Meta-analysis of Trials Comparing beta-Blockers, Calcium Antagonists, and Nitrates for Stable Angina

REVIEW

Meta-analysis of Trials Comparingb-Blockers, Calcium Antagonists,and Nitrates for Stable AnginaPaul A. Heidenreich, MD, MSKathryn M. McDonald, MMTrevor Hastie, PhDBahaa Fadel, MDVivian HaganByron K. Lee, MDMark A. Hlatky, MD

STABLE ANGINA AFFECTS MORE

than 7 million people in theUnited States,1 with an esti-mated 350 000 new cases an-

nually. Long-term pharmacotherapy toprevent anginal symptoms has con-sisted of b-blockers, calcium antago-nists, long-acting nitrates, or their com-binations.2 The choice of a first-lineagent has been controversial. Becauselong-term use of b-blockers has beenshown to reduce mortality followingmyocardial infarction,3 recent clinicalguidelines have suggested that b-block-ers be used as first-line agents in pa-tients with stable angina.4,5 However,calcium antagonists are often used asinitial therapy because they are as-sumed to have equal efficacy in reliev-ing angina, and fewer adverse ef-fects.6,7 Others have recommended thattherapy begin with long-acting ni-trates,6,8 but concern about the need fora nitrate-free period has led many phy-sicians to use long-acting nitrates as asecond-line agent.2 No single class oftherapy has been proven superior.9,10

Recent case-control studies andmeta-analyses of randomized trials

have suggested that short-acting cal-cium antagonists increase the risk ofcardiac events among patients withhypertension11 and that nifedipineincreases mortality following acuteischemic syndromes.12,13 These obser-vations have led to considerable dis-cussion and controversy.14 Even if

Author Affiliations: Veterans Affairs Palo Alto HealthCare System, Palo Alto, Calif (Dr Heidenreich); andthe Departments of Health Research and Policy (DrsHeidenreich, Hastie, and Hlatky and Mss McDonaldand Hagan), Medicine (Drs Heidenreich, Fadel, Lee,and Hlatky and Ms McDonald), and Statistics (Dr Has-tie), Stanford University, Stanford, Calif.Corresponding Author and Reprints: Paul A. Heiden-reich, MD, MS, 111C Cardiology, Palo Alto VA Medi-cal Center, 3801 Miranda Ave, Palo Alto, CA 94304(e-mail: [email protected]).

Context Which drug is most effective as a first-line treatment for stable angina isnot known.

Objective To compare the relative efficacy and tolerability of treatment with b-block-ers, calcium antagonists, and long-acting nitrates for patients who have stable angina.

Data Sources We identified English-language studies published between 1966 and1997 by searching the MEDLINE and EMBASE databases and reviewing the bibliog-raphies of identified articles to locate additional relevant studies.

Study Selection Randomized or crossover studies comparing antianginal drugs from2 or 3 different classes (b-blockers, calcium antagonists, and long-acting nitrates) last-ing at least 1 week were reviewed. Studies were selected if they reported at least 1 ofthe following outcomes: cardiac death, myocardial infarction, study withdrawal dueto adverse events, angina frequency, nitroglycerin use, or exercise duration. Ninety(63%) of 143 identified studies met the inclusion criteria.

Data Extraction Two independent reviewers extracted data from selected articles,settling any differences by consensus. Outcome data were extracted a third time by 1of the investigators. We combined results using odds ratios (ORs) for discrete dataand mean differences for continuous data. Studies of calcium antagonists were groupedby duration and type of drug (nifedipine vs nonnifedipine).

Data Synthesis Rates of cardiac death and myocardial infarction were not signifi-cantly different for treatment with b-blockers vs calcium antagonists (OR, 0.97; 95%confidence interval [CI], 0.67-1.38; P = .79). There were 0.31 (95% CI, 0.00-0.62; P = .05)fewer episodes of angina per week with b-blockers than with calcium antagonists. b-Block-ers were discontinued because of adverse events less often than were calcium antago-nists (OR, 0.72; 95% CI, 0.60-0.86; P,.001). The differences between b-blockers andcalcium antagonists were most striking for nifedipine (OR for adverse events with b-block-ers vs nifedipine, 0.60; 95% CI, 0.47-0.77). Too few trials compared nitrates with cal-cium antagonists or b-blockers to draw firm conclusions about relative efficacy.

Conclusions b-Blockers provide similar clinical outcomes and are associated withfewer adverse events than calcium antagonists in randomized trials of patients whohave stable angina.JAMA. 1999;281:1927-1936 www.jama.com

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these concerns prove to be valid inthe specific populations studied, it isuncertain whether the findings inthese patient groups can be applied topatients who have stable angina.

To determine the relative efficacy andsafety of antianginal therapies, we per-formed a meta-analysis of trials that di-rectly compared b-blockers, calciumantagonists, and long-acting nitrates inpatients who had stable angina. We alsoassessed the efficacy and safety of nifed-ipine and short-acting calcium antago-nists by examining trials that com-pared these agents with b-blockers.

METHODSData SourcesWe searched MEDLINE (1966-1997)and EMBASE (1974-1997), and re-viewed cited references of retrieved ar-ticles to identify relevant studies. Oursearch criteria were (1) the MedicalSubject Headings angina pectoris or thetext word angina and (2) publicationtype randomized controlled trial or textword containing a form of the word ran-dom. For this criteria set, we searchedMEDLINE, then EMBASE. We also per-formed searches replacing the secondcriterion with (3) publication type con-trolled clinical trial or (4) text worddouble-blind. Finally, we reviewed thebibliographies of identified trials to lo-cate other relevant studies.

Study SelectionWe restricted this review to con-trolled trials that directly compareddrugs from 2 or 3 major antianginaldrug classes, including long-acting ni-trates, b-blockers, and calcium antago-nists. Trials were included if the en-rolled patients had a history of stableangina. Studies were included if theywere either randomized parallel de-sign or crossover studies. Studies of thefollowing design were excluded: 1 drugvs placebo, comparison of different dos-age of the same drug, and 1 drug vs a2-drug combination. Studies with a du-ration of less than 1 week were ex-cluded. Trials that used a study medi-cation during a run-in period prior torandomization were also excluded.

For studies that compared more than1 drug from a given class, we limitedour analysis to the drug most com-monly used for stable angina. To de-termine the most commonly usedagents, we obtained pharmaceuticaldata from IMS Health, Plymouth Meet-ing, Pa, that described the frequency ofmedications prescribed for stable an-gina (in the absence of hypertension)in 1998. For studies comparing morethan 1 dosage, we chose the dosage clos-est to the midpoint of the recom-mended treatment dosage range fromthe Physicians’ Desk Reference.

Outcome MeasuresWe examined measures of antianginal ef-ficacy and tolerability, conducting sepa-rate meta-analyses for each outcome.Measures of antianginal efficacy in-cluded number of angina episodes perweek (patient recorded), nitroglycerinuse per week (patient recorded), total ex-ercise time, and time to 1-mm ST de-pression on a treadmill or upright bi-cycle. For crossover studies, meanbetween-person values were used to al-low comparison with parallel studies.The tolerability measure was the rate ofsubject withdrawal due to adverse events,defined as death or cardiac or noncar-diac symptoms. Withdrawal due to pro-tocol violation or loss to follow-up werenot counted as adverse events. We alsoexamined the combined end point of car-diac death and nonfatal myocardial in-farction for studies in which either wasreported.

Data ExtractionStudy selection was performed ini-tially by title review (P.A.H. andM.A.H.). Candidate abstracts were thenreviewed and appropriate studies wereselected for data retrieval. Two inde-pendent reviewers extracted data fromeach article, compared their results, andsettled any differences by consensus.One of the 2 reviewers had training incardiology and the other had trainingin epidemiology or health services re-search. All outcome data were ab-stracted a third time by 1 of the inves-tigators (P.A.H., B.F., or B.K.L.).

Subgroup ComparisonsWe examined several subgroups of tri-als to determine their contribution to thesummary differences between b-block-ers and calcium antagonists. The 2 pre-specified comparisons of interest werenifedipine vs nonnifedipine calcium an-tagonists and short- vs long-acting cal-cium antagonists. Short-acting prepa-rations were defined as those with usualdosing of 3 or more times per day ac-cording to the Physicians’ Desk Refer-ence. Additional comparisons were madebased on the funding source (industryvs other) and the location of the trial(Europe vs United States). Because sev-eral trials examined drugs that are notin common use for treatment of stableangina, we repeated our analysis afterlimiting the trials to those agents that hadat least 2% market share in the UnitedStates during the first quarter of 1998(data from IMS Health). Based on thesedata, common therapies were limited to4 calcium antagonists (amlodipine, dil-tiazem, nifedipine, and verapamil) and5 b-blockers (atenolol, carvedilol, pro-pranolol, metoprolol, and nadolol). Wecompared trials that were double-blindwith those that were not to determinethe effect of this quality measure. We didnot evaluate subgroups of long-acting ni-trates because the number of trials of thisclass of agents was small.

Statistical AnalysisWe combined estimates of the mean dif-ference for number of angina episodesand number of nitroglycerin tabletsused per week, the standardized meandifference for exercise time, and theodds ratio (OR) for adverse events, car-diac death, and myocardial infarc-tion.15 The mean differencei between thedrug treatment arms is equal to themeanai− meanbi, where a and b are the2 arms of the ith study. The estimatedvariance is vi= s2

i (1/nai+ 1/nbi), wheren is the within-study sample size for the2 study arms and s2 is estimated as thepooled within-group variance.

We used the standardized mean dif-ference to compare exercise times be-cause exercise protocols varied widelyacross studies. This measure ex-

B-BLOCKERS, CALCIUM ANTAGONISTS, AND NITRATES FOR STABLE ANGINA

1928 JAMA, May 26, 1999—Vol 281, No. 20 ©1999 American Medical Association. All rights reserved.


presses the difference in mean exer-cise time as a fraction of the SD. Themeasure is calculated as di= (meanai –meanbi)/pooled SD. The variance for thisvalue is estimated as vi= [(nai+ nbi)/ nai

nbi] + [di2/2(nai + nbi)]. For this com-

parison, a positive value indicates in-creased exercise time in the treatmentgroup. We pooled both mean differ-ences and standardized mean differ-ences by weighting the individual dif-ferences by the inverse of the variance.Random effects were assumed.

WeusedthePeto(fixed-effects)methodto estimate summary ORs for the out-comes of death or myocardial infarctionand withdrawal due to adverse events.16

Althoughwefoundnostatisticalevidenceof heterogeneity (P..20 for all) amongstudies using the Q statistic,16 we chosealso todisplayrandom-effects resultsus-ing the DerSimonian-Laird method17

where stated for comparison. For stud-iesthatreportednoevents,wesubstituted0.1inplaceof0fortherandom-effectscal-culation.Asummary ratedifferencewascalculatedfortrialswith1ormoreadverseevents.16,17ThismeasurecomplementstheOR by providing an absolute differencein the adverse event rate. We examineddifferences between study subgroups oftrials using analysis of variance.18

For the outcomes of cardiac death,myocardial infarction, and adverseevents, the study sample size was de-fined as the number of patients ran-domized. For the outcomes of anginaepisodes, nitroglycerin use, and exer-cise time, the sample size was definedas the number of patients who com-pleted the study. P values are 2-tailed.

RESULTSExcluded Studies

A total of 143 articles were identified bythe MEDLINE and EMBASE searchesand citation review. We excluded 25studies that may have fulfilled the in-clusion criteria but were not written inEnglish; 17 that were duplicates or sub-studies of an included study; 6 that useda study drug during a run-in period priorto randomization; and 5 that did not re-port any of the primary outcomes. Theremaining 90 articles (63%) (TABLE 1)

were abstracted and included in theanalysis.19-108

b-Blockers vs Calcium AntagonistsThe majority of studies (n = 72) com-pared b-blockers with calcium antago-nists (TABLES 1, 2, and 3). The includedstudieshadamean lengthof8weeksandonly 2 trials67,71 were longer than 6months. Most studies (n = 64) that com-pared b-blockers with calcium antago-nists requiredevidenceofcoronaryarterydisease or ischemia, in addition to a his-tory of stable angina. A positive tread-mill test result was required in 57 trials.Exclusion criteria were mentioned in 56

of the reports and included congestiveheart failure (n = 46), recent myocar-dial infarction (n = 45), bradyarrhyth-mia or heart block (n = 31), significantlungdisease (n = 26), anddiabetesmelli-tus (n = 13). The trials were predomi-nately crossover in design (n = 49), andwere most often conducted in Europe(n = 50) or North America (n = 16).Source of study funding was stated in 31studies; of those, 14 received supportfrom the pharmaceutical industry. Sig-nificantdifferences in theabstractedout-come measures between b-blockers andcalcium antagonists were reported inonly 17 of 72 trials.

Table 1. Study Characteristics of the Included Trials*

Characteristics

b-Blockers vsCalcium Antagonists

(n = 72)

Nitrates vsCalcium Antagonists

(n = 12)

b-Blockers vsNitrates(n = 6)

Age, y 57 (3) [70] 62 (6) [12] 57 (2) [5]

Sex, male, % 84 (16) [63] 77 (12) [12] 80 (13) [5]

History of myocardial infarction, % 35 (3) [42] 46 (14) [9] 39 (12) [4]

Diabetes mellitus, % 11 (19) [18] 2 (4) [4] 24 [1]

Study duration, wk 9 (24) [72] 3 (2) [12] 5 (2) [6]

Exercise-induced ischemiarequired for study entry, %

79 [72] 75 [12] 67 [6]

*Data are presented as mean (SD) [number of trials reporting data] or percentage (SD) [number of trials reporting data].

Table 2. Calcium Antagonists and b-Blockers Evaluated in Direct Comparisons

Medications No. of Trials

Formulation,Short-Acting, No./Long-Acting, No.*

Initial Dosage,Mean, mg/d

Calcium antagonistsNifedipine† 26 19/7 41

Verapamil† 17 15/2 313

Diltiazem† 17 15/2 222

Bepridil 5 0/5 200

Nicardipine 5 5/0 78

Amlodipine† 1 0/1 3

Felodipine 1 0/1 10

b-BlockersPropranolol† 27 26/1 183

Atenolol† 19 0/19 95

Metoprolol† 13 0/13 177

Nadolol† 3 0/3 107

Bisoprolol 2 0/2 10

Carvedilol† 2 0/2 50

Epanolol 2 0/2 200

Bopindolol 1 0/1 1

Labetolol 1 0/1 400

Penbutolol 1 0/1 40

Pindolol 1 1/0 60

*Short-acting is defined as the usual dosage of 3 or more times per day according to the Physicians’ Desk Reference.†These medications had greater than 2% market share in the first quarter of 1998 for treatment of patients with stable

angina but without hypertension (IMS Health, Plymouth Meeting, Pa).




Cardiac Death or Nonfatal Myocar-dial Infarction. Only the TIBET71 andAPSIS67 trials were long-term (.6months) comparisons of b-blockers andcalcium antagonists; these 2 studies ac-counted for 103 of the 116 cardiac eventsrecorded in all trials (FIGURE 1). Thepooled OR for these 2 trials for risk withb-blockers was 0.98 (95% confidence in-terval [CI], 0.66-1.47). For the 59 short-term trials, there was no obvious differ-

ence in cardiac death or myocardialinfarction (OR, 0.90; 95% CI, 0.40-2.00). When both long- and short-term trials were combined (Table 3),there were 57 events in the b-blockerand 59 in the calcium antagonist groups.The OR for risk with b-blockers was 0.97(95% CI, 0.67-1.38). A random-effectsanalysis (DerSimonian-Laird method)produced similar results (OR, 0.98; 95%CI, 0.67-1.43). No significant differ-

ences were found when the trials weregrouped by type of calcium antagonist(nifedipine vs nonnifedipine) or dura-tion of action (FIGURE 2, top).

Angina Episodes. The patients en-rolled in the trials that comparedb-blockers with calcium antagonists hadmoderately frequent angina (mean [SD],4.0 [5.9] episodes per week during treat-ment). Compared with calcium antago-nists, b-blockers were associated with0.31 (95% CI, 0.00-0.62) fewer epi-sodes of angina per week (P = .05) (Table3). When the comparison was re-stricted to trials comparing b-blockerswith nifedipine, there were 0.63 (95% CI,0.23-1.00) fewer angina events per weekwith b-blockers (FIGURE 3, top). We didnot observe a significant effect of the du-ration of action of calcium antagonistswhen short- and long-acting calcium an-tagonists were compared separately withb-blockers (Figure 3, top). Short-acting calcium antagonists were associ-ated with an increase of 0.44 angina epi-sodes per week (95% CI, −0.87 to −0.02),while long-actingcalciumantagonistsde-creased angina frequency by 0.08 epi-sodes per week (95% CI, −0.75 to 0.91).

Nitroglycerin Use. Despite the dif-ferences in the frequency of angina, ni-

Figure 1. Odds Ratios for Cardiac Death or Myocardial Infarction With b-Blockers vs CalciumAntagonists

TIBET71

APSIS67

59 Short-Term Studies

All Studies

0 0.5 1 1.5 2

Favors β-Blockers Favors Calcium Antagonists

Individual odds ratios are displayed for 2 long-term trials along with the combined odds ratio for 60 short-termstudies. TIBET indicates Total Ischaemic Burden European Trial; APSIS, Angina Prognosis Study in Stockholm;and error bars, 95% confidence intervals.

Table 3. Outcomes in Stable Angina for b-Blockers vs Calcium Antagonists*

OutcomesNo. ofTrials

b-Blockers,No.

CalciumAntagonists, No.

MeasuresEffectSize 95% CI

PValue ReferencesPatients Events Patients Events

Cardiac deathor MI

61 3090 57 3054 59 Odds ratio(,1 favorsb-blockers)

0.97 0.67 to 1.38 .85 19-26, 28-41, 48-56,58-64, 66-78, 80-84,86-90

Angina episodesper week

32 1127 NA 1107 NA Mean difference(,0 favorsb-blockers)

−0.31 −0.62 to 0.00 .05 19-50

Nitroglycerin useper week

25 736 NA 726 NA Mean difference(,0 favorsb-blockers)

−0.14 −0.41 to 0.32 .32 19, 22-24, 26, 27, 29-35,37-41, 43-47, 49, 50

Time to 1-mmST depression

20 567 NA 557 NA Standardized meandifference(.0 favorsb-blockers)†

0.06 −0.06 to 0.18 .33 23, 26, 30-32, 34, 36,37, 40-42, 49, 51-58

Total exercisetime

32 840 NA 831 NA Standardized meandifference(.0 favors

b-blockers)†

−0.10 −0.20 to 0.00 .05 19, 23, 24, 27-33, 35,36, 40-42, 47-49,51-54, 56, 57, 59-66

Withdrawal foradverseevents

51 2811 239 2778 317 Odds ratio(,1 favors

b-blockers)

0.72 0.60 to 0.86 ,.001 19, 20, 22-26, 28, 30,32, 33, 35, 37-41,49-51, 53-56, 58, 59,61, 63, 64 66-87

*CI indicates confidence interval; MI, myocardial infarction; and NA, not applicable. No statistical evidence of trial heterogeneity was observed for any of the outcomes listed(Q statistic, P..20).

†Standardized mean differences were calculated as mean exercise time (b-blockers) − mean exercise time (calcium antagonists)/pooled SD.




troglycerin tablet use per week was notsignificantly different between pa-tients treated with b-blockers and withcalcium antagonists (Table 3). Therewas a nonsignificant reduction of 0.14(95% CI, −0.19 to 0.46) fewer nitro-glycerin tablets per week with b-block-ers in studies that compared b-block-ers with nifedipine. We found nodifferences when short- and long-acting calcium antagonist prepara-tions were examined separately.

Exercise Time. There were no sig-nificant differences in time to ische-mia (1-mm ST depression) between cal-cium antagonists and b-blockers (Table3). Similarly, no difference in exercisetime to ischemia was observed whenonly trials comparing b-blockers withnifedipine were evaluated (Figure 3,bottom). No differences were notedwhen short- and long-acting prepara-tions of calcium antagonists were evalu-ated separately.

Withdrawal Due to Adverse Events.Adverse events that led to study with-drawal occurred in 8% of patients. Pa-tients were less likely to discontinueb-blockers than calcium antagonists inthe 51 studies that compared theseagents (OR, 0.72; 95% CI, 0.60-0.86)(FIGURE 4 and Table 3). The absolutedifference in the adverse event ratewas 2.0 (95% CI, 0.5-3.4) fewer eventswith b-blockers compared with cal-cium antagonists for every 100 pa-tients treated.

Trials comparing nifedipine withb-blockers had significantly fewer ad-verse events with b-blockers (OR, 0.60;95% CI, 0.47-0.77) (Figure 2, bot-tom). In contrast, there was no signifi-cant difference in the rate of adverseevents between nonnifedipine cal-cium antagonists and b-blockers. Ad-verse events were not significantly dif-ferent between long- and short-actingcalcium antagonists when these agentswere compared separately withb-blockers (Figure 2, bottom).

Secondary Analyses. When we lim-ited the trials to those that studied cal-cium antagonists and b-blockers thathad at least 2% market share in theUnited States in 1998, we noted sig-

nificantly fewer adverse events (OR,0.73; 95% CI, 0.59-0.92), and anginaepisodes per week (absolute differ-ence, 0.40; 95% CI, 0.05-0.75) forb-blockers compared with calcium an-tagonists. No significant differences inany of the outcome measures werefound when the trials were grouped byfunding source or study location.

We compared b-blockers with dihy-dropyridine calcium antagonists sepa-rately (nifedipine, n = 26; nicardipine,n = 5; amlodipine, n = 1; felodipine,n = 1) and found fewer adverse events(OR, 0.63; 95% CI, 0.50-0.80), and an-gina episodes per week (OR, 0.61; 95%CI, 0.23-0.99) with b-blocker therapy.However, nifedipine accounted for 79%of all dihydropyridines, and an effectof dihydropyridine therapy indepen-

dent of nifedipine could not be dem-onstrated. Random- and fixed-effectsmethods of pooling gave similar esti-mates for all comparisons.

Long-Acting Nitrates vsCalcium AntagonistsThere were 12 studies that comparedcalcium antagonists with long-acting ni-trates (Table 1). Patient characteris-tics were similar to those in the trialspreviously described that comparedb-blockers with calcium antagonists.There were no significant differences inoutcome between these classes of medi-cations (TABLE 4); however, a trend(P = .10) was noted for greater num-ber of angina episodes per week in pa-tients who were taking long-actingnitrates.

Figure 2. Summary Odds Ratios for Benefit With b-Blockers vs Calcium Antagonists forCardiac Death or Myocardial Infarction and Adverse Events

β-Blockers vs Nifedipine

β-Blockers vs Other

β-Blockers vs Short-ActingCalcium Antagonists

β-Blockers vs Long-ActingCalcium Antagonists

All Studies

0 0.5 1

Cardiac Death or Myocardial Infarction

Adverse Events Leading to Study Withdrawal

1.5 2





All Studies

0 0.5 1 1.5 2


A greater rate of adverse events leading to withdrawal was observed with calcium antagonists compared withb-blockers for the nifedipine, long-acting, and short-acting calcium antagonist subgroups. Error bars indicate95% confidence intervals.




Long-Acting Nitrates vs b-BlockersOnly 6 studies compared b-blockerswith long-acting nitrates (Table 1). Pa-tient characteristics were similar tothose in the trials that comparedb-blockers with calcium antagonists.There were no significant differencesbetween b-blockers and long-acting ni-trates in any of the outcomes mea-sured (TABLE 5). A trend (P = .08) to-ward increased nitroglycerin use perweek was noted for patients who weretaking long-acting nitrates.

Effect of ExcludingNon-English ArticlesTo determine the effect of excluding ar-ticles written in languages other thanEnglish, we reviewed the abstracts (in

English) of 12 (48%) of 25 studieswhose full text was not written in En-glish. None of the studies reported a sig-nificant difference in death or myocar-dial infarction rates, exercise time,angina episodes, or nitroglycerin use forcomparisons between b-blockers andcalcium antagonists (n = 6), b-block-ers and nitrates (n = 2), or calcium an-tagonists and nitrates (n = 4). Two stud-ies that compared calcium antagonistswith nitrates noted fewer adverse ef-fects with calcium antagonists.

COMMENTThis quantitative overview shows thatcalcium antagonists were associatedwith a greater number of adverse eventscompared with b-blockers in trials of

patients who have stable angina. An-gina relief, as measured by number ofangina episodes, nitroglycerin use, andexercise time, was not significantly dif-ferent between b-blockers and cal-cium antagonists. Trial duration was tooshort to determine differences in long-term rates of survival or myocardial in-farction between calcium antagonistsand b-blockers. Similarly, too few stud-ies compared long-acting nitrates withcalcium antagonists or b-blockers to de-termine differences in survival, symp-toms, or adverse events.

The safety of calcium antagonists forpatients who have coronary artery dis-ease has been questioned. Prior meta-analyses and case-control studies havedemonstrated an increased risk of myo-cardial infarction in hypertensive pa-tients who take short-acting calcium an-tagonists.11 In patients who have acutecoronary syndromes, mortality in-creased with increasingly large dos-ages of short-acting nifedipine.12,13 Ina recent case-control study, short-acting calcium antagonists were asso-ciated with a 4-fold increase in the riskof cardiovascular deaths and hospitaladmission compared with b-block-ers.109 We were unable to determinewhether there were important differ-ences in mortality or myocardial in-farction rates between antianginals be-cause follow-up was less than 6 monthsin all but 2 studies. This importantquestion could be addressed by largerlong-term comparisons of these agents.

Our finding that b-blockers were aswell tolerated as calcium antagonistswas not expected. Past reviews havenoted frequent adverse effects withb-blockers,8 whereas calcium antago-nists have been recommended and usedwidely because of their low adverse-effect profile.6,7 Our findings must betempered by noting that patients whowere thought unlikely to tolerateb-blockers (such as those with conges-tive heart failure, heart block, or sig-nificant pulmonary disease) were gen-erally excluded from the randomizedstudies. Nonetheless, our findings sug-gest that patients without these con-traindications should have success

Figure 3. Summary Mean Difference Between b-Blockers and Calcium Antagonistsfor Angina Episodes per Week and Exercise Time to 1-mm ST Depression





All Studies

–2 –1 0

Angina Episodes per Week

Exercise Time to Ischemia

1 2





All Studies

–0.5 –0.25 0 0.25 0.5

Favors Calcium Antagonists Favors β-Blockers

P =.008}

Values less than 0 indicate fewer angina episodes and shorter exercise time with b-blockers. Because exerciseprotocols varied, a standardized mean difference in exercise time is displayed. Both nifedipine and short-acting calcium antagonists were associated with a greater frequency of angina compared with b-blockers. Er-ror bars indicate 95% confidence intervals.




in finding angina relief and freedomfrom adverse events when they usea b-blocker instead of a calcium an-tagonist.

Our study suggests that short- andlong-acting nifedipine may not be aswell tolerated as other calcium antago-nists, consistent with past investiga-tions of long-acting nifedipine. In 6small randomized studies of at least 1week in duration that compared long-acting nifedipine with other calcium an-tagonists, nifedipine was associated withmore symptoms and adverse effects in2110,111 and was equivalent to other cal-cium antagonists in 4.112-115

Our findings have several clinical im-plications. They suggest that b-block-ers should be considered first-lineagents because they are as effective asand better tolerated than calcium an-tagonists and have been shown to im-prove prognosis in other populationswith coronary disease. For patients whohave a history of myocardial infarc-tion, b-blockers are already recom-mended as first-line agents because theyare associated with decreased rates ofcardiac death and myocardial infarc-tion.3 These recommendations do notapply to patients with contraindica-tions to b-blockers (eg, severe reac-tive airway disease).

Current treatment of angina in theUnited States frequently does not in-clude b-blockers. A study using the Na-tional Ambulatory Medical Survey foundthat treatment with b-blockers was re-ported in only 21% of office visits by pa-tients with coronary artery disease andno strong contraindication to b-block-ade.116 Pharmaceutical data from the firstquarter of 1998 (IMS Health) suggestthat physicians prefer long-acting ni-trates to calcium antagonists or b-block-ers. European data also suggest that cal-cium antagonists are more often usedthan b-blockers for first-line therapy forpatients with stable angina.7

The choice of a first-line agent for usein patients who have stable angina hasbeen addressed by recent clinical guide-lines. The European Society of Cardi-ology recommends b-blockers forpatients who have clear-cut effort-

related angina or a prior myocardial in-farction.5 The North of England StableAngina Guideline Development Grouprecommends b-blockers for all pa-tients who have no contraindication,4

citing evidence that b-blockers lowermortality after myocardial infarction, re-duce mortality for patients who have asubsequent myocardial infarction whiletaking medication, and reduce ad-verse vascular events in patients whohave hypertension. Our study data sup-port these recommendations and addevidence that b-blockers are equallywell or better tolerated than and pro-vide angina relief equivalent to that of

calcium antagonists and long-actingnitrates.

Like those of any meta-analysis, ourfindings may have been affected by pub-lication bias.117 It is possible that stud-ies that failed to demonstrate signifi-cant differences were not submitted oraccepted for publication. However, few(25%) of the studies included demon-strated significant differences be-tween drugs, suggesting that any suchbias may be small. Patients who havecongestive heart failure, chronic ob-structive lung disease, and nonexer-tional chest pain were rarely includedin the studies; thus, our findings are not

Figure 4. Individual and Summary Odds Ratios for Adverse Events With b-BlockersCompared With Calcium Antagonists

Bepridil (Long-Acting)78

Bepridil (Long-Acting)28

Diltiazem (Long-Acting)71

Diltiazem (Short-Acting)79

Verapamil (Long-Acting)66

Verapamil (Short-Acting)24



Amlodipine (Long-Acting)81

Nicardipine (Short-Acting)65

Nicardipine (Short-Acting)63

Nifedipine (Long-Acting)73





Nifedipine (Short-Acting)25







Summary

0.01 0.1 1 10 100


The summary estimate is significantly less than 1.0, indicating that there were fewer adverse events with b-blockertherapy. Only trials that reported adverse events for both calcium antagonists and b-blockers are displayed.The summary estimate is based on all trials reporting adverse events. Error bars indicate 95% confidence intervals.




applicable to those types of patients.Only a few small studies comparedlong-acting nitrates with calcium an-tagonists or b-blockers; thus, our analy-sis was unlikely to detect any clini-cally important differences betweenthese agents. We did not include stud-ies reported in foreign-language pub-lications in our meta-analysis. A re-cent study has found that studiespublished in English were more likelyto report P ,.05.118 However, review ofthe English abstracts that were avail-able (50% of foreign-language stud-

ies) did not demonstrate a difference insignificant findings. Our study did notexamine measures of quality of life. Al-though adverse events severe enoughto lead to withdrawal from the study oc-curred less frequently in patients treatedwith b-blockers than in those treatedwith calcium antagonists, less severe ad-verse effects were not consistently re-ported, so we could not measure dif-ferences in their rates.

In summary, our quantitative reviewsuggests that b-blockers provide anequivalent reduction in angina and lead

to similar or reduced rates of adverseevents compared with either calcium an-tagonists or long-acting nitrates. The dif-ferences in adverse event rates and fre-quency of angina between b-blockersand calcium antagonists are accountedfor in large part by nifedipine, which wasassociated with a higher rate of adverseevents and angina symptoms. More long-term comparative trials are requiredto determine whether the different thera-pies confer a significant mortalitydifference in patients who have stableangina.

Table 4. Outcomes in Stable Angina for Nitrates vs Calcium Antagonists*


Nitrates, No.Calcium

Antagonists, No.



Cardiac deathor MI

10 377 0 376 0 Odds ratio (,1favors nitrates)

NA NA NA 92-101


5 143 NA 143 NA Mean difference(,0 favorsnitrates)

0.52 −0.12 to 1.2 .10 93, 95, 97,98, 100


5 143 NA 143 NA Mean difference(,0 favorsnitrates)

0.19 −0.23 to 0.60 .38 93, 95, 97,98, 100

Time to 1-mmST depression

3 81 NA 81 NA Standardized meandifference (.0favors nitrates)†

−0.19 −0.50 to 0.11 .22 93, 97, 100

Total exercisetime

5 126 NA 126 NA Standardized meandifference (.0favors nitrates)†

−0.11 −0.36 to 1.40 .39 93, 97, 100,102, 103

Withdrawal foradverse events

9 340 12 339 9 Odds ratio (,1favors nitrates)

1.34 0.57 to 3.10 .50 92-97, 100,101, 103

*CI indicates confidence interval; MI, myocardial infarction; and NA, not applicable. No statistical evidence of trial heterogeneity was observed for any of the outcomes listed (Qstatistic, P..20).

†Standardized mean differences were calculated as [mean exercise time (nitrates) − mean exercise time (calcium antagonists)]/pooled SD.

Table 5. Outcomes in Stable Angina for b-Blockers vs Nitrates*


b-Blockers, No.Calcium

Antagonists, No.



Cardiac death or MI 6 129 1 129 1 Odds ratio (,1 favorsb-Blockers)

1.0 0.21 to 4.70 ..99 104-109


5 86 NA 84 NA Mean difference (,0favors b-blockers)

−0.83 −4.70 to 3.10 .68 104, 106-109


3 53 NA 53 NA Mean difference (,0favors b-blockers)

−1.90 −0.40 to 0.20 .08 104, 108, 109

Time to 1-mm STdepression

1 27 NA 27 NA Standardized meandifference (.0favors b-blockers)†

0.12 −0.42 to 0.65 .66 104

Total exercise time 1 21 NA 21 NA Standardized meandifference (.0favors b-blockers)†

0.29 −0.90 to 0.32 .35 109

Withdrawal foradverse events

5 124 6 124 13 Odds ratio (,1 favorsb-blockers)

0.47 0.18 to 1.18 .11 104-107, 109

*CI indicates confidence interval; MI, myocardial infarction; and NA, not applicable. Statistical evidence of trial heterogeneity (Q statistic) was observed for the outcomes of anginaepisodes (P= .003) and nitroglycerin use (P = .04).

†Standardized mean differences were calculated as [mean exercise time (b-blockers) − mean exercise time (nitrates)]/pooled SD.




Funding/Support: This study was funded by contract290-97-0013 to the UCSF-Stanford Evidence-basedPractice Center from the Agency for Health Care Policyand Research. Dr Heidenreich is supported by a careerdevelopment award from the Veterans Affairs HealthServices Research and Development Service.

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Meta-analysis of Trials Comparing beta-Blockers, Calcium Antagonists, and Nitrates for Stable Angina

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Transcript of Meta-analysis of Trials Comparing beta-Blockers, Calcium Antagonists, and Nitrates for Stable Angina