The Role of Existing and Newer Calcium Channel Blockers in the Treatment of Hypertension

Abstract

Calcium channel blockers (CCBs), which include both dihydropyridines such as nifedipine and amlodipine and non‐dihydropyridines (verapamil and diltiazem), are among the most widely prescribed agents for the management of essential hypertension. Several large outcome risk trials and comprehensive meta‐analyses have found that CCBs reduce the cardiovascular morbidity and mortality associated with uncontrolled hypertension, including stroke. CCBs, however, appear less effective than angiotensin‐converting enzyme inhibitors and diuretics for preventing heart failure and myocardial infarction. CCBs are among the agents listed as potential first‐line therapy, either alone or in combination with other agents in hypertension management guidelines. Furthermore, CCBs are suitable for add‐on therapy in combination with diuretics, angiotensin‐converting enzyme inhibitors, and angiotensin‐II receptor blockers. CCBs may be partially suitable for patients with comorbid Raynaud's syndrome, isolated systolic hypertension (dihydropyridine), or angina pectoris (non‐dihydropyridine). The newer inherently long‐acting dihydropyridine agents (e.g., lacidipine, lercanidipine), which are not currently available in the United States, appear to have comparable efficacy to older agents of the dihydropyridine class but may have an improved tolerability profile, especially with regard to peripheral edema.

Calcium channel blockers (CCBs) have been used for more than a quarter of a century and are among the most widely prescribed drugs for the treatment of hypertension. While their efficacy is well established, the safety of these agents and their effects on cardiovascular (CV) and non‐CV morbidity and mortality have been the subject of debate over the last decade. ¹ , ² , ³ , ⁴ , ⁵ , ⁶ , ⁷ Recently, several large outcome studies and comprehensive meta‐analyses have been published that shed further light on the impact of CCBs on CV morbidity and mortality in hypertensive patients. These findings have been incorporated into the most recent national and international guidelines for hypertension management. ⁸ , ⁹ , ¹⁰

PHARMACOLOGY OF CCBs

CCBs are a heterogeneous group of drugs that can be divided into two major categories based on predominant physiologic effects: 1) dihydropyridines (DHPs), which preferentially bind L‐type calcium channels in vascular smooth muscle, resulting in vasodilatation and lowering of blood pressure (BP), and 2) non‐DHPs (verapamil and diltiazem), which exert equipotent effects on L‐type calcium channels in the myocardium and the vasculature and preferentially bind calcium channels at the sinoatrial and atrioventricular node (Table I). ¹¹ Consequently, verapamil and diltiazem are less potent vasodilators than DHPs and are associated with negative chronotropic effects and a decrease in sympathetic nervous system activity, effects not clinically observed with DHP CCBs.

Table I.

Calcium Channel Blockers

Generic Name	Brand Name (Manufacturer)
Dihydropyridines
Amlodipine besylate*	Norvasc (Pfizer, Inc.)
Amlodipine maleate*	AmVaz (Reddy Pharmaceuticals,
	Inc.) Not available in the United
	States
Azelnidipine*	Not available in the United States
Felodipine	Plendil (AstraZeneca)
Isradipine	DynaCirc, DynaCirc CR
	(Reliant Pharmaceuticals)
Lacidipine*	Not available in the United States
Lercanidipine*	Not available in the United States
Nicardipine	Cardene, Cardene SR (Roche
	Pharmaceuticals)
Nifedipine	Adalat CC (Bayer
	Pharmaceuticals)
	Procardia, Procardia XL (Pfizer, Inc.)
Nisoldipine	Sular (First Horizon
	Pharmaceuticals)
Non‐Dihydropyridines
Diltiazem	Cardizem (Aventis Pharmaceuticals)
	Cardizem CD (Biovail Labs Pharmaceuticals)
	Cardizem LA (Biovail Labs Pharmaceuticals)
	Cardizem SR (Aventis Pharmaceuticals)
	Cartia XT (Andrx Pharmaceuticals)
	Dilacor XR (Watson Laboratories)
	Tiazac (Biovail Labs Pharmaceuticals)
Verapamil	Calan, Calan SR (GD Searle & Co.)
	Covera‐HS (GD Searle & Co.)
	Isoptin, Isoptin SR (Abbott Laboratories)
	Verelan, Verelan PM (Elan Pharmaceuticals)
*Inherently long‐acting calcium channel blockers

CCBs can also be categorized by duration of action: 1) short‐acting agents (nifedipine [capsule containing liquid], nicardipine, isradipine, diltiazem, verapamil); 2) long‐acting agents that are modified‐release, once‐daily formulations (e.g., nifedipine gastrointestinal therapeutic system (GITS) and nifedipine CCB, sustained‐released verapamil); and 3) inherently long‐acting agents (e.g., amlodipine, lacidipine, lercanidipine). The short‐acting DHPs, most of which have never been approved and are not recommended for the treatment of hypertension, are associated with a reflex sympathetic nervous system activation, which causes an increase in heart rate. Heart rate usually decreases about 5%–10% after treatment with the non‐DHPs.

The pharmacologic diversity among CCBs accounts for differences in side effects among the agents. Headache, dizziness, flushing, and peripheral edema are more common with DHPs, especially the short‐acting ones. Verapamil is associated with constipation, especially in its short‐acting formulation. In addition, both verapamil and, to a lesser extent, diltiazem can diminish cardiac contractility and slow cardiac conduction; they should be avoided in patients with severe systolic dysfunction, sick sinus syndrome, or second‐or third‐degree atrioventricular block. ¹²

CONTROVERSIES OVER CCB SAFETY

In 1995, several retrospective, observational, case‐control studies suggested that treatment with short‐acting CCBs were associated with an increased incidence of coronary events and mortality. ¹ , ² , ³ Although short‐acting agents are rarely used today, these widely debated studies were intrinsically “confounded by indication” such that patients receiving short‐acting CCBs usually had more underlying coronary disease and, therefore, were more likely to experience coronary events. ⁷ Since only short‐acting CCBs were used in these studies, the results cannot be extrapolated to the longer‐acting agents, which do not cause the wide fluctuations in BP or the same degree of neurohormonal activation as their short‐acting counterparts. ⁷ Furthermore, the results of recent outcome trials and meta‐analyses of long‐acting CCBs (discussed below) do not support the deleterious findings of these earlier observational studies.

Observational studies also suggested an increased risk of cancer and gastrointestinal hemorrhage with CCB use. ⁴ , ⁵ These studies had intrinsic confounding as well, and, since their publication, several other studies, including large prospective clinical trials such as the Systolic Hypertension in Europe (Syst‐Eur) ¹³ trial and the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), ¹⁴ did not find an increased cancer or bleeding risk with CCBs of the DHP class. ⁶

CLINICAL OUTCOME TRIALS OF CCBs FOR HYPERTENSION

The efficacy of CCBs for BP control has compared favorably against other types of antihypertensive drugs. The Veterans Affairs Cooperative Study, ¹⁵ which evaluated monotherapy with six different antihypertensive agents, as well as placebo, found that diltiazem had the highest treatment success rate, with 59% of treated patients achieving BP goal (diastolic blood pressure [DBP] <90 mm Hg) at the end of titration (4‐8 weeks) and maintaining DBP <95 mm Hg at 1 year; this was significantly different from captopril, prazosin, and placebo (Table II). ¹⁵ A longer‐term evaluation of five active single‐agent treatments or placebo on BP and CV events, when added to lifestyle modification, was investigated in the Treatment of Mild Hypertension Study (TOMHS) ¹⁶ (Table II). At 48 months, amlodipine maleate was associated with the highest percentage of patients maintained on monotherapy (82.5% compared with 67.5%–77.8% for the other drug treatments; p=0.01); thus the greatest proportion of individuals achieving target BP on monotherapy compared with those treated with other drug classes.

Table II.

Clinical Trials Evaluating DHP and Non‐DHP Calcium Antagonists in Hypertensive Populations

Trial name	Study Design/Total Number of Patients/BP Entry Criteria/Follow‐Up	Initial Study Drugs	blood pressureand primary outcome results (ccb vs. Comparator) (Except Where Otherwise Specified)
VA Cooperative 15	R, DB, PC	Atenolol	At end of titration, p=0.05 for DBP for diltiazem vs. all
	N=1292	Captopril	treatments, except clonidine, and for SBP for diltiazem
	DBP 95–109 mm Hg	Clonidine	vs. captopril or placebo
	All drugs titrated to a goal of	SR Diltiazem	% of patients achieving BP goal during titration (DBP
	DBP <90 mm Hg	HCTZ	<90 mm Hg) and maintaining BP control (DBP <95
	Titration: 4–8 weeks	Prazosin	mm Hg) at 1 year: 59% diltiazem*; 51% atenolol; 50%
	Maintenance: At least 1 year	Placebo	clonidine; 46% HCTZ; 42% captopril; 42% prazosin; 25% placebo*
TOMHS 16	R, DB, PC	Acebutolol	BP reduction: all active treatments 15.9/12.3, placebo
	N=902	Amlodipine	9.1/8.6 mm Hg (p<0.0001). Among the active
	DBP 90–99 mm Hg	maleate	treatments, there were significant differences in SBP
	4.4 years	Chlorthalidone	reduction, ranging from 14.2 for doxazosin to 17.7 for
		Doxazosin	chlorthalidone
		Enalapril	All active treatments vs. placebo:
		Placebo	Death or major nonfatal CV event: 0.69 (0.59–1.23), p=0.21; including other clinical events, 0.66 (0.44–0.97), p=0.03
STOP‐2 17	R, O, BE	Conventional	BP reduction similar in all groups
	N=6614	(HCTZ/	Fatal stroke, fatal MI, other fatal CV disease:
	SBP ≥180 mm Hg, DBP	Amiloride, BB,	Conventional vs. newer: 0.99 (0.84–1.16; p=0.89); also, no
	≥105 mm Hg, or both	or both)	difference when CCBs compared with D/BB or with ACEI
	5 years	Newer agents:  ACEI or DHP CCP
INSIGHT 18	R, DB	Nifedipine GITS	BP reduction similar in both groups
	N=6321	HCTZ/Amiloride	Death from any CV or cerebrovascular cause; nonfatal
	SBP/DBP ≥150/95 or SBP		stroke, MI, and HF:
	≥160 mm Hg, plus ≥1 additional CV risk factor 4 years		1.10 (0.91–1.34), p=0.35
MIDAS 19	R, DB	Isradipine	SBP reduction was 3.5 mm Hg greater for HCTZ than
	N=883	HCTZ	for isradipine (p=0.002); no difference in DBP
	SBP/DBP 150/97		1° outcome: Rate of progression of mean maximum IMT
	maximum IMT 1.17		(p=0.68)
	3 years		2° outcome: Major vascular events (MI, stroke, HF, angina, sudden death)—(isradipine 25 events vs. HCTZ angina, sudden death—(isradipine 25 events vs. HCTZ 14 events; p=0.07)
NORDIL 20	R, O, BE	Diltiazem	SBP reduction was 3 mm Hg greater for diltiazem
	N=10,881	Conventional	compared with conventional therapy (p<0.001); no
	DBP ≥100 mm Hg	therapy (D, BB,	difference in DBP
	4.5 years	or both)	1° outcome: Fatal and nonfatal stroke, fatal and nonfatal MI, and other CV death 1.00 (0.87–1.15; p=0.97) 2° outcome: fatal and nonfatal stroke 0.80 (0.65–0.99) p=0.04
INVEST 21	R, O, BE	Verapamil SR	Similar SBP and DBP reductions
	N=22,576	Atenolol	1° First occurrence of death (all‐cause), nonfatal MI, or
	Hypertension (JNC VI defined) with coronary artery disease 2.7 years	plus Trandolapril for patients with renal impairment, DM, or HF	nonfatal stroke 0.98 (0.90–1.06; p=0.57) 2° outcome: nonfatal stroke 0.89 (0.70–1.12), p=0.33
CONVINCE 22 , 39	R, DB	Verapamil COER	Similar SBP and DBP reductions
	N=16,476	Atenolol or HCTZ	1° outcome: First occurrence of stroke, MI, or CV‐related
	SBP/DBP: <175/<100 mm Hg (if treated for ≥2 months) or SBP 140–190 mm Hg, DBP 90–110 mm Hg (untreated/treated for <2 months), with ≥1 additional CV risk factor 3 years		death 1.02 (0.88–1.18), p=0.77 Other outcome: nonfatal and fatal stroke 1.15 (0.90–1.48), p=0.26)
ALLHAT 14	R, DB	Chlorthalidone	Amlodipine (A) vs. chlorthalidone (C):
	N=24,303 (+9054 Lisinopril)	Amlodipine	5‐year BP differences: SBP ‐0.8 mm Hg (p=0.03), DBP
	Stage 1 or stage 2	Lisinopril	–0.8mm Hg (p<0.001)
	hypertensives with ≥1		1° outcome: fatal CHD or nonfatal MI combined 0.98
	additional CHD risk factor		(0.90–1.07), p=0.65
	4.9 years		2° outcome: nonfatal and fatal stroke 0.93 (0.82–1.06), p=0.28 HF, 6‐year rate: 10.2% (A) vs. 7.7% (C); 1.38 (1.25–1.52), p<0.001
Syst‐Eur 13	R, DB, PC	Nitrendipine	Between‐group difference: SBP: 10.1 (95% CI, 8.8–11.4)
	N=4695	Placebo	DBP: 4.5 (95% CI, 3.9–5.1)
	SBP 160–219 mm Hg &		Fatal and nonfatal strokes combined, 42% risk reduction
	DBP <95 mm Hg 2 years		(p=0.003)
Syst‐China 24	DB, PC, BE	Nitrendipine	Intergroup group: SBP: 9.1 (95% CI: 7.6–10.7) DBP: 3.2
	N=2394	Placebo	(95% CI 2.4–4.0)
	SBP 160–219 mmHg 3 years		Fatal and nonfatal strokes combined, 38% risk reduction (p=0.01)
HOT 25	R, O, BE	Felodipine	26.2/20.3 (≤90 mm Hg group)
	N=18, 790	Patients	28.0/22.3 (≤85 mm Hg group)
	DBP 100–115 mm Hg	randomized to	29.9/24.3 (≤80 mm Hg group)
	3.8 years	different BP	Major CV events (all MI, all stroke, all other CV deaths)**:
		goals:	≤90 mm Hg group: 0.99 (0.83–1.19)
		≤90 mm Hg	≤85 mm Hg group: 1.08 (0.89–1.29)
		≤85 mm Hg	≤80 mm Hg group: 1.07 (0.89–1.28)
		Dihydropyridine
		≤80 mm Hg
DHP=dihydropyridine; BP=blood pressure; CCB=calcium channel blocker; R=randomized; DB=double‐blind; PC=placebo‐controlled; DBP=diastolic blood pressure; SR=sustained release; HCTZ=hydrochlorothiazide; SBP=systolic blood pressure; CV=cardiovascular; O=open‐label; BE=blinded end point; MI=myocardial infarction; BB=β blocker; D=diuretic; ACEI=angiotensin‐converting enzyme inhibitor; GITS=gastrointestinal therapeutic system; HF=heart failure; IMT=intimal‐medial thickness; JNC VI=the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; DM=diabetes mellitus; COER=controlled‐onset, extended‐release; CHD=coronary heart disease; CI=confidence interval; *p<0.001 for diltiazem vs. captopril or prazosin and for each active treatment group vs. placebo; **no significant differences among the groups in event rates

A growing number of trials have demonstrated that at the same level of BP control, most antihypertensives provide a similar degree of CV protection. The Swedish Trial in Old Patients with hypertension‐2 (STOP‐2) ¹⁷ reported similar degrees of BP reduction in 6614 patients 70–84 years of age who were treated with conventional therapy (a β blocker or diuretic), an angiotensin‐converting enzyme (ACE) inhibitor, or a DHP CCB (Table II). ¹⁷ In addition, all treatment groups had similar occurrences of CV mortality and of the combined end point including stroke, fatal and nonfatal myocardial infarction (MI), and other CV mortality. It is of interest to note that the relative risk of MI and heart failure (HF) were significantly lower in the ACE inhibitor treatment group compared with the CCB treatment group (MI: relative risk [RR] 0.77 [0.61‐0.96], p=0.018; HF: RR 0.78 [0.63‐0.97], p=0.025); however, the authors caution interpretation of these results since 48 statistical comparisons were performed, and for all other CV morbidity and mortality end point comparisons, there were no differences between CCBs, ACE inhibitors, or conventional therapy.

In the Intervention as a Goal in Hypertension Treatment (INSIGHT) trial, ¹⁸ both nifedipine GITS and co‐amilozide (hydrochlorothiazide [HCTZ] plus amiloride) produced equivalent BP control in 6321 patients aged 55–80 years of age with hypertension and at least one additional risk factor (Table II). Both regimens were also associated with similar incidences of the primary outcome (composite of death from any CV or cerebrovascular cause together with nonfatal stroke, MI, and HF); 18.2 vs. 16.5 events per 1000 patient‐years for nifedipine GITS vs. co‐amilozide, respectively; p=034); however, the incidences of fatal MI (16 events vs. five events; p=0.017) and nonfatal HF (24 events vs. 11 events; p=0.028) were significantly higher for nifedipine GITS than co‐amilozide. In addition, there was a higher rate of treatment discontinuation in the nifedipine group (p<0.0001), which was largely attributed to complaints of peripheral edema.

In the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS), ¹⁹ there was no difference between isradipine and diuretic therapy in the rate of progression of mean maximum carotid intimal‐medial thickness over 3 years (Table II). There was, however, a higher (but nonsignificant, p=0.07) incidence of major vascular events (MI, stroke, HF, angina, sudden death) with isradipine (25 events) compared with HCTZ (14 events). Although the mean reduction in systolic blood pressure (SBP) was higher for HCTZ than isradipine (3.5 mm Hg difference, p=0.002) at 6 months and at the end of the study, the investigators suggested that this difference did not explain the increased incidence of vascular events in the isradipine group.

Several recently published trials have examined the efficacy of the non‐DHP CCBs, verapamil and diltiazem, for the prevention of CV outcomes in hypertensive patients. In the Nordic Diltiazem (NORDIL) study, ²⁰ which compared diltiazem with conventional therapy (diuretics, β blockers, or both) in 10,881 patients between the ages of 50 and 74 years, mean DBP reduction at 24 months was similar between treatment groups, but the mean reduction in SBP was significantly greater with diltiazem than with conventional therapy (3 mm Hg difference; p<0.001). The primary end point (fatal and nonfatal stroke, fatal and nonfatal MI, and other CV death) occurred at a similar rate in both the diltiazem and conventional therapy treatment groups (16.6 vs. 16.2 events per 1000 patient‐years; p=0.97) (Table II). For stroke alone (fatal and nonfatal), there was a significant risk reduction with diltiazem compared to conventional therapy (6.4 vs. 7.9 events per 1000 patient‐years; RR 0.80 [0.65–0.99; p=0.04]). It is possible, however, that this finding was due to chance, given the many statistical comparisons performed. In the International Verapamil SR‐Trandolapril Study (INVEST), ²¹ BP control at 24 months in 22,756 patients aged 50 years or older from 15 countries, all of whom had documented hypertension and coronary artery disease, was similar in patients receiving either sustained‐release verapamil or atenolol as initial therapy (Table II). ²¹ Both treatment strategies were equally effective for reducing the primary outcome (first occurrence of death [all cause], nonfatal MI, non‐fatal stroke; 36 vs. 37 events per 1000 patient‐years for verapamil and atenolol groups, respectively; p=0.57). In all of these trials, medications other than the study drugs were given in a large number of patients in an attempt to achieve satisfactory BP lowering.

The Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) ²² trial also demonstrated similar reductions in BP among 16,602 hypertensive patients with at least one additional risk factor for CV disease who were randomized to receive either controlled‐onset, extended‐release verapamil (plus other medications) or conventional treatment with either the β blocker, atenolol, or the diuretic, HCTZ (Table II). Both groups experienced similar incidences of the primary outcome (first occurrence of acute MI, stroke, or CV disease‐related death; 4.5% in the verapamil group vs. 4.4% in the atenolol/HCTZ group; p=0.77). Of note, cancer incidence did not vary by treatment group, however, deaths or hospitalizations due to bleeding (and unrelated to stroke) occurred more frequently in patients assigned controlled‐onset, extended‐release verapamil (1.4%) than atenolol or HCTZ (1.0%); p=0.003. The incidence of deaths alone from bleeding not related to stroke was similar between the groups.

The ALLHAT trial randomized 42,418 hypertensive patients aged 55 years or older with at least one additional coronary heart disease (CHD) risk factor to a diuretic (chlorthalidone), a CCB (amlodipine), an ACE inhibitor (lisinopril), or an α blocker (doxazosin). ¹⁴ Due to the early termination of the α‐blocker arm, ²³ 33,357 patients remained randomized to active treatment. ¹⁴ The differences in SBP and DBP with chlorthalidone vs. amlodipine were statistically, but not clinically, significant. At a mean follow‐up of 5 years, for example, the differences were only 0.8 mm Hg. The incidence of the primary outcome (fatal CHD or nonfatal MI, 6‐year rate, 11.3% for amlodipine vs. 11.5% for chlorthalidone; p=0.65) was similar between the groups (Table II). There was, however, a significantly higher rate of HF with amlodipine compared with chlorthalidone (6‐year rate, 10.2% vs. 7.7% for chlorthalidone; RR 1.38 [1.25–1.52; p<0.001]). There were no differences between treatment groups in the incidences of cancer or of hospitalization for gastrointestinal bleeding.

In the Syst‐Eur trial, ¹³ 4695 patients aged ≥60 years with isolated systolic hypertension were randomized to the DHP CCB, nitrendipine, or placebo. SBP and DBP decreased significantly more with nitrendipine than placebo (Table II). For the primary end point of fatal and non‐fatal stroke combined, active treatment produced a 42% rate reduction (from 13.7 [placebo] to 7.9 [nitrendipine] events per 1000 patient‐years, p=0.003). Nitrendipine was also associated with a 44%(p=0.007) reduction in nonfatal stroke and a 26% (p=0.03) reduction in all fatal and nonfatal cardiac end points. Similar results were achieved in the nonblinded Systolic Hypertension in China (Syst‐China) study ²⁴ (Table II). In that study of 2394 patients aged ≥60 years, nitrendipine significantly reduced SBP 9 mm Hg more than that achieved with placebo, as well as the primary end point (total stroke) and many secondary CV end points, compared with placebo. Active treatment reduced the total stroke rate by 38% (from 20.8 [placebo] to 13.0 [nitrendipine] events per 1000 patient‐years [p=0.001]). The study also found that CCBs reduced the risk of CV mortality by 39% (p=0.03) and total mortality by 39% (p=0.003). While the study design of Syst‐China (lack of true randomization and the potential for physician unblinding) is cause for cautious interpretation of these results, the blinded Endpoint Committee validated the events.

The Hypertension Optimal Treatment (HOT) trial ²⁵ assessed optimum target DBP in 19,196 hypertensive patients who initially received the DHP CCB felodipine with the addition of other agents, as necessary, to achieve a target DBP of ≤90 mm Hg, ≤85 mm Hg, or ≤80 mm Hg (Table II). While the differences in event rates among the three groups were small and nonsignificant, the HOT trial demonstrated the benefits of lowering DBP to at least 85 mm Hg. The benefits of lowering DBP to ≤80 mm Hg was particularly evident among the subset of patients with diabetes (n=1501). The incidences of major CV events and CV mortality were significantly lower among diabetic patients in the ≤80 mm Hg group compared with those in the ≤90 mm Hg group (p=0.005).

RECENT META‐ANALYSIS OF ANTIHYPERTENSIVE OUTCOMES WITH CCBs

Several recent meta‐analyses have assessed the impact of CCBs on CV morbidity and mortality in hypertensive patients. Pahor et al. ²⁶ analyzed data from nine clinical trials in which patients received CCBs or other antihypertensive agents (diuretics, β blockers, ACE inhibitors, or clonidine) (Table III). The reduction in SBP and DBP was similar for all agents, and no differences were observed between CCBs and other agents for the end points of stroke and all‐cause mortality; however, CCBs were associated with higher rates of MI, HF, and major CV events compared with other antihypertensive agents.

In a more recent meta‐analysis of six clinical trials, investigators reported similar rates of mortality (total and CV) and major CV events with CCBs compared with conventional therapy (β blocker or diuretic) (Table III). ²⁷ CCBs were associated with a lower risk of nonfatal stroke by 16% (p=0–013) and a higher (18%) risk of nonfatal MI (p=0.036). After correction for multiple comparisons, these p values became 0.052 and 0.144, respectively.

Neither of the above analyses included ALLHAT, which is incorporated into three other analyses. Of the 15 trials included in the Staessen et al. ²⁸ meta‐analysis, nine included hypertensive patients randomized to conventional therapy (diuretics or β blockers) or CCBs, which were assessed for differences in SBP and incidences of morbidity and mortality. No differences were observed between the groups in total mortality, CV mortality, or fatal and nonfatal MI (Table III). CCBs were associated with a nonsignificant (7.6%) reduction in stroke (p=0.07) but a significant (33%) increased risk of HF (p<0.0001).

In the most recent systematic overview by the Blood Pressure Lowering Treatment Trialists' Collaboration, ²⁹ BP control was comparable between CCBs and other active treatments (Table III). Compared with placebo, CCBs reduced BP by a weighted average of 8.4/4.2 mm Hg and significantly reduced the risk of stroke by 38%, CHD by 22%, and major CV events (stroke, CHD, HF, CV death) by 18%. There were no significant differences between CCBs and other active treatments in the rates of CHD, major CV events, CV deaths, or total mortality. For stroke, there were trends toward greater risk reductions with CCBs compared to diuretics or β blockers (7% [‐1% to 14%]) and also when compared to ACE‐inhibitor therapy (12% [1%–25%]), but both ACE‐inhibitor therapy (18% [8%–27%]) and diuretic or β‐blocker therapy (33%[21%–47%]) produced greater risk reductions for HF than CCBs.

In a network meta‐analysis by Psaty et al., ³⁰ eight of 42 eligible trials compared CCB therapy with low‐dose diuretic therapy. CCBs were comparable to low‐dose diuretics (the reference agent) for many morbidity and mortality outcomes, except for CV disease events and HF, where diuretics were associated with lower risks (Table III).

Table III.

Meta‐Analyses and Systematic Reviews Evaluating DHP and Non‐DHP Calcium Antagonists in Hypertensive Populations

Trial Author, Publication Year/Number of Trials (n)	CCB vs. Comparator Agent(S)/Number of Patients (n)/Duration of Follow‐up	Blood Pressure and Primary Outcome Results (CCBS vs. Comparator)
Pahor et al., 2000 26 n=9	Amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, or verapamil (N=12,669) D, BB, ACEI, or clonidine (N=15,044) (“other agents”) 2–7 years	No significant differences in SBP or DBP reduction but MI 1.26 (1.11–1.43; p=0.0003); HF 1.25 (1.07–1.46; p=0.005); combined major CV events 1.10 (1.02–1.18; p=0.018) Similar risks for stroke 0.90 (0.80–1.02), all‐cause mortality, CV mortality, and non‐CV mortality
Opie and Schall, 2002 27 n=6	Diltiazem, felodipine, isradipine, nicardipine, nifedipine, or verapamil (N=12,116) D or BB (N=12,206) 2–6 years	BP: no data provided Nonfatal stroke 0.84 (0.74–0.96; p=0.013); nonfatal MI 1.18 (1.01–1.37; p=0.036). (Note: After Bonferroni correction for multiplicity; p=0.052 for nonfatal stroke and p=0.144 for nonfatal MI) Similar risks for fatal stroke, fatal MI, total mortality, CV mortality, and major CV events
Staessen et al., 2003 28 n=9	Amlodipine, diltiazem, felodipine, isradipine, lacidipine, nicardipine, nifedipine, or verapamil (N=30,520) D or BB (N=36,915) 2–6 years	BP: no data provided Fatal and nonfatal stroke: 0.92 (0.84–1.01; p=0.07), if exclude verapamil (CONVINCE trial) 0.90 (0.82–0.98; p=0.02); CHF: 1.33 (1.22–1.44; p<0.0001) Similar risks for total mortality, CV mortality, all CV events, and MI
Trialists, 2003 29 n=29 (17 of which included CCBs)	Amlodipine, diltiazem, felodipine, isradipine, lacidipine, nicardipine, nifedipine, nisoldipine, nitrendipine, verapamil CCB (N=3794) vs. placebo (N=3688) 2.6–3.0 years CCB (N=31,031) vs. D/BB (N=37,418) 2–5 years CCB (N=12,998) vs. ACEI (N=12,758) 3–5.3 years	CCB vs. placebo: SBP:–8.4 mm Hg and DBP:–4.2 mm Hg Stroke 0.62 (0.47–0.82), CHD 0.78 (0.62–0.99), major CV events 0.82 (0.71–0.95), CV death 0.78 (0.61–1.00); HF 1.21 (0.93–1.58); total mortality 0.89 (0.75–1.05) ] CCB vs. D/BB: SBP: 0.8 mm Hg and DBP:–0.2 mm Hg Stroke 0.93 (0.86–1.00); HF 1.33 (1.21–1.47) No statistical difference in the incidences of death or other CV outcomes CCB vs. ACEI: SBP:–0.6 mm Hg and DBP:–0.9 mm Hg CCBs trended toward 12% (1–25) risk reduction in stroke, while ACE inhibitors significantly reduced HF by 18% (0.82 [0.73–0.92]) No statistical difference in the incidences of death or other CV outcomes
Psaty et al., 2003 30 n=42 (total of 14 CCB trials, 8 of which qualified for the low‐dose diuretic comparison)	Amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, verapamil (no short‐acting agents) (N=29,343) Low‐dose diuretics (N=35,758) 2–5 years (for the eight CCB trials)	Low‐dose diuretics vs. CCBs: No difference between groups in change in SBP or DBP HF 0.74 (0.67–0.81; p<0.001); CV disease events 0.94 (0.89–1.00; p=0.045) No significant differences in death or other CV outcomes, including stroke CCBs were significantly better than placebo in all these outcomes.
DBP=diastolic blood pressure; ACEI=angiotensin‐converting enzyme inhibitor; BB=β blocker; CCB=calcium channel blocker; CHD=coronary heart disease; CV=cardiovascular; D=diuretic; DHP=dihydropyridine; HF=heart failure; MI=myocardial infarction; SBP=systolic blood pressure

CURRENT HYPERTENSION GUIDELINES: ROLE OF CCBs

Based, in large part, on the results of ALLHAT, the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)8 recommends thiazide‐type diuretics as initial therapy for most patients, either alone or in combination with ACE inhibitors, angiotensin receptor blockers (ARBs), β blockers, or CCBs. Since most patients will require two or more agents to achieve BP goals, ACE inhibitors, ARBs, β blockers, or CCBs are suggested as add‐on therapy when needed or in combination with thiazide‐type diuretics as initial therapy in the case of patients presenting with stage 2 hypertension (SBP >160 mm Hg or DBP >100 mm Hg). High‐risk conditions benefited by the use of CCBs include high coronary disease risk and diabetes (particularly in combination with other agents). In addition, CCBs may be particularly useful in patients with comorbid Raynaud's syndrome. While CCB or diuretic monotherapy has also been noted to produce better BP responses in African Americans when compared with ACE inhibitors, ARBs, or β blockers, this differential benefit is largely eliminated when these latter agents are combined with a diuretic.

The European Society of Hypertension‐European Society of Cardiology guidelines, ⁹ on the other hand, conclude that all major classes of antihypertensives (diuretics, β blockers, CCBs, ACE inhibitors, ARBs) are suitable for initial and maintenance therapy, either alone or in combination. Conditions favoring the choice of a DHP CCB for hypertension include: advanced age, isolated systolic hypertension, angina pectoris, peripheral vascular disease, carotid atherosclerosis, and pregnancy. Diltiazem or verapamil should be considered for use in patients with angina pectoris or supraventricular tachycardia. These guidelines also recommend the avoidance of all CCBs in HF, of DHP CCBs in tachyarrhythmias, and of diltiazem and verapamil in grade 2 or 3 atrioventricular block.

Like the JNC 7 Report, the most recent World Health Organizations10/International Society of Hypertension statement on hypertension management recommends a thiazide diuretic as first choice in the absence of a compelling indication for another drug class. In addition, a thiazide diuretic should be a component of combination therapy in most cases. According to this group, an indication exists for initial use of DHP CCBs for isolated systolic hypertension in the elderly.

NEWER CCBs ON THE HORIZON

There are several newer CCBs under investigation, some of which offer the potential for improved tolerability with comparable efficacy to currently available agents. Lercanidipine is a long‐acting DHP CCB approved for use in Europe and other countries but not yet available in the United States. In comparative trials of up to 16 weeks' duration, it has demonstrated similar antihypertensive efficacy to nifedipine slow‐release, amlodipine, felodipine, nifedipine GITS, and verapamil SR. ³¹ Lercanidipine has been well tolerated in clinical trials, with its most common adverse events related to vasodilation (i.e., headache, flushing, peripheral edema). The reported incidence of vasodilatory edema is significantly lower with lercanidipine compared with other DHP CCBs. The recently published COHORT study ³² in 828 older (≥ 60 years) patients with hypertension reported lower rates of edema and of study discontinuation due to edema with lercanidipine (9% and 2.1%, respectively) and lacidipine (4% and 1.4%, respectively) than with amlodipine (19% and 8.5%, respectively). Results of a pooled analysis of data from 20 clinical trials reported an incidence of ankle edema of 0.9%‐6.1 % with lercanidipine vs. 1.3% with placebo. ³¹

Lacidipine, another long‐acting DHP CCB not yet available in the United States, has also demonstrated similar antihypertensive efficacy to other long‐acting DHP CCBs in randomized, controlled trials. ³³ In addition, the recently published Systolic Hypertension in the Elderly: Lacidipine Long‐term (SHELL) ³⁴ study demonstrated comparable incidences of CV events and total mortality between lacidipine and chlorthalidone in over 1800 older (>60 years) patients with isolated systolic hypertension who received treatment for a median of 32 months. Similarly, there were no significant differences in the incidence of any CV events among more than 2000 hypertensive patients receiving either lacidipine or atenolol as initial therapy in the 4‐year European Lacidipine Study on Atherosclerosis (ELSA). ³⁵ Lacidipine appears to have a similar tolerability profile to other DHPs but with a lower incidence of pedal edema demonstrated in some studies (e.g., the COHORT study discussed above). ³² , ³³

Azelnidipine is a new long‐acting DHP CCB recently approved for use in Japan but not yet available elsewhere. Results from small, mostly short‐term, studies suggest comparable efficacy to amlodipine and nitrendipine in reducing BP. ³⁶ The tolerability profile of azelnidipine appears similar to that of other DHP CCBs, with a low incidence of vasodilatory‐related adverse effects.

A new extended‐release formulation of diltiazem (Cardizem LA, Biovail Pharmaceuticals, Inc.) that uses a graded‐release system to slow drug release into the bloodstream has recently become available. Studies with this formulation demonstrate reduced morning BP with evening dosing. ³⁷ , ³⁸ No outcome data, however, are yet available demonstrating an associated reduction in the morning spike in adverse CV events.

CONCLUSIONS

Lowering BP is of primary importance in preventing adverse CV outcomes. A large body of evidence demonstrates the safety and efficacy of CCBs for treatment of hypertension and for the prevention of morbidity and mortality outcomes, including stroke. CCBs appear to be less effective, however, for preventing HF and MI than ACE inhibitors or diuretics. In patients with nondiabetic renal disease, a DHP should not be used as initial therapy. CCBs are among the classes of agents recommended by some national guideline committees for initial therapy, either alone or in combination with other therapies, for lowering BP. Since therapy should be tailored to individual patient needs, recommendations from some updated hypertension guidelines identify several situations that suggest consideration of CCBs as first‐line antihypertensive agents. In addition, CCBs are suitable as add‐on therapy in the majority of patients who usually require two or more agents to achieve BP goals. Several newer long‐acting CCBs on the horizon are expected to provide similar benefits to those currently seen with existing agents within the CCB class with perhaps fewer side effects, most notably a reduction in peripheral edema.