verapamil on glucoregulatory hormones in humans during hyperglycemic clamp studies. They demonstrated that neither plasma insulin nor glucagon levels were altered in response to verapamil administration. Subsequent studies have demonstrated that dihydropyridine CCBs do not impair glucose tolerance [21-23]. Studies by Lithell demonstrated that CCBs are generally neutral in their effects on insulin sensitivity [26]. A review of 35 published reports concluded that CCBs have no untoward effects on blood glucose levels, insulin response, hemoglobin Alc levels, or lipid profiles [27].

For example, Ferrier et al. [28] reported that treatment with verapamil did not adversely affect serum cholesterol, lipid fractions, fructosamine, and gly- cosylated hemoglobin, while fasting plasma glucose was reduced. These observations were corroborated by Bakris et al. in a group of non-insulin-dependent diabetic subjects [29]. This observation is particularly important because insulin release involves calcium and, consequently, if high doses of CCBs are used alone in an attempt to adequately reduce arterial pressure, a worsening of pre-existing hyperglycemia is

886 Epstein

theoretically possible. Thus, given their good side- effect profile, CCBs are excellent agents for the treatment of hypertension both generally and among both type I and type [[ diabetic patients.

Lasseter et al. [30] recently reviewed the changes in biochemical and lipid parameters in patients treated with nisoldipine coat core (CC). In contrast with the increases in triglycerides and uric acid induced by hydrochlorothiazide, nisoldipine CC tended to decrease triglycerides and uric acid.

Salutary Effects on Target Organs: Kidney We have recently reviewed the pharmacologic effects of CCBs on renal hemodynamics [5,31]. In brief, un- der conditions of in vitro perfusion using the isolated rat kidney, CCBs preferentially augment the glomerular filtration rate (GFR) during norepinephrine- (NE) and angiotensin II-induced vasoconstriction. For example, studies from our laboratory have demonstrated that nisoldipine reverses the reductions in GFR induced by the acute administration of norepinephrine [32]. The ability of nisoldipine CC to produce a marked increase in GFR, with only a modest increase in renal plasma flow, is consistent with the no- ti~n that niso~dipine CC preferentially a~tenuates NE- induced constriction of preglomerular resistance vessels. The ability to preferentially vasodilate the afferent arteriole indicates that CCBs are capable of maintaining renal perfusion at a time when systemic blood pressure is lowered toward normal levels. A large body of data has accrued indicating that CCBs lower systemic blood pressure while preserving renal perfusion and GFR [33,34]. In light of recent increasing interest in preventing decrements of perfusion to vital target organs such as the heart and kidney, this attribute commends the use of a dihydropyridine CCB, such as nisoldipine CC [5].

[n addition to their renal vasodilatory effects, CCBs also affect renal excretory function. There is a large body of evidence indicating that CCBs are acutely natriuretic [6]. It should be emphasized that the increases in sodium excretion were observed despite decreases in blood pressure, which would ordi- narily favor increased sodium reabsorption hy reducing renal blood flow.

Although CCBs obviously cannot be continuously natriuretic on a long-term basis, they act to prevent sodium retention. Recent studies from our laboratories confirm previous suggestions that the natriuretic potential of dihydropyridines is sustained Zoag term [35]. Specifically, we demonstrated that although CCBs are not actively natriuretic long term, they are capable of inducing a sustained state of increased natriuretic potential. Consequently, they augment and amplify natriuretic stimuli such as ~olume expansion, and more specifically, ingestion of a large

sodium load [6]. The clinical relevance of these observations is that CCI~s attenuate the expected adaptive changes that offset blood pressure lowering. CCRs also potentiate the natriuretic response to volume expansion, resulting in an absence of sodium retention. Consequently, volume-expansion-induced pseudotolerance is avoided and the antihypertensive efficacy of CCBs is enhanced [6].

Effects on Left Ventricular Hypertrophy Echocardiographic studies have revealed that as many as 50% of asymptomatic patients who have mild to moderate hypertension have Zeft ventricular hypertrophy (LVH) [36,37]. Hemodynamic overload from long-standing systemic hypertension is the primary factor in the pathogenesis of LVH, but nonhemody- namic factors play a significant role as well. Recent experimental work has implicated proto-oncogenes, cell-growth-regulating genes, and various growth factors in the pathogeaesis of the myocytotic hypertrophy, disordered collagen structure, and fibroblastic dysfunction that constitute LVH.

Effective antihypertensive therapy can prevent or even reverse established LVH. All effective antihypertensive agents, if given for a long enough time, witl cause regression of LVH. However, the time required to achieve measurable regression differs markedly between the commonly used antihypertensive drugs. The most rapid and extensive LVH regression occurs with agents that block the renin-angiotensin system or reduce the entry of calcium into the cells. Dahlof et al. [38] have suggested that inhibitors of angiotensin-converting enzyme (ACE) reduce left ventricular (LV) wall thickness to a greater extent than any other class of drugs, but this meta-analysis has been criticized. These classes of antihypertensive drugs are particularly effective because, in addition to their beneficial effects on blood pressure, they inhibit speci~c cellular mechanisms that promote LVH. Al- though CCBs are generally effective in LVH reduction, there are differences between specific agents.

Regression of LVH leads to improved LV filling and contractility, enhanced coronary reserve, and reduced ventricular dysrrhythmias. The Framingham Study documented a 25% reduction in the risk of cardiovascular events in patients who had electrocardio- graphic or radiologic evidence of LVH reversal [39]. However, a long-term clinical benefit of LVH regression has not been demonstrated conclusively in a placebo-controlled, double-blind study.

Recent Controversy Regarding Safety of Calcium Channel Blockers

Despite the attributes of CCBs as antihypertensive agents already enumerated, a ~umber of retrospee-

Calcium Channel Blockers and Hypertension 887

tive analyses have suggested that CCBs may be detrimental and may promote adverse cardiovascular events. Recently Psaty et al. [40] presented the results of a meta-analysis at the 35th Annual Conference on Cardiovascular Disease Epidemiology and Preven- tion sponsored by the American Heart Association. Subsequently, the study was published in a recent issue of the Journal of the American Medical Associ- ation [41]. They concluded that hypertensive patients receiving CCBs had a significantly greater risk of myocardial infarction compared with those receiving beta-blockers [RR = 1.63, 95% confidence interval (CI) = 1.23-2.16]. The study was observational and used a case-control design.

The case-control method, as used by Psaty and colleagues, defines comparative groups by the presence (case) or absence (control) of a disease endpoint. These patients were interviewed or their records were reviewed "retrospectively" to determine past or current exposures. Because exposure information is gathered retrospectively, case-control studies are more susceptible to certain forms of bias, including interview bias and recall bias.

In contrast to such an observational study design, the randomized controlled clinical trial is more rigorous, yielding the strongest inferences. Randomization ensures that the groups being compared are as similar as possible, except for drug exposure. The clinical trial design maximizes the likelihood that differences in the occurrence rates of various adverse events are caused by drug rather than other, unmeasured sources of bias.

Several epidemiologists and statisticians have criticized the Psaty study, suggesting that because the disease endpoint being treated and the treatments themselves are so interrelated, it may be difficult to attribute a finding to the treatment or to the underly- ing disease [42]. This interrelationship is known as "confounding by indication" and the question of whether hypertensives treated with certain antihypertensive drugs are at a greater risk of myocardial infarction (MI) falls within this group.

Selection bias may play an important role in studies in which there is a potential for confounding by indication. Without randomization, there is no certainty that the patients prescribed various antihypertensive agents have the same inherent risk of MI when first prescribed the drug. For example, factors that could account for selective differences in treatment in the Psaty study specifically include the following: (a) sicker patients may be selectively put on CCBs because better compliance may be achieved due to fewer nuisance side effects or because of institutional treatment protocols, (b) subgroups of patients who have an inherently higher risk of MI, such as diabetics, are more likely to be prescribed CCBs than beta-blockers because of differential effects on blood glucose control, and (c) differences in dose response may result in sicker patients receiving a higher dose of CCBs. An

editorial accompanying the J A M A article emphasizes that the hypothesis proposed by Psaty and colleagues has "not yet been tested" and that the " . . . known risks of uncontrolled hypertension are far greater than the postulated but unproven hazards of calcium channel blockers" [42].

A recent major study from Israel in a large popula- tion of patients with chronic coronary disease fails to support the allegations that CCBs increase the risk of mortality in patients with chronic coronary artery disease, Braun et al. [43] analyzed the data obtained from 11,575 patients screened for the Bezafibrate In- farction Prevention study (5843 with and 5732 without CCBs) after a mean follow-up period of 3.2 years. There were 495 deaths (8.5%) in the CCB group compared with 410 in the control group (7.2%). The age- adjusted risk ratio for mortality was 1.08 (95% CI = 0.95-1.24). After adjustment for the differences between the groups in age and gender and the preva- lence of previous MI, angina pectoris, hypertension, New York Heart Association functional class, peripheral vascular disease, chronic obstructive pulmonary disease, diabetes, and current smoking, the adjusted risk ratio declined to 0.97 (95% CI = 0.84-1.11). After further adjustment for concomitant medication, the risk ratio was estimated at 0.94 (95% CI = 0.82-1.08). Thus the analysis of Braun et al. [43] does not support the claim that CCB therapy in patients with chronic coronary artery disease, whether MI survivors or oth- ers, increases the risk of mortality.

Despite questions regarding the rigor of the observational studies of Psaty et al. [40,41] and Pahor et al. [44], these investigators have posed an appropriate and important question that we should consider-- whether CCBs promote adverse cardiovascular events. Several lines of evidence suggest that while this may have been true for the earlier rapid-acting CCB formulations, it is unlikely that such an increased risk complicates the use of the newer slow-release formulations. A brief consideration of the differing phar- macokinetic and pharmacodynamic effect of differing formulations serves to support this contention [45].

As noted previously, CCBs are markedly heterogeneous agents. Perhaps what is not appreciated is the fact that different formulations of the same chemical moiety can produce markedly differing hemodynamic and neurohumoral effects [7,45,46]. The earliest CCBs were short acting. Subsequently, the drug-delivery systems for the short-acting agents were modified in order to provide more fully and consistently main- tained CCB activity. Although such new formulations were developed primarily to produce a sustained 24- hour therapeutic effect, with minimal peak-to-trough fluctuations, thereby encouraging compliance, addi- tional benefits accrued. An added benefit that is equally important, albeit not widely appreciated, is that these uniform plasma concentrations avoid provoking the activation of the renin-angiotensin and sympathetic nervous systems [7,45].

888 Epstein

(a)

100

5o

§ 10

u-u Rapid bolus (and exponential infusion)

H Slow infusion

I I I I I I I

0 2 4 6 8 10 12 14

Time (hours)

(b)

H Slow infusion 15 10 5

n- _

m -10 t f r I r r

Rapid bolus (and exponential infusion)

0 13. m ~ ~ -5

D

-15 I I I I I

2 4 6 8 10

Time (hours)

I

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Fig. 2. a: Comparison of the effects of a rapid bolus dose and a slow infusion on blood pressure a~wl heart rate. A rapid intravenous bolus dose (and exponential infusion) rapidly attained an effective level of nifedipine. In contrast, a progressive incremental intravenous infusion attained an identical plasma nifedipine level more gradually. Results are mean ± SD. (Adapted with permission from Kleinbloesem et al. [47].) b: Rapid attainment of an effective plasma concentration via a rapid intravenous bolus dose (and exponential infusion) caused no appreciable fall in blood pressure. In contrast, if an identical plasma nifedipine concentration was attained graduaUy, there was a significant decrease in blood pressure but no increase in heart rate. Results are mean ± SD. (Adapted with pe~w~ission from Kleinbloesem et al. [47].)

As I have detailed in a recent review, the rate of drug delivery into the systemic circulation has profound effects on the hemodynamic and neurohumoral responses to a dihydropyridine CCB drug [45]. In an elegant study of intravenously administered nifedipine, Kleinbloesem et al. [46] clearly showed that the rate of drug delivery determined the pattern of response (Fig. 2a). They compared the effects of a rapid bolus dose and slow infusion on systemic hemodynamics. Thus the rapid attainment of an effective plasma

concentration via a rapid intravenous bolus drug (and exponential infusion) caused no appreciable fall in blood pressure because there was an associated increase in adrenergic activity and a marked increase in heart rate (and presumably cardiac output; Fig. 2b). In contrast, if an identical plasma nifedipine concentration was gradually attained over several hours by means of a progressive incremental intravenous infusion, there was no adrenergic response and no increase in heart rate, but there was a significant decrease in blood pressure (see Fig. 2b). These studies clearly highlight the importance of the rate of attainment of plasma levels in determining the consequent adrenergic and cardioacceleratory response.

Slow-release formulations of otherwise rapidly absorbed dihydropyridines, however, achieved a more gradual and sustained antihypertensive effect [45,47,48]. Consequently, different formulations differ in their ability to evoke intermittent increases in sympathetic activity after dosing. As an example, a comparison of the effects of differing formulations of nifedipine on the neurohormonal and PRA response at trough in patients with mild to moderate hypertension disclosed differences. Both the nifedipine gastrointes- tinal therapeutic system (GITS) once daily and nifedipine capsule lid reduced mean arterial pressure and total peripheral resistance to a similar extent. Plasma noradrenaline levels at the trough of the patients receiving nifedipine GITS were virtually identical to those of patients receiving placebo. In contrast, trough noradrenaline levels tended to be substantially higher in patients receiving nifedipine capsules [47].

These considerations of the differences between the rapidly absorbed and short-acting formulations and the more recently introduced longer acting formulations may account, at least in part, for the negative results to date of human studies on the regression of atherosclerosis [45]. None of the drugs administered so far has provided sustained blood levels over the entire 24 hours. All of the CCB formulations utilized in regression studies to date have been shown to evoke reactive cardioacceleration during apparent steady-state conditions. Consequently, a reasonable hypothesis to account for increased adverse vascular events in regression studies would propose that medications provoking a counterregulatory response with cardioacceleration may exacerbate ischemia in patients with basal myocardial ischemia. Conversely, agents producing true steady-state levels (i.e., a GITS-like preparation, amlodipine, or lacidipine) do not evoke such unwanted counterregulatory responses and may consequently not promote increased adverse vascular events.

Recently Pahor et al. [49] reported the findings of an observational study suggesting that CCBs increase the risk of cancer. As pointed out in a number of recent critiques and reviews, the study of Pahor et al. [49] is confounded for several reasons.

Calcium Channel Blockers and Hypertension 889

• This was solely a subgroup study with results based on only a small group of patients. Of the 6566 patients in the cohort, only 750 are included in the current analysis.

• There was no control group. Consequently, no comparison of cancer rates among patients not taking CCBs--either with or without hypertension--can be made.

• The magnitude of the relative risk of two is weak. As an example, Robert Temple, Director of Drug Evaluation at the Food and Drug Administration has observed, "My basic rule is if the relative risk isn't at least three or four, forget it" [50].

• The only evidence of antihypertensive therapy for the 4 years of follow-up is based on information collected at a single point in time--at the beginning of the study. Consequently, there is no way of as- sessing the duration of therapy or whether therapy was changed during follow-up.

Finally, it should be remembered that drugs for chronic therapy are rigorously tested for cancer potential and must pass rigorous safety studies man- dated and reviewed by the FDA and other national regulatory bodies.

In summary, it is clear the large prospective studies utilizing such slow-release formulations are urgently needed to validate such a formulation and to allay the apprehension engendered by these recent retrospective observational studies. While we await the completion of such studies, it is reasonable and prudent to continue using CCBs as antihypertensive agents. Indeed, the National Kidney Foundation has recently issued a Public Advisory stating, "The National Kidney Foundation strongly recommends that patients now on calcium channel blockers should continue taking their medication. Failure to take prescribed antihypertensive drugs may result in dangerously high blood pressure." A prudent approach is to restrict the use of CCBs to the newer slow-release formulations that, by virtue of their ability to attain more gradual and sustained plasma levels, do not evoke reactive sympathetic activation.

C o n c l u s i o n s

Over the past decade, multiple lines of research have implicated transmembrane calcium ion fluxes as an important mediator of the increased systemic vascular resistance that characterizes the majority of hypertensive states. CCBs exhibit a potent vasodilating effect by directly relaxing vascular smooth muscle. They seem to work in all populations and may perhaps have a more pronounced antihypertensive effect when administered to older patients with low renin levels and high vascular resistance. Because of their rela-

tively short half-lives, slow-release formulations must be used.

CCBs have a unique spectrum of pharmacologic effects as well as actions on the cardiovascular system, so these agents have potentially important advan- tages in several groups of patients. Included in these categories are patients with coexisting coronary disease, variant angina, and supraventricular arrhyth- mias. The role of certain CCBs in patients with previous MI, and whether the actions of CCBs on the coronary circulation and their putative ability to reverse the progression of LVH, and possibly to prevent or delay atherogenesis, will prove to be of major clinical importance requires further study.

Finally, there is mounting concern that the choice of an antihypertensive agent should be predicated in part by its effect on the lipid profile and potassium metabolism. The demonstration that CCBs do not ex- ert adverse effects in this respect has thus assumed considerable importance. This paucity of adverse effects increasingly commends CCBs as initial monotherapy in the management of hypertension.

A c k n o w l e d g m e n t s

Portions of this review have been adapted with permission from an earlier article by the author: Epstein M. Calcium antagonists should continue to be used for first-line treatment of hypertension. Arch Intern Med 1995;155:2150-2156. Copyright 1995, American Medical Association.

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calcium channel blockers and hypertension: evolving perspectives—1996

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