the role of existing and newer calcium channel blockers in the treatment of hypertension

VOL. VI NO. XI NOVEMBER 2004 THE JOURNAL OF CLINICAL HYPERTENSION 621

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 out-come risk trials and comprehensive meta-analyses have found that CCBs reduce the cardiovascular morbidity and mortality associated with uncontrolled hyperten-sion, including stroke. CCBs, however, appear less effec-tive than angiotensin-converting enzyme inhibitors and diuretics for preventing heart failure and myocardial infarction. CCBs are among the agents listed as poten-tial 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 comor-bid Raynaud’s syndrome, isolated systolic hypertension (dihydropyridine), or angina pectoris (non-dihydropyri-dine). 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 dihydropyri-

dine class but may have an improved tolerability profile, especially with regard to peripheral edema. (J Clin Hypertens. 2004;6:621–631) ©2004 Le Jacq Communications, Inc.

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.1–7 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 incor-porated into the most recent national and international guidelines for hypertension management.8–10

PHARMACOLOGY OF CCBSCCBs are a heterogeneous group of drugs that can be divided into two major categories based on pre-dominant physiologic effects: 1) dihydropyridines (DHPs), which preferentially bind L-type calcium channels in vascular smooth muscle, resulting in vaso-dilatation 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 atrioven-tricular 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.

CCBs can also be categorized by duration of action: 1) short-acting agents (nifedipine [capsule containing

R e v i e w P a p e r • C M E

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

Jan Basile, MD

From the Division of General Internal Medicine/Geriatrics, Medical University of South Carolina, Charleston, SCAddress for correspondence:Jan Basile, MD, Professor of Medicine, Ralph H. Johnson VA Medical Center, Division of General Internal Medicine/Geriatrics, Medical University of South Carolina, 109 Bee Street, Charleston, SC 29401-5799E-mail: [email protected] received April 7, 2004;revised May 12, 2004;accepted May 19, 2004

www.lejacq.com ID: 3683

The Journal of Clinical Hypertension (ISSN 1524-6175) is published monthly by Le Jacq Communications, Inc., Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2004 by Le Jacq Communications, Inc., All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at [email protected] or 203.656.1711 x106.

THE JOURNAL OF CLINICAL HYPERTENSION VOL. VI NO. XI NOVEMBER 2004622

liquid], nicardipine, isradipine, diltiazem, verapamil); 2) long-acting agents that are modified-release, once-daily formulations (e.g., nifedipine gastrointes-tinal therapeutic system (GITS) and nifedipine CCB, sustained-released verapamil); and 3) inherently long-acting agents (e.g., amlodipine, lacidipine, lercani-dipine). 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 con-duction; they should be avoided in patients with severe systolic dysfunction, sick sinus syndrome, or second- or third-degree atrioventricular block.12

CONTROVERSIES OVER CCB SAFETYIn 1995, several retrospective, observational, case-con-trol studies suggested that treatment with short-acting CCBs were associated with an increased incidence of coronary events and mortality.1–3 Although short-act-ing 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 confound-ing 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 HYPERTENSIONThe efficacy of CCBs for BP control has compared favorably against other types of antihypertensive drugs. The Veterans Affairs Cooperative Study,15 which evalu-ated 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

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 StatesFelodipine Plendil (AstraZeneca)Isradipine DynaCirc, DynaCirc CR

(Reliant Pharmaceuticals)Lacidipine* Not available in the United StatesLercanidipine* Not available in the United StatesNicardipine Cardene, Cardene SR (Roche

Pharmaceuticals)Nifedipine Adalat CC (Bayer

Pharmaceuticals)Procardia, Procardia XL (Pfizer, Inc.)

Nisoldipine Sular (First Horizon Pharmaceuticals)

Non-DihydropyridinesDiltiazem 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



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.

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-convert-ing 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 includ-ing 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 significant-ly 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=0.34); 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 nife-dipine GITS than co-amilozide. In addition, there was a higher rate of treatment discontinuation in the nifedip-ine group (p<0.0001), which was largely attributed to complaints of peripheral edema.

In the Multicenter Isradipine Diuretic Athero-sclerosis 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 dil-tiazem, for the prevention of CV outcomes in hyper-tensive 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 reduc-tion 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 hyperten-sion 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 pri-mary outcome (first occurrence of acute MI, stroke, or CV disease-related death; 4.5% in the verapamil group



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 PRESSURE AND PRIMARY OUTCOME RESULTS (CCB VS. COMPARATOR) (EXCEPT WHERE OTHERWISE SPECIFIED)

VA Cooperative15 R, DB, PCN=1292DBP 95–109 mm HgAll drugs titrated to a goal of

DBP <90 mm HgTitration: 4–8 weeksMaintenance: At least 1 year

AtenololCaptoprilClonidineSR DiltiazemHCTZPrazosinPlacebo

At end of titration, p=0.05 for DBP for diltiazem vs. all treatments, except clonidine, and for SBP for diltiazem vs. captopril or placebo

% of patients achieving BP goal during titration (DBP <90 mm Hg) and maintaining BP control (DBP <95 mm Hg) at 1 year: 59% diltiazem*; 51% atenolol; 50% clonidine; 46% HCTZ; 42% captopril; 42% prazosin; 25% placebo*

TOMHS16 R, DB, PCN=902DBP 90–99 mm Hg4.4 years

AcebutololAmlodipine

maleateChlorthalidoneDoxazosinEnalaprilPlacebo

BP reduction: all active treatments 15.9/12.3, placebo 9.1/8.6 mm Hg (p<0.0001). Among the active treatments, there were significant differences in SBP reduction, ranging from 14.2 for doxazosin to 17.7 for chlorthalidone

All active treatments vs. 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-217 R, O, BEN=6614SBP ≥180 mm Hg, DBP

≥105 mm Hg, or both5 years

Conventional (HCTZ/Amiloride, BB, or both)

Newer agents: ACEI or DHP CCB

BP reduction similar in all groupsFatal stroke, fatal MI, other fatal CV disease:Conventional vs. newer: 0.99 (0.84–1.16; p=0.89); also, no

difference when CCBs compared with D/BB or with ACEI

INSIGHT18 R, DBN=6321SBP/DBP ≥150/95 or SBP

≥160 mm Hg, plus ≥1 additional CV risk factor

4 years

Nifedipine GITSHCTZ/Amiloride

BP reduction similar in both groupsDeath from any CV or cerebrovascular cause; nonfatal

stroke, MI, and HF:1.10 (0.91–1.34), p=0.35

MIDAS19 R, DBN=883SBP/DBP 150/97maximum IMT 1.173 years

IsradipineHCTZ

SBP reduction was 3.5 mm Hg greater for HCTZ than for isradipine (p=0.002); no difference in DBP

1° outcome: Rate of progression of mean maximum IMT (p=0.68)

2° outcome: Major vascular events (MI, stroke, HF, angina, sudden death)—(isradipine 25 events vs. HCTZ 14 events; p=0.07)

NORDIL20 R, O, BEN=10,881DBP ≥100 mm Hg4.5 years

DiltiazemConventional

therapy (D, BB, or both)

SBP reduction was 3 mm Hg greater for diltiazem compared with conventional therapy (p<0.001); no difference in DBP

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

INVEST21 R, O, BEN=22,576Hypertension (JNC VI

defined) with coronary artery disease

2.7 years

Verapamil SRAtenolol

plus Trandolapril for patients with renal impairment, DM, or HF

Similar SBP and DBP reductions1° First occurrence of death (all-cause), nonfatal MI, or

nonfatal stroke 0.98 (0.90–1.06; p=0.57) 2° outcome: nonfatal stroke 0.89 (0.70–1.12), p=0.33



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 addi-tional 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, signifi-cant. 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 chlortha-lidone; p=0.65) was similar between the groups (Table II). There was, however, a significantly higher rate of HF with amlodipine compared with chlorthalidone

CONVINCE22,39 R, DBN=16,476SBP/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

Verapamil COERAtenolol or HCTZ

Similar SBP and DBP reductions1° outcome: First occurrence of stroke, MI, or CV-related

death 1.02 (0.88–1.18), p=0.77Other outcome: nonfatal and fatal stroke 1.15 (0.90–

1.48), p=0.26)

ALLHAT14 R, DBN=24,303 (+9054 Lisinopril)Stage 1 or stage 2

hypertensives with ≥1 additional CHD risk factor

4.9 years

ChlorthalidoneAmlodipineLisinopril

Amlodipine (A) vs. chlorthalidone (C): 5-year BP differences: SBP 0.8 mm Hg (p=0.03), DBP

–0.8mm Hg (p<0.001)1° outcome: fatal CHD or nonfatal MI combined 0.98

(0.90–1.07), p=0.652°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-Eur13 R, DB, PCN=4695SBP 160–219 mm Hg &

DBP <95 mm Hg2 years

NitrendipinePlacebo

Between-group difference: SBP: 10.1 (95% CI, 8.8–11.4)DBP: 4.5 (95% CI, 3.9–5.1)Fatal and nonfatal strokes combined, 42% risk reduction

(p=0.003)

Syst-China24 DB, PC, BEN=2394SBP 160–219 mmHg3 years

NitrendipinePlacebo

Intergroup group: SBP: 9.1 (95% CI: 7.6–10.7) DBP: 3.2 (95% CI 2.4–4.0)

Fatal and nonfatal strokes combined, 38% risk reduction (p=0.01)

HOT25 R, O, BEN=18, 790DBP 100–115 mm Hg3.8 years

FelodipinePatients

randomized to different BP goals:

≤90 mm Hg≤85 mm Hg

Dihydropyridine≤80 mm Hg

26.2/20.3 (≤90 mm Hg group)28.0/22.3 (≤85 mm Hg group)29.9/24.3 (≤80 mm Hg group)Major CV events (all MI, all stroke, all other CV deaths)**:≤90 mm Hg group: 0.99 (0.83–1.19)≤85 mm Hg group: 1.08 (0.89–1.29)≤80 mm Hg group: 1.07 (0.89–1.28)

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



(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 place-bo (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) study24 (Table II). In that study of 2394 patients aged ≥60 years, nitrendipine significantly reduced SBP 9 mm Hg more than that achieved with pla-cebo, 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 cau-tious interpretation of these results, the blinded Endpoint Committee validated the events.

The Hypertension Optimal Treatment (HOT) trial25 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 com-pared with those in the ≤90 mm Hg group (p=0.005).

RECENT META-ANALYSIS OF ANTIHYPERTENSIVE OUTCOMES WITH CCBSSeveral 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 antihyper-tensive 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 asso-ciated 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 conven-tional 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 diuret-ics 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%]) pro-duced 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).

CURRENT HYPERTENSION GUIDELINES: ROLE OF CCBSBased, 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 combina-tion 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 ben-

efited 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.

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., 200026

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 butMI 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, 200227

n=6

Diltiazem, felodipine, isradipine, nicardipine, nifedipine, or verapamil (N=12,116)

D or BB (N=12,206)2–6 years

BP: no data providedNonfatal 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., 200328

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 providedFatal 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, 200329

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 yearsCCB (N=31,031) vs. D/BB (N=37,418)2–5 yearsCCB (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 HgStroke 0.93 (0.86–1.00); HF 1.33 (1.21–1.47)No statistical difference in the incidences of death or other CV

outcomesCCB vs. ACEI: SBP: –0.6 mm Hg and DBP: –0.9 mm HgCCBs 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., 200330

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 DBPHF 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



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 ath-erosclerosis, and pregnancy. Diltiazem or verapamil should be considered for use in patients with angina pectoris or supraventricular tachycardia. These guide-lines 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 Organization10/International Society of Hypertension statement on hypertension management recommends a thiazide diuretic as first choice in the absence of a com-pelling 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 indi-cation exists for initial use of DHP CCBs for isolated systolic hypertension in the elderly.

NEWER CCBS ON THE HORIZONThere are several newer CCBs under investigation, some of which offer the potential for improved toler-ability with comparable efficacy to currently avail-able 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 simi-lar 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 sig-nificantly lower with lercanidipine compared with other DHP CCBs. The recently published COHORT study32 in 828 older (>60 years) patients with hypertension reported lower rates of edema and of study discontinu-ation 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 tri-als 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 addi-tion, 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 chlortha-lidone 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 receiv-ing either lacidipine or atenolol as initial therapy in the 4-year European Lacidipine Study on Atherosclerosis (ELSA).35 Lacidipine appears to have a similar toler-ability 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 else-where. Results from small, mostly short-term, studies suggest comparable efficacy to amlodipine and nitren-dipine in reducing BP.36 The tolerability profile of azelni-dipine 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, how-ever, are yet available demonstrating an associated reduction in the morning spike in adverse CV events.

CONCLUSIONSLowering BP is of primary importance in preventing adverse CV outcomes. A large body of evidence dem-onstrates 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, recommen-dations 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.



REFERENCES 1 Psaty BM, Heckbert SR, Koepsell TD, et al. The risk of

myocardial infarction association with antihypertensive drug therapies. JAMA. 1995;274:620–625.

2 Pahor M, Guralnik JM, Corti MC, et al. Long-term surviv-al and use of antihypertensive medications in older persons. J Am Geriatr Soc. 1995;43:1191–1197.

3 Furberg CD, Psaty BM, Meyer JV. Nifedipine. Dose-related increase in mortality in patients with coronary heart dis-ease. Circulation. 1995;92:1326–1331.

4 Pahor M, Guralnik JM, Salive ME, et al. Do calcium chan-nel blockers increase the risk of cancer. Am J Hypertens. 1996;9:695–699.

5 Pahor M, Guralnik JM, Furberg CD, et al. Risk of gastroin-testinal haemorrhage with calcium antagonists in hypertensive persons over 67 years old. Lancet. 1996;347:1061–1065.

6 Mason RP. Calcium channel blockers, apoptosis and can-cer: is there a biologic relationship? J Am Coll Cardiol. 1999;34:1857–1866.

7 Kizer JR, Kimmel SE. Epidemiologic review of the calcium channel blocker drugs. An up-to-date perspective on the proposed hazards Arch Intern Med. 2001;161:1145–1158.

8 The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA. 2003;2560–2572.

9 Guidelines Committee. 2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens. 2003;21:1011–1053.

10 World Health Organization, International Society of Hypertension Writing Group. 2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens. 2003;21:1983–1992.

11 Opie LH, Yusuf S, Kubler W. Current status of safety and efficacy of calcium channel blockers in cardiovascular diseases: a critical analysis based on 100 studies. Prog Cardiovasc Dis. 2000;43:171–196.

12 Opie LH. Calcium channel antagonists in the treatment of coronary artery disease: fundamental pharmacological properties relevant to clinical use. Prog Cardiovasc Dis. 1996;38:273–290.

13 Staessen JA, Fagard R, Thijs L, et al., for the Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet. 1997;350:757–764.

14 The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-con-verting enzyme inhibitor or calcium channel blocker vs. diuretic. JAMA. 2002;288:2981–2997.

15 Materson BJ, Reda DJ, Cushman WC, et al., for the Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Single-drug therapy for hyper-tension in men. A comparison of six antihypertensive agents with placebo. N Engl J Med. 1993;328:914–921.

16 Neaton JD, Grimm RH, Prineas RJ, et al., for the Treatment of Mild Hypertension Study Research Group. Treatment of mild hypertension study. JAMA. 1993;270:713–724.

17 Hansson L, Lindholm LH, Ekbom T, et al., for the STOP-Hypertension-2 study group. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascu-lar mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study. Lancet. 1999;354:1751–1756.

18 Brown MJ, Palmer CR, Castaigne A, et al. Morbidity and mortal-ity in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet. 2000;356:366–372.

19 Borhani NO, Mercuri M, Borhani PA, et al. Final outcome results of the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS). A randomized controlled trial. JAMA. 1996;276:785–791.

20 Hansson L, Hedner T, Lund-Johansen P, for the NORDIL Study Group. Randomised trial of effects of calcium antago-

nists compared with diuretics and beta-blockers on cardio-vascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study. Lancet. 2000;356:359–365.

21 Pepine CJ, Handberg EM, Cooper-DeHoff RM, et al., for the INVEST Investigators. A calcium antagonist vs. a non-cal-cium antagonist hypertension treatment strategy for patients with coronary artery disease. JAMA. 2003;290:2805–2816.

22 Black HR, Elliott WJ, Grandits G, et al., for the CONVINCE Research Group. Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial. JAMA. 2003;289:2073–2082.

23 Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipid-low-ering treatment to prevent heart attack trial (ALLHAT). ALLHAT Collaborative Research Group. JAMA. 2000;283:1967–1975.

24 Liu L, Wang JG, Gong L, et al., for the Systolic Hypertension in China (Syst-China) Collaborative Group. Comparison of active treatment and placebo in older Chinese patients with isolated systolic hypertension. J Hypertens. 1998;18:1823–1829.

25 Hansson L, Zanchetti A, Carruthers SG, et al., for the HOT Study Group. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: princi-pal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998;351:1755–1762.

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

27 Opie LH, Schall R. Evidence-based evaluation of calcium channel blockers for hypertension: equality of mortality and cardiovascular risk relative to conventional therapy. J Am Coll Cardiol. 2002;39:315–322. [Erratum in: J Am Coll Cardiol 2002;39:1409–1410.]

28 Staessen JA, Wang JG, Thijs L. Cardiovascular prevention and blood pressure reduction: a quantitative overview updated until 1 March 2003. J Hypertens. 2003;21:1055–1076.

29 Turnbull F. Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of pro-spectively-designed overviews of randomised trials. Lancet. 2003;362:1527–1535.

30 Psaty BM, Lumley T, Furberg CD, et al. Health outcomes associated with various antihypertensive therapies used as first line agents. JAMA. 2003;289:2534–2544.

31 Bang LM, Chapman TM, Goa KL. Lercanidipine: a review of its use in the management of hypertension Drugs. 2003;63:2449–2472.

32 Leonetti G, Magnani G, Pessina AC, et al., on behalf of the COHORT Study Group. Tolerability of long-term treat-ment with lercanidipine versus amlodipine and lacidipine in elderly hypertensives. Am J Hypertens. 2002;15:932–940.

33 McCormack PL, Wagstaff AJ. Lacidipine: a review of its efficacy in the management of hypertension. Drugs. 2003;63:2327–2356.

34 Malacco E, Mancia G, Rappelli A, et al. Treatment of iso-lated systolic hypertension: the SHELL study results. Blood Press. 2003;12:160–167.

35 Zanchetti A, Bond MG, Hennig M, et al., on behalf of the ELSA investigators. Calcium antagonist lacidipine slows down progression of asymptomatic carotid atherosclero-sis: principal results of the European Lacidipine Study on Atherosclerosis (ELSA), a randomized, double-blind, long-term trial. Circulation. 2002;106:2422–2427.

36 Wellington K, Scott LJ. Azelnidipine. Drugs. 2003;63: 2613–2621.

37 Sista S, Lai JCK, Eradiri O, et al. Bioavailability of once-daily dosing of graded-release diltiazem in the morning ver-sus evening [abstract]. Pharmacotherapy. 2002;22:1331.

38 Glasser SP, Neutel JM, Gana TJ, et al. Efficacy and safety of a once daily graded-release diltiazem formulation in essential hypertension. Am J Hypertens. 2003;16:51–58.

39 Black HR, Elliot WJ, Neaton JD, et al., for the CONVINCE Trial Research Group. Rationale and Design for the Controlled ONset Verapamil INvestigation of Cardiovascular End points (CONVINCE) Trial. Control Clin Trials. 1998;19:370–390.



INSTRUCTIONS FOR COMPLETING THIS FORM: Read the selected paper and answer all the questions that follow. After each question there is a series of possible correct answers. Please select the one best answer for each question and place your selection on the answer grid. YOU MUST ALSO COMPLETE THE CME EVALUATION SECTION and return the form within 6 months of the paper’s publication to receive credit. Letters of credit will be mailed to participants biannually.

ACCREDITATION STATEMENT: Winthrop-University Hospital (WUH) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing medical education for physicians. WUH designates this Continuing Medical Education activity for a maximum of (1) credit hour in Category 1 credit towards the AMA Physicians’ Recognition Award. Each physi-cian should claim only those hours of credit that he/she actually spent on the educational activity. WUH relies upon faculty participants in its CME programs to provide educational information that is objective and as free of bias as possible. In this spirit, and in accordance with the guidelines of the program sponsor, faculty participants are expected to indicate any commercial relationship that might be per-ceived as a real or apparent conflict of interest.

OBJECTIVE AND TARGET AUDIENCE: All primary care physicians and cardiologists are eligible to receive credit. At the conclusion of this activity, participants should be able to: 1) summarize the important points discussed in the paper reviewed; 2) identify patients to whom the paper is relevant; 3) modify management practices as new information is learned and; 4) identify deficiencies in their knowledge base.

1. Which of the following statements regarding the pharmacology of calcium channel block-ers (CCBs) is false?A __Amlodipine is a short-acting CCB that is

modified to a once daily preparation.B __The predominant effect of dihydropyridine

CCBs is vasodilatation.C __Non-dihydropyridine CCBs bind calcium

channels in the sinoatrial and atrioven-tricular nodes.

D __Dihydropyridine CCBs are not significant negative inotropes.

2. Which of the following statements regarding the side effects of CCBs is false?A __The short-acting dihydropyridine CCBs

are associated with fluctuations in blood pressure and reflex sympathetic nervous system activation.

B __Non-dihydropyridine CCBs are relatively contraindicated in patients with systolic heart failure.

C __Peripheral edema is more common with non-dihydropyridine CCBs.

D __Verapamil is known to cause constipation.

3. Which of the following statements regarding CCBs in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is false?A __The 6-year incidence of myocardial infarc-

tion was similar in the chlorthalidone and amlodipine patients.

B __Amlodipine was superior to chlorthalidone

in lowering systolic blood pressure.C __ There was a higher rate of heart failure in the

amlodipine treatment group when compared with the chlorthalidone treatment group.

D __An increased incidence of malignancies was not seen in the amlodipine group.

4. Which of the following meta-analyses of CCB trials is true?A __CCBs are less effective at lowering blood

pressure than thiazide diuretics.B __CCBs seem to be associated with higher

incidences of myocardial infarction and heart failure than thiazide diuretics and angiotensin-converting enzyme inhibitors.

C __CCBs should be considered first-line thera-py for most patients.

D __CCBs may be associated with a decreased incidence of stroke.

5. Which of the following statements regarding the current JNC 7 guidelines is false?A __ Thiazide diuretics are generally recommend-

ed as the first-line therapy for most patients.B __Combination therapy should be started

in patients presenting with systolic blood pressure >160 mm Hg.

C __Angiotensin-converting enzyme inhibi-tors, angiotensin receptor blockers, CCBs and β blockers are recommended add-on therapies to a thiazide diuretic in refrac-tory patients.

D __All CCBs are contraindicated in patients with heart failure.

CME QuestionsTodd C. Kerwin, MD, Section Editor, Winthrop Cardiology Associates, Mineola, NY

Please Select the One Best Answer for Each Question and Place Your Selection on the Answer Grid.



Answer the questions from the previous page by selecting the best choice of A, B, C, or D.

Questions: 1.__ 2.__ 3.__ 4.__ 5.__

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1. My knowledge was enhanced by this activity. 1.__ 2.__ 3.__ 4.__ 5.__

2. The activity helped to clarify issues specific to hypertension patients. 1.__ 2.__ 3.__ 4.__ 5.__

3. The information obtained from this exercise will have an impact on my care of patients. 1.__ 2.__ 3.__ 4.__ 5.__

4. The format of the exercise was useful. 1.__ 2.__ 3.__ 4.__ 5.__

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