ORIGINAL CONTRIBUTION

-Blocker Use and Clinical Outcomes

in Stable Outpatients With and Without
Coronary Artery Disease
Sripal Bangalore, MD, MHA
Ph. Gabriel Steg, MD
Prakash Deedwania, MD
Kevin Crowley, MS
Kim A. Eagle, MD
Shinya Goto, MD, PhD
E. Magnus Ohman, MD
Christopher P. Cannon, MD
Sidney C. Smith Jr, MD
Uwe Zeymer, MD
Elaine B. Hoffman, PhD
Franz H. Messerli, MD
Deepak L. Bhatt, MD, MPH
for the REACH Registry Investigators

REATMENT WITH -BLOCKERS

remains the standard of care for
patients with coronary artery
disease (CAD), especially when
they have had a myocardial infarction
(MI).1,2 The evidence is derived from
relatively old post-MI studies, most of
which antedate modern reperfusion or
medical therapy, and from heart failure trials, but has been widely extrapolated to patients with CAD and even to
patients at high risk for but without established CAD. It is not known if these
extrapolations are justified. Moreover, the long-term efficacy of these
agents in patients treated with contemporary medical therapies is not known,
even in patients with prior MI.
-Blockers are not without adverse
effects and their tolerability is not ideal.
Among 17 035 patients with MI, only
45% of patients were adherent to
-blocker use 1-year after an MI.3 The
objective of the present longitudinal,
1340

JAMA, October 3, 2012Vol 308, No. 13

Context -Blockers remain the standard of care after a myocardial infarction (MI).
However, the benefit of -blocker use in patients with coronary artery disease (CAD)
but no history of MI, those with a remote history of MI, and those with only risk factors for CAD is unclear.
Objective To assess the association of -blocker use with cardiovascular events in
stable patients with a prior history of MI, in those with CAD but no history of MI, and
in those with only risk factors for CAD.
Design, Setting, and Patients Longitudinal, observational study of patients in the
Reduction of Atherothrombosis for Continued Health (REACH) registry who were divided into 3 cohorts: known prior MI (n=14 043), known CAD without MI (n=12 012),
or those with CAD risk factors only (n=18 653). Propensity score matching was used
for the primary analyses. The last follow-up data collection was April 2009.
Main Outcome Measures The primary outcome was a composite of cardiovascular death, nonfatal MI, or nonfatal stroke. The secondary outcome was the primary
outcome plus hospitalization for atherothrombotic events or a revascularization procedure.
Results Among the 44 708 patients, 21 860 were included in the propensity score
matched analysis. With a median follow-up of 44 months (interquartile range, 35-45
months), event rates were not significantly different in patients with -blocker use compared with those without -blocker use for any of the outcomes tested, even in the prior
MI cohort (489 [16.93%] vs 532 [18.60%], respectively; hazard ratio [HR], 0.90 [95%
CI, 0.79-1.03]; P=.14). In the CAD without MI cohort, the associated event rates were
not significantly different in those with -blocker use for the primary outcome (391
[12.94%]) vs without -blocker use (405 [13.55%]) (HR, 0.92 [95% CI, 0.79-1.08]; P=.31),
with higher rates for the secondary outcome (1101 [30.59%] vs 1002 [27.84%]; odds
ratio [OR], 1.14 [95% CI, 1.03-1.27]; P=.01) and for the tertiary outcome of hospitalization (870 [24.17%] vs 773 [21.48%]; OR, 1.17 [95% CI, 1.04-1.30]; P=.01). In the
cohort with CAD risk factors only, the event rates were higher for the primary outcome
with -blocker use (467 [14.22%]) vs without -blocker use (403 [12.11%]) (HR, 1.18
[95% CI, 1.02-1.36]; P=.02), for the secondary outcome (870 [22.01%] vs 797 [20.17%];
OR, 1.12 [95% CI, 1.00-1.24]; P=.04) but not for the tertiary outcomes of MI (89 [2.82%]
vs 68 [2.00%]; HR, 1.36 [95% CI, 0.97-1.90]; P=.08) and stroke (210 [6.55%] vs 168
[5.12%]; HR, 1.22 [95% CI, 0.99-1.52]; P=.06). However, in those with recent MI (1
year), -blocker use was associated with a lower incidence of the secondary outcome
(OR, 0.77 [95% CI, 0.64-0.92]).
Conclusion In this observational study of patients with either CAD risk factors only,
known prior MI, or known CAD without MI, the use of -blockers was not associated
with a lower risk of composite cardiovascular events.
www.jama.com

JAMA. 2012;308(13):1340-1349

observational study was to evaluate the

differential association of -blocker use
on long-term cardiovascular outcomes in patients with known prior MI,

Author Affiliations appear at the end of this article.

A complete list of the REACH Registry Investigators
appears in JAMA. 2006;295(2):180-189, E1-E8.
Corresponding Author: Sripal Bangalore, MD, MHA,
New York University School of Medicine, 550 First Ave,
New York, NY 10016 (sripalbangalore@gmail.com).

2012 American Medical Association. All rights reserved.

-BLOCKERS AND CLINICAL OUTCOMES IN CORONARY ARTERY DISEASE

in patients with known CAD without

MI, and in patients with only risk factors for CAD.
METHODS
The design, methods, and results of the
Reduction of Atherothrombosis for
Continued Health (REACH) registry, an
international, prospective, observational registry, have been published
elsewhere.4-7 Briefly, REACH enrolled
consecutive eligible patients aged 45
years or older with established CAD,
cerebrovascular disease, or peripheral
arterial disease, or with at least 3 atherothrombotic risk factors during a
7-month recruitment period between
December 2003 and June 2004; because of regulatory requirements in Japan, the enrollment in that country was
delayed and occurred between August
2004 and December 2004. The last patient was enrolled in December 2004
and the date of final data collection was
April 2009. Signed informed consent
was obtained from all patients and the
institutional review board in each country approved the protocol. The study
participants were from 7 geographical
regions.
Patients with data on -blocker use
were divided into 3 groups: known
prior MI, CAD without known MI, and
CAD risk factors only. Each of these
groups was divided into 2 subgroups
based on -blocker use at the time of
enrollment. The CAD cohort was identified by documented history of percutaneous coronary intervention, coronary artery bypass graft surgery, or
ischemia but without a known history
of MI. Data were collected centrally
using standardized case report forms.
Patients were followed-up prospectively for up to 4 years for the occurrence of cardiovascular outcomes, hospitalization, or vascular interventions.
The primary outcome was a composite of cardiovascular death, nonfatal MI,
or nonfatal stroke. The secondary outcome was the primary outcome plus
hospitalization for atherothrombotic
events or a revascularization procedure (coronary, cerebral, or peripheral). Tertiary outcomes were all-

cause mortality, cardiovascular

mortality, nonfatal MI, nonfatal stroke,
and hospitalization, which were considered as separate outcomes.
Statistical Analysis

All analyses were performed using SAS

software version 9.2 (SAS Institute
Inc). Power calculations were performed using accrual over 7 months
and a median follow-up of 44 months.
For the known prior MI cohort, which
had 14 000 patients and 30% without
-blocker use, there was 80% power
to detect a hazard ratio (HR) of 0.87.
Similarly, for the known CAD without
MI cohort, which had 12 000 patients
and 40% without -blocker use, there
was 80% power to detect an HR of
0.87 to show benefit and 1.14 to show
harm. For the cohort with only risk
factors for CAD, which had 19 000
patients and 75% without -blocker
use, there was 80% power to detect an
HR of 0.89 to show benefit and 1.13 to
show harm.
Propensity Score Matching

The analysis was based on the intentionto-treat principle regardless of subsequent -blocker use. Because of differences in key baseline characteristics
(TABLE 1, TABLE 2, and TABLE 3), we
used propensity score matching for the
3 cohorts to assemble a cohort for each
comparison, in which all the measured covariates would be well balanced across comparator groups. The
propensity score is the conditional
probability of having a particular exposure (-blocker use) given a set of
measured baseline covariates.8,9 Propensity scores were estimated using a
nonparsimonious multivariable logistic regression model,10 with the dependent variable of -blocker use, and the
27 baseline characteristics entered as covariates. Matching was performed using
a SAS macro with a greedy matching
protocol (matching ratio of 1 to 1 without replacement) and a caliper width
of 0.6 of the standard deviation. We estimated standardized differences for all
covariates before and after matching to
assess prematch imbalance and post-

2012 American Medical Association. All rights reserved.

match balance.11 Standardized differences of less than 10% for a given covariate indicate a relatively small
imbalance.11
Paired comparisons were performed using conditional logistic regression analysis for categorical variables and paired t test for continuous
variables. The risk of outcomes in the
group with -blocker use vs without
-blocker use was estimated using a
Cox proportional hazard regression
model stratified on the matched pairs.
The analyses were exploratory in nature so no P value adjustment for multiple testing was applied.
In the propensity scorematched
analysis, many patients remained unmatched and were thus excluded from
the analysis (which may lead to slightly
reduced efficiency). Therefore, a regression adjustment with the propensity score (as a continuous variable) was
also performed,12 in which all the patients in the cohort were analyzed.
For both the propensity score
matched and propensity score
adjusted analyses, the proportional hazards assumptions were violated for
hospitalization-related outcomes because the exact dates of hospitalization were not available. For these outcomes, odds ratios (ORs) are reported
rather than HRs. The proportional hazards assumption was tested using
Schoenfeld residuals, which help determine nonproportionality over time
either graphically or by testing for a
nonzero slope in a regression model of
residuals on time.
The differential association of
-blocker use across the 3 cohorts was
tested using a test for interaction with
a P value of less than .10 considered statistically significant. All tests were
2-tailed and (aside from the test for interaction) a P value of less than .05 was
considered statistically significant.
Sensitivity Analysis

Given the well-known, beneficial association of -blocker use with reduction in morbidity and mortality among
patients with heart failure, a sensitivity analysis was conducted after exJAMA, October 3, 2012Vol 308, No. 13 1341

-BLOCKERS AND CLINICAL OUTCOMES IN CORONARY ARTERY DISEASE

cluding patients with known heart

failure. In addition, analyses were performed using -blocker use as a timedependent covariate that incorporates
changes in -blocker use over time. In
addition, analyses based on inverse
probability weighting were performed.13 For this purpose, a propensity score weight, also referred to as the

inverse probability of treatment weight,

was calculated as the inverse of the propensity score. Analyses were conducted to test for internal validity of the
data set using one cohort with recent
MI (1 year) and another with known
heart failure, both of which have
shown utility of -blocker use in prior
studies.

RESULTS
FromtheREACHregistry,44 708patients
satisfied the inclusion criteria of whom
14 043 patients (31%) had prior MI,
12 012 patients (27%) had documented
CAD but without MI, and 18 653 patients
(42%) had CAD risk factors only. In the
included cohort, 96% of patients had
2-year follow-up and 74% of the cohort

Table 1. Baseline Characteristics of Cohort With Known Prior Myocardial Infarction

-Blocker Use After
Propensity Score Matching a

-Blocker Use a,b

Age, mean (SD), y

Body mass index, mean (SD) c
Male sex
United States
Region
North America
Latin America
Western Europe
Eastern Europe
Middle East
Asia
Japan
Medical history
Current smoker
Hypertension
Hypercholesterolemia
Transient ischemic attack
Stroke
Carotid angioplasty or stenting
Carotid surgery
Congestive heart failure
Aortic valve stenosis
Diabetes
Stable angina
Baseline medications
Acetylsalicylic acid
Other antiplatelet agents
Oral anticoagulant
NSAIDs
Statins
Other lipid-lowering agent
Calcium channel blocker
Nitrates or other antiangina agents
Diuretics
ACE inhibitors
Angiotensin II receptor antagonists
Other antihypertensive drug
Peripheral arterial claudication drug

Yes
(n = 9451)
66.42 (10.13)
28.25 (5.08)
7142 (75.62)
2746 (29.06)

No
(n = 4592)
69.07 (9.96)
27.20 (5.15)
3449 (75.13)
1339 (29.16)

P
Value
.001
.001
.52
.001

Yes
(n = 3379)
68.67 (9.99)
27.59 (5.06)
2541 (75.20)
1111 (32.88)

No
(n = 3379)
68.5 (10.04)
27.52 (5.11)
2531 (74.90)
1090 (32.26)

P
Value
.48
.58
.78
.99

3318 (35.11)
269 (2.85)
3382 (35.78)
1449 (15.33)
143 (1.51)
508 (5.38)
382 (4.04)

1585 (34.52)
205 (4.46)
1348 (29.36)
322 (7.01)
53 (1.15)
325 (7.08)
754 (16.42)

.001

1325 (39.21)
125 (3.70)
1026 (30.36)
266 (7.87)
47 (1.39)
236 (6.98)
354 (10.48)

1290 (38.18)
114 (3.37)
1008 (29.83)
279 (8.26)
44 (1.30)
256 (7.58)
388 (11.48)

.69

933 (9.87)
7578 (80.19)
7634 (80.85)
802 (8.62)
881 (9.40)
255 (2.74)
350 (3.72)
2268 (24.34)
293 (3.21)
3410 (36.08)

478 (10.41)
3298 (71.84)
3180 (69.31)
492 (10.90)
673 (14.77)
138 (3.07)
206 (4.52)
995 (22.06)
153 (3.48)
1743 (37.96)

.32
.001
.001
.001
.001
.28
.02
.003
.41
.03

324 (9.59)
2487 (73.60)
2505 (74.13)
330 (9.77)
423 (12.52)
98 (2.90)
165 (4.88)
760 (22.49)
119 (3.52)
1268 (37.53)

332 (9.83)
2488 (73.63)
2514 (74.40)
333 (9.85)
421 (12.46)
96 (2.84)
155 (4.59)
744 (22.02)
115 (3.40)
1255 (37.14)

.74
.98
.80
.90
.94
.88
.56
.64
.79
.74

4181 (44.63)

1808 (39.87)

.001

1389 (41.40)

1350 (40.30)

.35

7649 (81.02)
2528 (26.93)
1301 (14.21)
748 (8.14)
7788 (82.47)
1012 (10.72)
2280 (24.20)
3793 (40.55)
4044 (42.92)
5391 (57.22)
1634 (17.38)
672 (7.15)
418 (4.49)

3355 (73.21)
1146 (25.09)
667 (14.97)
395 (8.81)
3183 (69.39)
479 (10.45)
1898 (41.33)
1802 (39.75)
1777 (38.72)
2094 (45.67)
973 (21.22)
377 (8.24)
304 (6.72)

.001
.02
.24
.18
.001
.62
.001
.37
.001
.001
.001
.02
.001

2558 (75.70)
776 (22.97)
505 (14.95)
309 (9.14)
2507 (74.19)
376 (11.13)
1246 (36.87)
1300 (38.47)
1387 (41.05)
1661 (49.16)
702 (20.78)
284 (8.40)
213 (6.30)

2564 (75.88)
794 (23.50)
497 (14.71)
292 (8.64)
2527 (74.79)
359 (10.62)
1252 (37.05)
1322 (39.12)
1350 (39.95)
1634 (48.36)
691 (20.45)
275 (8.14)
195 (5.77)

.86
.61
.78
.47
.56
.51
.87
.58
.36
.50
.74
.69
.35

Abbreviations: ACE, angiotensin-converting enzyme; NSAIDs, nonsteroidal anti-inflammatory drugs.

a Values expressed as number (percentage) unless otherwise indicated.
b The percentages are slightly off because of denominator changes due to missing observations in some of the variables.
c Calculated as weight in kilograms divided by height in meters squared.

1342

JAMA, October 3, 2012Vol 308, No. 13

2012 American Medical Association. All rights reserved.

-BLOCKERS AND CLINICAL OUTCOMES IN CORONARY ARTERY DISEASE

had 4-year follow-up. The overall median

follow-up was 44 months (interquartile
range [IQR], 35-45 months). Among the
44 708 patients, 21 860 were included in
the propensity scorematched analysis.
Prior MI Cohort

In the prior MI cohort, there were 9451

patients (67%) with -blocker use. There

were significant differences between patients with -blocker use and those without -blocker use in the baseline characteristics prior to matching (Table 1).
Propensity score matching matched
3379 patients with -blocker use (36%
of the cohort) with 3379 patients without -blocker use (74% of the cohort)
with similar propensity scores. After pro-

pensity score matching, there were no

significant differences in baseline variables (Table 1), with absolute standardized differences of less than 10% for all
variables, indicating an adequate match
(eFigure 1 at http://www.jama.com).
The median follow-up was 43 months
(IQR, 30-45 months) in the group with
-blocker use vs 43 months (IQR, 29-45

Table 2. Baseline Characteristics of the Cohort With Known Coronary Artery Disease Without Myocardial Infarction
-Blocker Use After
Propensity Score Matching a

-Blocker Use a,b

Age, mean (SD), y

Body mass index, mean (SD) c
Male sex
United States
Region
North America
Latin America
Western Europe
Eastern Europe
Middle East
Asia
Japan
Medical history
Current smoker
Hypertension
Hypercholesterolemia
Transient ischemic attack
Stroke
Carotid angioplasty or stenting
Carotid surgery
Congestive heart failure
Aortic valve stenosis
Diabetes
Stable angina
Baseline medications
Acetylsalicylic acid
Other antiplatelet agents
Oral anticoagulant
NSAIDs
Statins
Other lipid-lowering agent
Calcium channel blocker
Nitrates or other antiangina agents
Diuretics
ACE inhibitors
Angiotensin II receptor antagonists
Other antihypertensive drug
Peripheral arterial claudication drug

Yes
(n = 6864)
68.10 (9.79)
28.40 (5.24)
4474 (65.21)
2231 (32.50)

No
(n = 5148)
69.86 (9.73)
27.39 (5.46)
3392 (65.89)
1593 (30.94)

P
Value
.001
.001
.44
.001

Yes
(n = 3599)
69.39 (9.60)
27.96 (5.14)
2382 (66.19)
1259 (34.98)

No
(n = 3599)
69.27 (9.75)
27.92 (5.51)
2380 (66.13)
1219 (33.87)

P
Value
.58
.72
.96
.99

2537 (36.96)
143 (2.08)
2294 (33.42)
945 (13.77)
91 (1.33)
542 (7.90)
312 (4.55)

1817 (35.30)
150 (2.91)
1400 (27.20)
455 (8.84)
40 (0.78)
472 (9.17)
814 (15.81)

.001

1431 (39.76)
95 (2.64)
1080 (30.00)
345 (9.59)
30 (0.83)
313 (8.70)
305 (8.47)

1394 (38.73)
92 (2.56)
1051 (29.20)
376 (10.45)
32 (0.89)
329 (9.14)
325 (9.03)

.76

512 (7.46)
5920 (86.26)
5381 (78.42)
634 (9.35)
617 (9.05)
192 (2.83)
326 (4.77)
1056 (15.53)
312 (4.70)
2588 (37.70)

491 (9.54)
3954 (76.82)
3467 (67.39)
550 (10.84)
748 (14.65)
165 (3.25)
239 (4.68)
672 (13.23)
234 (4.75)
2039 (39.61)

.001
.001
.001
.01
.001
.19
.82
.001
.89
.03

300 (8.34)
2911 (80.88)
2645 (73.49)
379 (10.53)
424 (11.78)
100 (2.78)
179 (4.97)
525 (14.59)
179 (4.97)
1397 (38.82)

314 (8.72)
2905 (80.72)
2596 (72.13)
372 (10.34)
434 (12.06)
105 (2.92)
173 (4.81)
501 (13.92)
175 (4.86)
1413 (39.26)

.56
.85
.18
.79
.71
.72
.74
.42
.83
.70

4207 (61.57)

3229 (63.05)

.10

2194 (61.22)

2223 (62.06)

.51

5433 (79.21)
1704 (24.92)
718 (10.77)
669 (9.98)
5359 (78.10)
833 (12.15)
2264 (33.13)
2523 (37.22)
2974 (43.43)
3154 (46.12)
1398 (20.47)
620 (9.08)
379 (5.60)

3577 (69.55)
1303 (25.40)
612 (12.16)
544 (10.77)
3359 (65.26)
605 (11.77)
2387 (46.39)
1984 (38.95)
1811 (35.19)
2033 (39.57)
1187 (23.12)
483 (9.41)
371 (7.30)

.001
.54
.02
.17
.001
.52
.001
.05
.001
.001
.001
.54
.001

2644 (73.46)
854 (23.73)
423 (11.75)
390 (10.84)
2571 (71.44)
466 (12.95)
1507 (41.87)
1355 (37.65)
1426 (39.62)
1599 (44.43)
819 (22.76)
360 (10.00)
247 (6.86)

2660 (73.91)
873 (24.26)
419 (11.64)
383 (10.64)
2531 (70.33)
453 (12.59)
1506 (41.84)
1366 (37.95)
1387 (38.54)
1549 (43.04)
805 (22.37)
350 (9.72)
244 (6.78)

.67
.60
.88
.79
.27
.64
.98
.79
.33
.23
.69
.69
.89

Abbreviations: ACE, angiotensin-converting enzyme; NSAIDs, nonsteroidal anti-inflammatory drugs.

a Values expressed as number (percentage) unless otherwise indicated.
b The percentages are slightly off because of denominator changes due to missing observations in some of the variables.
c Calculated as weight in kilograms divided by height in meters squared.

2012 American Medical Association. All rights reserved.

JAMA, October 3, 2012Vol 308, No. 13 1343

-BLOCKERS AND CLINICAL OUTCOMES IN CORONARY ARTERY DISEASE

months) in the group without -blocker

use.
The event rates were not significantly different in those with -blocker
use (489 [16.93%]) vs those without
-blocker use (532 [18.60%]) for the
primary outcome (HR, 0.90 [95% CI,
0.79-1.03]; P=.14; FIGURE 1), the secondary outcome (30.96% vs 33.12%, re-

spectively; OR, 0.91 [95% CI, 0.821.00]; FIGURE 2), or any of the tertiary
outcomes (Figure 2; eFigures 2-4) of
cardiovascular death (9.68% vs 10.27%;
P= .31), MI (5.50% vs 5.51%; P=.42),
and stroke (4.44% vs 5.21%; P=.28) in
the matched cohort. The results were
similar in the propensity score
adjusted model (eFigure 5).

CAD Without MI Cohort

In the CAD without MI cohort, there

were 6864 patients (57%) with
-blocker use. There were significant
differences between patients with
-blocker use vs those without
-blocker use in the baseline characteristics prior to matching (Table 2).
Propensity score matching matched

Table 3. Baseline Characteristics of the Cohort With Risk Factors Only But No Known Coronary Artery Disease
-Blocker Use After
Propensity Score Matching a

-Blocker Use a,b

Age, mean (SD), y

Body mass index, mean (SD) c
Male sex
United States
Region
North America
Latin America
Western Europe
Eastern Europe
Middle East
Asia
Japan
Medical history
Current smoker
Hypertension
Hypercholesterolemia
Transient ischemic attack
Stroke
Carotid angioplasty or stenting
Carotid surgery
Congestive heart failure
Aortic valve stenosis
Diabetes
Stable angina
Baseline medication
Acetylsalicylic acid
Other antiplatelet agents
Oral anticoagulant
NSAIDs
Statins
Other lipid-lowering agent
Calcium channel blocker
Nitrates or other antiangina agents
Diuretics
ACE inhibitors
Angiotensin II receptor antagonists
Other antihypertensive drug
Peripheral arterial claudication drug

Yes
(n = 4854)
69.01 (9.77)
28.78 (5.75)
2412 (49.69)
1743 (35.91)

No
(n = 13 799)
68.89 (9.92)
27.39 (5.71)
8065 (58.48)
3794 (27.49)

P
Value
.46
.001
.001
.001

Yes
(n = 3952)
68.86 (9.72)
28.72 (5.71)
1986 (50.25)
1441 (36.46)

No
(n = 3952)
68.83 (9.96)
28.76 (6.23)
1997 (50.53)
1463 (37.02)

P
Value
.89
.81
.80
.99

1869 (38.50)
110 (2.27)
1711 (35.25)
468 (9.64)
44 (0.91)
407 (8.38)
245 (5.05)

4278 (31.00)
489 (3.54)
4302 (31.18)
861 (6.24)
86 (0.62)
1238 (8.97)
2545 (18.44)

.001

1548 (39.17)
92 (2.33)
1335 (33.78)
367 (9.29)
35 (0.89)
347 (8.78)
228 (5.77)

1572 (39.78)
87 (2.20)
1321 (33.43)
381 (9.64)
35 (0.89)
328 (8.30)
228 (5.77)

.98

522 (10.76)
4665 (96.11)
3376 (69.65)
908 (19.09)
1496 (31.00)
70 (1.46)
243 (5.04)
444 (9.26)
126 (2.73)
2537 (52.27)
0

2145 (15.55)
10 869 (78.77)
8382 (60.80)
2216 (16.35)
4868 (35.44)
132 (0.97)
505 (3.68)
562 (4.12)
211 (1.62)
7114 (51.56)
0

.001
.001
.001
.001
.001
.005
.001
.001
.001
.40

436 (11.03)
3803 (96.23)
2760 (69.84)
724 (18.32)
1202 (30.41)
53 (1.34)
192 (4.86)
297 (7.52)
91 (2.30)
2070 (52.38)
0

436 (11.03)
3799 (96.13)
2755 (69.71)
735 (18.60)
1189 (30.09)
49 (1.24)
187 (4.73)
309 (7.82)
97 (2.45)
2094 (52.99)
0

.99
.74
.90
.75
.75
.68
.79
.59
.65
.59

2821 (58.20)
948 (19.66)
619 (13.15)
560 (11.88)

7187 (52.15)
3303 (24.02)
1267 (9.40)
1424 (10.51)

.001
.001
.001
.01

2291 (57.97)
747 (18.90)
476 (12.04)
437 (11.06)

2262 (57.24)
738 (18.67)
488 (12.35)
442 (11.18)

.51
.79
.67
.86

3076 (63.42)
646 (13.34)
1847 (38.38)
327 (6.90)
2601 (53.88)
2093 (43.47)
1298 (27.00)
609 (12.71)
329 (6.96)

7685 (55.71)
1468 (10.66)
4915 (35.64)
450 (3.30)
4597 (33.36)
5408 (39.30)
3515 (25.53)
1219 (8.86)
1242 (9.14)

.001
.001
.001
.001
.001
.001
.04
.001
.001

2521 (63.79)
526 (13.31)
1529 (38.69)
224 (5.67)
2071 (52.40)
1740 (44.03)
1064 (26.92)
485 (12.27)
257 (6.50)

2553 (64.60)
502 (12.70)
1566 (39.63)
235 (5.95)
2132 (53.95)
1748 (44.23)
1118 (28.29)
511 (12.93)
257 (6.50)

.45
.42
.40
.58
.14
.85
.17
.37
.99

Abbreviations: ACE, angiotensin-converting enzyme; NSAIDs, nonsteroidal anti-inflammatory drugs.

a Values expressed as number (percentage) unless otherwise indicated.
b The percentages are slightly off because of denominator changes due to missing observations in some of the variables.
c Calculated as weight in kilograms divided by height in meters squared.

1344

JAMA, October 3, 2012Vol 308, No. 13

2012 American Medical Association. All rights reserved.

-BLOCKERS AND CLINICAL OUTCOMES IN CORONARY ARTERY DISEASE

-blocker use vs 43 months (IQR, 31-45

months) in the group without -blocker
use.
The event rates were higher in those
with -blocker use (467 [14.22%]) vs

Known prior MI matched cohort

Event Rate for Primary Outcome, %

20
HR, 0.90 (95% CI, 0.79-1.03); P = .14

18
16
14
12

No -blocker

10

-Blocker

8
6
4
2
0
0

10

15

20

25

30

35

40

Follow-up, mo
No. at risk
No -blocker
-Blocker

3379
3379

3165
3178

2850
2899

2357
2424

2029
2061

Known CAD without MI matched cohort

14
HR, 0.92 (95% CI, 0.79-1.08); P = .31
12
10
8
6

No -blocker

-Blocker

4
2
0
0

10

15

20

25

30

35

40

Follow-up, mo
No. at risk
No -blocker
-Blocker

Risk Factors Alone Cohort

3599
3599

3420
3447

3105
3148

2615
2634

2270
2251

CAD risk factor only matched cohort

16

Event Rate for Primary Outcome, %

In the risk factors alone cohort, there

were 4854 patients (26%) with
-blocker use. Prior to propensity score
matching, there were significant differences between patients with -blocker
use vs those without -blocker use in the
baseline characteristics (Table 3). Propensity score matching matched 3952
patients with -blocker use (81% of the
cohort) with 3952 patients without
-blocker use (29% of the cohort) with
similar propensity scores. After propensity score matching (Table 3), the absolute standardized differences were less
than 10% for all matched variables, indicating an adequate match (eFigure 10).
The median follow-up was 43 months
(IQR, 32-45 months) in the group with

those without -blocker use (403

[12.11%]) for the primary outcome
(HR, 1.18 [95% CI, 1.02-1.36]; P=.02;
Figure 1), for the secondary outcome
(870 [22.01%] vs 797 [20.17%], re-

Figure 1. Cumulative Incidence Curve for the Risk of Primary Outcome by -Blocker Use

Event Rate for Primary Outcome, %

3599 patients with -blocker use (52%

of the cohort) with 3599 patients without -blocker use (70% of the cohort)
with similar propensity scores. After
propensity score matching (Table 2),
the absolute standardized differences
were less than 10% for all matched variables, indicating an adequate match
(eFigure 6). The median follow-up was
43 months (IQR, 31-45 months) in the
group with -blocker use vs 43 months
(IQR, 31-45 months) in the group without -blocker use.
The event rates were not different in
those with -blocker use (391
[12.94%]) vs those without -blocker
use (405 [13.55%]) for the primary outcome (HR, 0.92 [95% CI, 0.79-1.08];
P = .31; Figure 1), for cardiovascular
death (5.90% vs 6.97%, respectively;
P=.32; eFigure 7), for stroke (4.84% vs
4.79%; P=.39; eFigure 8), and for MI
(3.79% vs 2.98%; OR, 1.24 [95% CI,
0.91-1.69]; P = .16; eFigure 9). The
event rates were higher in those with
-blocker use (1101 [30.59%]) vs those
without -blocker use (1002 [27.84%])
for the secondary outcome (OR, 1.14
[95% CI, 1.03-1.27]; P = .01) and for
hospitalization (870 [24.17%] vs 773
[21.48%], respectively; OR, 1.17 [95%
CI, 1.04-1.30]; P= .01) in the propensity scorematched model (Figure 2).
The results were similar in the propensity scoreadjusted model (eFigure 5).

HR, 1.18 (95% CI, 1.02-1.36); P = .02

14
12
10
8

-Blocker

No -blocker

4
2
0
0

10

15

20

25

30

35

40

Follow-up, mo
No. at risk
No -blocker
-Blocker

3952
3952

3779
3761

3441
3402

2864
2864

2487
2428

Y-axis range shown in blue indicates event rate from 0% to 14%. The primary outcome was a composite of
cardiovascular death, nonfatal MI, or nonfatal stroke. CAD indicates coronary artery disease; HR, hazard ratio;
and MI, myocardial infarction.

2012 American Medical Association. All rights reserved.

JAMA, October 3, 2012Vol 308, No. 13 1345

-BLOCKERS AND CLINICAL OUTCOMES IN CORONARY ARTERY DISEASE

spectively; OR, 1.12 [95% CI, 1.001.24]; P = .04) but not for MI (89
[2.82%] vs 68 [2.00%]; HR, 1.36 [95%
CI, 0.97-1.90]; P=.08; eFigure 11), and
for stroke (210 [6.55%] vs 168 [5.12%];
HR, 1.22 [95% CI, 0.99-1.52]; P = .06;
eFigure 12). In the propensity score
matched model, there were similar
event rates for cardiovascular death
(6.41% in patients with -blocker use
vs 6.40% in those without -blocker
use; P=.66; eFigure 13) and for hospitalization (14.62% vs 13.74%, respectively; P = .26; Figure 2). The results
were similar in a propensity score
adjusted model (eFigure 5).
-Blocker Use Cohort Interaction

A significant interaction was found for

secondary outcome risk both in the propensity scorematched (P=.003 for in-

teraction; Figure 2) and the propensity scoreadjusted models (P=.006 for

interaction; eFigure 5), such that the effect of -blocker use was not uniform
across the cohorts. The secondary outcome risk was not different in the prior
MI cohort, whereas in the CAD cohort and the risk factors alone cohort,
patients with -blocker use had a 12%
to 14% higher secondary outcome risk
compared with the group without
-blocker use. A similar interaction was
noted for the outcomes of MI (P =.08
for interaction) and hospitalization
(P=.03 for interaction; Figure 2), such
that the effect of -blocker use was not
uniform across the cohorts.
Sensitivity Analysis

A sensitivity analysis that was performed in the cohort of patients with-

out known heart failure yielded largely

similar results (eFigures 14-15). Similar results were seen for the primary
outcome across various statistical models including models using -blocker
as a time-dependent covariate for both
propensity-adjusted and inverse probability weighting (eTable). The analysis performed in the cohort with recent MI (1 year) showed an
association of -blocker use with a
lower incidence of the secondary outcome (OR, 0.77 [95% CI, 0.64-0.92])
and hospitalization (OR, 0.77 [95% CI,
0.62-0.95]), but not with the primary
outcome (HR, 0.79 [95% CI, 0.601.04]). Propensity scoreadjusted
analysis restricted to the cohort with
heart failure (n=6056) showed no benefit for the primary outcome (HR, 0.89
[95% CI, 0.79-1.01]; P =.08).

Figure 2. Risk of Event Outcomes in the Matched Cohort

-Blocker, No.

No -Blocker, No.

Events

Total
Sample

Primary outcome
Prior MI
Known CAD without MI
Risk factor without MI

Events

Total
Sample

HR
(95% CI)

P Value

489
391
467

3379
3599
3952

532
405
403

3379
3599
3952

0.90 (0.79-1.03)
0.92 (0.79-1.08)
1.18 (1.02-1.36)

.14
.31
.02

.14

Secondary outcome a
Prior MI
Known CAD without MI
Risk factor without MI

1046
1101
870

3379
3599
3952

1119
1002
797

3379
3599
3952

0.91 (0.82-1.00)
1.14 (1.03-1.27)
1.12 (1.00-1.24)

.06
.01
.04

.003

Death
Prior MI
Known CAD without MI
Risk factor without MI

406
312
348

3379
3599
3952

430
353
365

3379
3599
3952

0.93 (0.80-1.08)
0.91 (0.77-1.07)
0.97 (0.82-1.14)

.34
.25
.71

.53

Cardiovascular death
Prior MI
Known CAD without MI
Risk factor without MI

273
178
207

3379
3599
3952

291
207
203

3379
3599
3952

0.91 (0.76-1.09)
0.90 (0.72-1.11)
1.05 (0.85-1.30)

.31
.32
.66

.51

Nonfatal MI
Prior MI
Known CAD without MI
Risk factor without MI

157
110
89

3379
3599
3952

150
84
68

3379
3599
3952

1.10 (0.87-1.41)
1.24 (0.91-1.69)
1.36 (0.97-1.90)

.42
.16
.08

.29

Nonfatal stroke
Prior MI
Known CAD without MI
Risk factor without MI

123
141
210

3379
3599
3952

142
140
168

3379
3599
3952

0.87 (0.66-1.13)
0.89 (0.69-1.16)
1.22 (0.99-1.52)

.28
.39
.06

.08

Hospitalizationa
Prior MI
Known CAD without MI
Risk factor without MI

780
870
578

3379
3599
3952

816
773
543

3379
3599
3952

0.94 (0.84-1.05)
1.17 (1.04-1.30)
1.07 (0.95-1.22)

.30
.01
.26

.03

Favors
-Blocker

0.10

Favors No
-Blocker

1.00

P Value for
Interaction

10.00

HR (95% CI)

The primary outcome was a composite of cardiovascular death, nonfatal MI, or nonfatal stroke. The secondary outcome was the primary outcome plus hospitalization
for atherothombotic events or a revascularization procedure. CAD indicates coronary artery disease; HR, hazard ratio; and MI, myocardial infarction.
a Outcomes analyzed using a logistic regression analysis.
1346

JAMA, October 3, 2012Vol 308, No. 13

2012 American Medical Association. All rights reserved.

-BLOCKERS AND CLINICAL OUTCOMES IN CORONARY ARTERY DISEASE

COMMENT
In this analysis of 44 708 patients from
the REACH registry, -blocker use was
not associated with a lower incidence of
cardiovascular events among individuals with a prior history of MI, among individuals with CAD but no MI history,
or among individuals with risk factors
only for atherosclerotic disease.
-Blocker Use After MI

In patients after MI, there is evidence

that -blocker use reduces mortality.14-16 In a meta-analysis published
in 1999,17 a 23% reduction in death in
trials of -blocker use was observed.
However, in this meta-analysis,17 the
mean follow-up was only 1.4 years,
the median publication date of the 82
randomized trials included was 1982,
and most of the trials were performed
in the era before modern reperfusion
or medical therapy was routine for MI.
A reperfused, viable myocardium has
little in common with a necrotic or
scarred myocardium, which generates
arrhythmias because of reentry mechanisms, enhancing the capability of
-blockers to prevent sudden death.
In the present study, more than 80%
of patients with prior MI and with
-blocker use also used aspirin or
lipid-lowering agents and more than
50% used an angiotensin-converting
enzyme inhibitor. In a subgroup
analysis from a cohort with prior MI
from the International VerapamilTrandolapril Study (INVEST), a non
-blockerbased strategy (verapamiltrandolapril) did not significantly
differ from a -blockerbased strategy
for the prevention of cardiovascular
events, and was also associated with a
greater subjective feeling of well-being
and a trend toward lower incidence of
angina pectoris and stroke.18
Our observation that -blocker use
was not associated with a lower rate of
cardiovascular events among patients
with MI and among those with CAD but
no history of MI are consistent with the
recently updated American Heart Association secondary prevention guidelines in which -blocker therapy is a
class I recommendation for heart fail-

ure, MI, or acute coronary syndrome for

up to 3 years after MI, but it is a class
IIa recommendation for longer-term
therapy.19 Moreover, -blocker therapy
for all other patients with coronary or
other vascular disease was downgraded to a class IIb recommendation.19 Similarly, the updated 2011 European Society of Cardiology secondary
prevention guidelines recommend longterm -blocker therapy only in patients with reduced left ventricular systolic function (class I).20
In our analyses, we did not have data
on the type of -blocker used. However, our results are important for several reasons. First, although guidelines recommend -blocker therapy,
there are no clear recommendations as
to the -blocker type (except for heart
failure). Second, in the only randomized trial (Carvedilol Acute Myocardial Infarction Study; CAMIS)21 comparing carvedilol with atenolol in
patients with acute coronary syndrome (left ventricular ejection fraction of 53.9%), there was no superiority of the newer -blocker compared
with the older one for composite cardiovascular events (P=.99). Third, atenolol is still the second most commonly prescribed -blocker in the
United States with more than 33.8 million prescriptions,22 and a total retail
cost of more than $260 million in
201023; even if atenolol was the most
commonly prescribed -blocker in the
study, the results would be widely applicable.
-Blocker Use in Patients
Without MI

Ever since the landmark studies of

-blocker use in patients after MI or
heart failure, -blockers have been considered to be a cardioprotective therapy.
Their benefits have been extrapolated
to patients with CAD without MI or
heart failure and also to patients at high
risk for CAD.
In the CAD and risk factors only cohorts in the present analysis, we observed higher event rates for certain outcomes with -blocker therapy. The
paucity of evidence for -blocker

2012 American Medical Association. All rights reserved.

therapy is described in the European Society of Cardiology guidelines on stable

angina. As noted in these guidelines,24
a cardioprotective benefit of -blockers has not been demonstrated in randomized controlled trials of patients
with stable coronary disease.
Prior studies in patients with hypertension25-34 have shown that when compared with placebo, -blocker use is not
associated with reduction in all-cause
mortality or MI.35,36 -Blocker use is associated with a 19% to 20% reduction in
stroke,35,36 but this reduction is less than
that observed with other antihypertensive agents.37 Based on this evidence,
-blocker therapy has been downgraded by the European Society on Hypertension, the American Heart Association, and others38-41 to a fourth-line
agent for the treatment of hypertension.
Some of the purported mechanism for
lack of efficacy of -blockers include reduced efficacy at reducing central aortic pressure42,43 and metabolic adverse effects, including the risk of new diabetes
and dyslipidemia. 30,44 In addition,
-blockers are often not well tolerated
and adherence may be suboptimal.45-47
Available evidence suggests that
-blocker use is associated with benefit in patients with acute MI (without
impending shock or heart block),48 and
may be efficacious in the short-tointermediate term duration for patients after MI and in those with chronic
heart failure.
Limitations

We did not have data on the type of

-blocker, the medication dosage, or the
reason patients were without -blocker
use. In addition, we did not have data
on type of MI or prior -blocker use.
Anginal status and history of heart failure were controlled for, although ejection fraction was not recorded. However, the results were largely similar in
a sensitivity analysis excluding patients with known heart failure. Although propensity score matching adjusts for known confounders, other
unmeasured confounders cannot be accounted for and the possibility of residual confounding by indication canJAMA, October 3, 2012Vol 308, No. 13 1347

-BLOCKERS AND CLINICAL OUTCOMES IN CORONARY ARTERY DISEASE

not be completely ruled out. Although

our data are from a registry and are limited by the lack of nonrandomized design, contemporary data from a welldesigned large registry such as the
CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early
Implementation of the ACC/AHA
guidelines) registry,49 have been used
to modify guideline recommendations (morphine use in nonSTsegment elevation acute coronary syndrome downgraded from a class I to
class IIb). In addition, in an analysis
from the REACH registry,7 statin use
was associated with a significant reduction in the risk of events (HR, 0.73 [95%
CI, 0.69-0.77]; P.001), providing another internal validation of the data set.
CONCLUSIONS
Among patients enrolled in the international REACH registry, -blocker use
was not associated with a lower event
rate of cardiovascular events at 44month follow-up, even among patients with prior history of MI. Further research is warranted to identify
subgroups that benefit from -blocker
therapy and the optimal duration of
-blocker therapy.
Author Affiliations: Cardiovascular Clinical Research
Center, New York University School of Medicine, New
York, New York (Dr Bangalore); INSERM U-698, University Paris Diderot, Hospital Bichat, AP-HP, Paris,
France (Dr Steg); Department of Internal Medicine/
Cardiology, University of California San Francisco
School of Medicine, Fresno (Dr Deedwania); TIMI
Study Group, Boston, Massachusetts (Drs Cannon,
Hoffman, and Bhatt and Mr Crowley); Cardiovascular Center, University of Michigan Health System, Ann
Arbor (Dr Eagle); Tokai University School of Medicine, Isehara, Japan (Dr Goto); Duke University Medical Center, Durham, North Carolina (Dr Ohman); Cardiovascular Division, Department of Medicine,
Brigham and Womens Hospital and Harvard Medical School, Boston, Massachusetts (Drs Cannon and
Bhatt); Center for Cardiovascular Science and Medicine, University of North Carolina, Chapel Hill (Dr
Smith); Herzzentrum Ludwigshafen and Institut fur
Herzinfarktforschung Ludwigshafen, Ludwigshafen,
Germany (Dr Zeymer); St Lukes Roosevelt Hospital,
New York, New York (Dr Messerli); and VA Boston
Healthcare System, Boston, Massachusetts (Dr Bhatt).
Author Contributions: Dr Bangalore had full access
to all of the data in the study and takes responsibility
for the integrity of the data and the accuracy of the
data analysis.
Study concept and design: Bangalore, Steg, Deedwania,
Eagle, Ohman, Cannon, Bhatt.
Acquisition of data: Steg, Crowley, Goto, Zeymer,
Bhatt.
Analysis and interpretation of data: Bangalore, Steg,
1348

JAMA, October 3, 2012Vol 308, No. 13

Deedwania, Crowley, Eagle, Cannon, Smith, Zeymer,

Hoffman, Messerli, Bhatt.
Drafting of the manuscript: Bangalore, Crowley,
Messerli.
Critical revision of the manuscript for important intellectual content: Bangalore, Steg, Deedwania,
Crowley, Eagle, Goto, Ohman, Cannon, Smith, Zeymer,
Hoffman, Messerli, Bhatt.
Statistical analysis: Crowley, Hoffman.
Obtained funding: Steg, Goto, Cannon.
Administrative, technical, or material support: Steg,
Eagle, Ohman, Cannon.
Study supervision: Bangalore, Steg, Deedwania, Goto,
Messerli, Bhatt.
Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure
of Potential Conflicts of Interest. Dr Steg reported
receiving a research grant from sanofi-aventis and
Servier awarded to INSERM U-698 and the New York
University School of Medicine; serving as a consultant or receiving speakers fees from Ablynx, Amarin,
Amgen, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Meyers Squibb, Daiichi Sankyo, Eisai,
GlaxoSmithKline, Lilly, Medtronic, Merck Sharp &
Dohme, Novartis, Otsuka, Pfizer, Roche, sanofiaventis, Servier, the Medicines Company; and holding stock in Aterovax. Dr Deedwania reported serving as a consultant or receiving speakers fees from Forest
Pharmaceuticals, Novartis, Daichii Sankyo, Servier, and
Pfizer. Dr Goto reported receiving consulting fees and
honoraria from Eisai, sanofi-aventis, Otsuka, Bayer,
Novartis, AstraZeneca, Asteras, Pfizer, Medtronics
Japan, Mitsubishi Tanabe, Takeda, Daiichi Sankyo,
Mochida, Merck Sharp & Dohme; and receiving
research grants from sanofi-aventis, Eisai, Boehringer
Ingelheim, Otsuka, and Daiichi Sankyo. Dr Ohman
reported receiving research grants from Daiichi Sankyo, Eli Lilly & Company, Maquet; serving as a consultant to AstraZeneca, Boehringer Ingelheim, BristolMyers Squibb, Gilead Sciences, LipoScience, Merck,
Pozen, Roche, sanofi-aventis, the Medicines Company, and WebMD; and serving on the speakers
bureau for Boehringer Ingelheim, Gilead Sciences, and
the Medicines Company. Dr Cannon reported receiving research grants or support from Accumetrics,
AstraZeneca, Essentials, GlaxoSmithKline, Merck,
Regeneron, sanofi-aventis, and Takeda; serving on advisory boards (but funds donated to charity) for BristolMyers Squibb, Alnylam, Pfizer, and CSL; receiving
honoraria for the development of independent educational symposia for Pfizer and AstraZeneca; and serving as a clinical advisor for and owning equity in Automedics Medical Systems. Dr Bhatt reported serving on
an advisory board for Medscape Cardiology; serving
on the boards of directors for Boston VA Research Institute and the Society of Chest Pain Centers; serving as
chair for the American Heart Association Get With The
Guidelines Science Subcommittee; receiving honoraria from the American College of Cardiology for serving as editor of Clinical Trials, Cardiosource, Duke Clinical Research Institute for serving on clinical trial steering
committees, Slack Publications for serving as chief medical editor of Cardiology Today Intervention, and
WebMD for serving on continuing medical education
steering committees; serving as senior associate editor for the Journal of Invasive Cardiology; receiving
research grants from Amarin, AstraZeneca, BristolMyers Squibb, Eisai, Ethicon, Medtronic, sanofiaventis, and the Medicines Company; and unfunded
research from FlowCo, PLx Pharma, and Takeda. Drs
Bangalore, Eagle, Smith Jr, Zeymer, Hoffman, and Messerli and Mr Crowley did not report any disclosures.
Funding Source: The REACH Registry is sponsored by
sanofi-aventis, Bristol-Myers Squibb, and the Waksman Foundation (Tokyo, Japan) and is endorsed by
the World Heart Federation. Statistical analyses of the
REACH database by TIMI Study Group statisticians
were funded by sanofi-aventis.

Role of the Sponsor: The sponsors had no role in the

design and conduct of the study; in the collection,
analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.
Online-Only Material: eFigures 1-15 and the eTable
are available at http://www.jama.com.
Additional Contributions: We thank Sabina Murphy, MPH, of the TIMI study group for statistical support and supervision.

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