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HEALTH CARE REFORM

ORIGINAL INVESTIGATION
Comparative Effectiveness of 2 -Blockers
in Hypertensive Patients
Emily D. Parker, MPH, PhD; Karen L. Margolis, MD, MPH; Nicole K. Trower, BS;
David. J. Magid, MD, MPH; Heather M. Tavel, BS; Susan M. Shetterly, MS;
P. Michael Ho, MD, PhD; Bix E. Swain, MS; Patrick J. OConnor, MD, MPH
Background: Randomized controlled trials have dem-
onstrated the efficacy of selected -blockers for prevent-
ing cardiovascular (CV) events inpatients following myo-
cardial infarction (MI) or with heart failure (HF).
However, the effectiveness of -blockers for preventing
CV events in patients with hypertension has been ques-
tioned recently, but it is unclear whether this is a class
effect.
Methods: Using electronic medical record and health
plan data fromthe Cardiovascular Research Network Hy-
pertension Registry, we compared incident MI, HF, and
stroke in patients who were new -blocker users be-
tween 2000 and 2009. Patients had no history of CVdis-
ease and had not previously filled a prescription for a
-blocker. Cox proportional hazards regression was used
to examine the associations of atenolol and metoprolol
tartrate with incident CVevents using both standard co-
variate adjustment (n=120 978) and propensity score
matching methods (n=22 352).
Results: Duringfollow-up(median, 5.2years), therewere
3517incidentMI, 3272incidentHF, and3664incidentstroke
events. Hazardratios for MI, HF, andstroke inmetoprolol
tartrateusers were0.99(95%CI, 0.97-1.02), 0.99(95%CI,
0.96-1.01), and0.99(95%CI, 0.97-1.02), respectively. An
alternativeapproachusingpropensityscorematchingyielded
similar results in11176newmetoprolol tartrateusers, who
were similar to 11 176 new atenolol users with regard to
demographic and clinical characteristics.
Conclusions: There were no statistically significant dif-
ferences inincident CVevents betweenatenolol andmeto-
prolol tartrate users with hypertension. Large registries
similar to the one used in this analysis may be useful for
addressing comparative effectiveness questions that are
unlikely to be resolved by randomized trials.
Arch Intern Med. 2012;172(18):1406-1412.
Published online August 27, 2012.
doi:10.1001/archinternmed.2012.4276
I
N THE TREATMENT OF HYPERTEN-
sion, -blockers are widely used
and are one of the drug classes
recommended as initial treat-
ment in hypertension guide-
lines based on reduction of morbidity and
mortality in placebo-controlled trials.
1-5
However, following the publication of
2 large trials that found that atenolol-
based regimens were less effective than
other antihypertensive drugs for preven-
tion of cardiovascular (CV) events in pa-
tients with hypertension,
6,7
the first-line
status of -blockers has increasingly been
called into question.
3,8-11
A recent meta-
analysis including these studies found that
-blockers were inferior to other agents
primarily with regard to stroke preven-
tion, but the authors and editorialist
pointed out that data on -blockers other
than atenolol were sparse enough that it
is unclear whether this conclusion ap-
plies to the entire -blocker class.
9,12
Asec-
ond meta-analysis and editorial echoed
these findings and concerns.
11,13
Within the drug class of -blockers,
there are differences in pharmacokinetic
properties.
14,15
Differences in lipophilic-
ity, bioavailability, and metabolism be-
tweenatenolol andmetoprolol tartrate may
have relevance for protecting the heart.
10,11
Despite these differences, it is unlikely
that they will be compared head to head
in a randomized controlled trial. There-
fore, we sought to compare the effective-
ness of 2 commonly used -blockers,
using data from a hypertension registry
from 3 large integrated health care deliv-
ery systems. We compared the incidence
of myocardial infarction (MI), stroke,
and heart failure (HF) in adult hyperten-
See Invited Commentary
at end of article
Author Affil
HealthPartn
Education a
Minneapolis
(Drs Parker,
OConnor an
Institute for
Kaiser Perm
Denver (Dr
Tavel and Sh
Medical Cen
Cardiology,
University o
(Dr Ho); and
Research, Ka
Northern Ca
(Mr Swain).
Author Affiliations:
HealthPartners Institute for
Education and Research,
Minneapolis, Minnesota
(Drs Parker, Margolis, and
OConnor and Ms Trower);
Institute for Health Research,
Kaiser Permanente Colorado,
Denver (Dr Magid and Mss
Tavel and Shetterly); Denver VA
Medical Center and Division of
Cardiology, School of Medicine,
University of Colorado, Denver
(Dr Ho); and Division of
Research, Kaiser Permanente
Northern California, Oakland
(Mr Swain).
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sive patients who were new users of atenolol and meto-
prolol tartrate.
METHODS
STUDY SETTING AND
REGISTRY POPULATION
This report is derived from the Hypertension Registry of the
Cardiovascular Research Network (CVRN). The registry in-
cludes all adult patients identified as having hypertension be-
tween 2000 and 2009 at 3 large integrated health care delivery
systems: HealthPartners of Minnesota, Kaiser Permanente Colo-
rado, and Kaiser Permanente Northern California. Electronic
data on longitudinal blood pressure (BP) measurements, pre-
scription drugs, laboratory test results, diagnoses, and health
care utilization were available from electronic health records
and administrative databases at all sites. Data from each of the
health plans were restructured into a common, standardized
format with identical variable names, definitions, labels, and
coding.
We defined hypertension using criteria adapted from pre-
vious CVRN studies
16-20
based on outpatient BP readings, di-
agnostic codes from outpatient and hospital records, phar-
macy prescriptions, and laboratory results. Patients entered the
registry on the date they first met 1 (or more) of the following
criteria: (1) 2 consecutive elevated BP measurements (ie, sys-
tolic BP [SBP] 140 mm Hg and/or diastolic BP [DBP] 90
mm Hg, or 130/80 mm Hg in the presence of diabetes melli-
tus or chronic kidney disease [CKD]); (2) 2 diagnostic codes
for hypertension (International Classification of Diseases, Ninth
Revision, Clinical Modification [ICD-9-CM] code 401.x-405.x)
recorded on separate dates; (3) 1 diagnostic code for hyper-
tension plus prescription for an antihypertensive medication;
or (4) 1 elevated BP measurement plus 1 diagnostic code for
hypertension. Blood pressure readings fromemergency and ur-
gent care settings were excluded because they were found to
be consistently higher than other ambulatory measurements
in the same patients in similar periods. To confirm that the al-
gorithms designed to identify hypertensive patients were valid
and that the analytic data accurately reflected the source data,
we conducted a reviewof 450 randomly selected medical charts
(150 from each site). We confirmed that hypertension was in
fact incident on the date assigned by the algorithm in 96% of
cases, and agreement on BP values between the electronic da-
tabase and medical chart records was 98%.
VARIABLES USED IN ANALYSIS
Patient age and sex were available for all patients from mem-
bership databases. Race/ethnicity was obtained from outpa-
tient registration data, hospital discharge records, member sat-
isfaction surveys, and other research survey data sets and was
available for 85% of cohort members. Systolic BPs and DBPs
measured within 2 months prior to the initiation of a -blocker
therapy and approximately 6 months (60 days) after the ini-
tiation of a -blocker therapy were included. Pharmacy rec-
ords were used to identify dates of treatment with -blockers
and other antihypertensive drug classes used within 90 days
of starting the -blocker therapy.
Cardiovascular disease (CVD) was identified using diagno-
ses and procedure codes from inpatient and ambulatory rec-
ords. These included ischemic heart disease (ICD-9-CM diag-
nosis codes 410.x-414.xx); stroke (ICD-9-CM diagnosis codes
430.xx-434.xx, 436.xx, 852.0, 852.2. 852.4, and 853.0); pe-
ripheral vascular disease (ICD-9-CM diagnosis codes 441.3-
441.7, 443.9, 444.0, and 444.2); and congestive HF (ICD-
9-CM diagnosis codes 428.xx, 402.xx, and 398.91). Incident
MI (ICD-9-CM code 410.xx), HF, and stroke events were de-
fined using the primary International Classification of Diseases,
Ninth Revision (ICD-9) codes from a discharge from an inpa-
tient stay.
Other comorbidities included in the analysis were diabetes
mellitus, CKD, and lipid disorders. Diabetes was defined by (1)
2 outpatient diagnoses or 1 primary inpatient discharge diag-
nosis of diabetes mellitus (ICD-9-CM code 250.x); (2) a pre-
scription for any antidiabetic medication other than metfor-
min or thiazolidinediones; (3) a prescription for metformin or
a thiazolidinedione plus a diagnosis of diabetes; or (4) a he-
moglobin A
1c
value higher than 7% or 2 fasting plasma glu-
cose values of 126 mg/dL or higher (to convert to millimoles
per liter, multiply by 0.0555) on separate dates. Chronic kid-
ney disease was defined by (1) 2 consecutive serum creatinine
values that yield estimated glomerular filtration rates lower than
60 mL/minor (2) anInternational Classification of Diseases, Ninth
Revision (ICD-9) diagnostic code for CKD (ICD-9-CM codes
585.1-585.9). Lipiddisorders were identifiedby ICD-9-CMcodes
272.x.
STUDY POPULATION
We used a newuser design, which restricts the analysis to per-
sons under observation at the start of the current course of treat-
ment.
21
The study population included all patients 18 years or
older with hypertension during 2000 through 2009, who were
started on therapy with either atenolol or metoprolol tartrate
after the date of first diagnosis withno prior use of any -blocker
for at least 12 months (n=193 123). Previous use of any other
class of antihypertensive drug was not an exclusion. Prescrip-
tion databases were searched as far back as 1996 or to health
plan enrollment if that occurred after 1996. Other -blockers,
including metoprolol succinate, were not usedfrequently enough
during the years of the study to be included in the analysis. We
excluded pregnant women (n=346). In addition, we excluded
46809 patients who hadevidence of CVDbefore starting therapy
withatenolol or metoprolol tartrate. These exclusions were based
on the previously described CV diagnosis codes as well as pro-
cedure codes for cardiac bypass surgery (Current Procedural Ter-
minology [CPT] codes 33510-33523 and 33533-33536) and per-
cutaneous coronary interventions (CPT codes 92980-92996).
To exclude patients with suspected CVD, we also excluded
24 990 patients with a visit to cardiology specialist within the
year prior to starting the -blocker therapy, leaving 120 978
patients for this analysis (Figure).
STATISTICAL ANALYSIS
All statistical analyses were completed using SAS version 9.2
(SAS Institute Inc). Baseline characteristics were compared be-
tween patients started on atenolol therapy vs metoprolol tar-
trate therapy using means and standard deviations for continu-
ous variables andpercentages for categorical andbinary variables.
Cox proportional hazards models were used to compare time
with outcome events between atenolol and metoprolol tar-
trate. Follow-up time was computed in days from the day fol-
lowing the first dispensing of the new -blocker to the date of
the first observed outcome event, termination of enrollment,
or December 31, 2009, whichever occurred first. Patients who
were lost to follow-up were censored at the last point of con-
tact. Multivariable models were adjusted for year of -blocker
therapy initiation, age, sex, number of visits in the prior year,
SBP at the start of -blocker therapy, lipid disorder, diabetes
mellitus, CKD, and use of other antihypertensive medica-
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tions. In a supplemental analysis of 68 882 patients in whom
we had follow-up BP data, we used linear regression to exam-
ine the effect of atenolol and metoprolol tartrate on lowering
SBP and DBP 6 months after the start of the -blocker therapy.
Because this is an observational study and patients were not
randomized to receive either treatment, we also used alterna-
tive strategies to minimize confounding by indication. To mini-
mize confounding by indication, we also ran a conditional lo-
gistic regression matched on propensity score. Alogistic model
(which included all the variables in Table 1 except for DBP)
was used to generate a propensity score for the probability of
being prescribed metoprolol tartrate. We then used a 5-digit
greedy 1:1 matching algorithm
23
to match metoprolol tartrate
users to atenolol users based on propensity score. After con-
ducting the propensity matching, there were 99 626 un-
matched patients, leaving 22 352 matched patients for statis-
tical analyses of adverse CVevents and 13 908 matched patients
with 6-month follow-up BPs for the analyses of BP lowering.
The selection of patients for the analyses is shown in the Figure.
Asecond alternative strategy was to conduct a sensitivity analy-
sis excluding patients who had events in the first 12 months of
follow-up so as to exclude those with CVD not excluded by
diagnosis codes or visits to a cardiologist that could have had
an impact on prescribing behavior.
RESULTS
The baseline characteristics for this cohort of new
-blocker users are given in Table 1. A total of 120 978
patients without history of CVD events from the CVRN
HypertensionRegistry initiatedtreatment witheither aten-
olol or metoprolol tartrate between 2000 and 2009. Dur-
ing this period atenolol was used in approximately 10-
fold more patients than metoprolol tartrate. Patients who
filled a prescription for metoprolol tartrate tended to be
older, have a government insurance payer, and have more
ambulatory visits. Metoprolol tartrate users had slightly
lower SBPs and DBPs at the start of -blocker treat-
ment, were more likely to be using other antihyperten-
sive medications, and more often had lipid disorders, dia-
betes, and CKD.
During the follow-up period (median, 5.2 years), there
were 3517 incident MIs, 3272 incident HF hospitaliza-
tions, and 3664 incident strokes. Multivariable Cox pro-
portional hazards regressionyielded hazard ratios of 0.99,
0.99, 0.99, and 0.98 and narrow 95% confidence inter-
vals that included the null value for MI, HF, stroke, and
any CV event, respectively (Table 2). In the propen-
sity scorematched Cox proportional hazards models, the
hazard ratios for MI, HF, stroke, and any CV event were
virtually identical to the multivariable results with nar-
row95%confidence intervals that included the null value
(Table 2). In sensitivity analyses excluding patients who
had events in the first 12 months of follow-up, the haz-
ard ratios were virtually unchanged (data not shown).
Estimates and standard errors of the supplemental
analysis of the BP-lowering effects of the 2 -blockers in
the subgroup with follow-up measures are given in
Table 3. In multivariable analysis of new-blocker us-
ers, at baseline there were statistically significant differ-
ences between atenolol and metoprolol tartrate users in
SBPs (148.5 and 145.4 mm Hg, respectively; P .001)
and DBPs (84.2 and 82.5, respectively; P .001). At the
6-month follow-up, SBPs were 137.4 and 137.5 mm Hg
in the atenolol- and metoprolol tartrate-treated pa-
tients, respectively (P = .82). At 6 months, DBPs were 77.3
and 77.7 mmHg in the atenolol- and metoprolol tartrate
treated patients, respectively (P = .005). There was no sta-
tistically significant difference inchange inSBPanda small
but statistically significant difference in change in DBP
(5.9 and 5.5 mm Hg for atenolol and metoprolol tar-
trate, respectively P = .005). The propensity score
matched analysis of BP lowering had similar results when
comparing newatenolol and metoprolol tartrate users in
SBP (144.2 and 143.3 mmHg, respectively; P = .007) and
DBP (81.3 and 80.2 mm Hg, respectively; P .001). At
the 6-month follow-up, there were no statistically sig-
nificant differences between atenolol and metoprolol tar-
trate users in SBP or DBP. In the propensity-matched
model, the mean BP lowering was slightly greater in aten-
olol vs metoprolol tartrate users (7.7 and 6.7 mmHg, re-
spectively; P = .02). Atenolol lowered DBP slightly more
than metoprolol tartrate (4.7 and 3.4 mm Hg, respec-
tively; P .001).
COMMENT
The objective of this study was to assess the compara-
tive effectiveness of 2 -blockers, atenolol and metopro-
lol tartrate, in patients without a history of CVD. To our
knowledge, this study is among the first to address this
important clinical question. In this retrospective cohort
study comparing patients initiating -blocker treat-
ment with either atenolol or metoprolol tartrate, there
were no statistically significant differences in rates of in-
cident MI, HF, or stroke after adjusting for potential con-
founders. In addition, there were no statistically signifi-
cant differences in SBP-lowering effects comparing
atenolol and metoprolol tartrate.
Until recently, -blockers had been widely recom-
mended as first-line therapy for hypertension,
1-5
but many
of the trials supporting their use had given investigators
193 123 New -blocker users with hypertension
18 years or older between 2001 and 2009
11 176 Atenolol users
98626 Unmatched
22 352 Included in propensity scorematched analysis
11 176 Metoprolol tartrate users
Matched on
propensity score
Exclusions:
46 809 History of CVD
24 990 Seen by cardiologist in last year
346 Pregnant women
120 978
Met inclusion criteria, included in multivariable regression analysis
91% Atenolol 9% Metoprolol tartrate
Figure. Selection of patients for analyses. CVD indicates cardiovascular
disease.
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the choice of using either a thiazide diuretic or -blocker
alone or in combination as conventional therapy. The
combination compared favorably against other antihy-
pertensive drugs classes for prevention of CV events.
1,24
The use of -blockers as a first-line therapy has recently
been challenged based on evidence of a weak effect on
stroke
25
and the absence of an effect on coronary heart
disease
25-27
compared with placebo, as well as inferiority
Table 1. Descriptive Characteristic of Patients Initiating -Blocker (BB) Use Between 2001 and 2009 (CVRN Hypertension Registry)
a
Variable
Total
(n = 120 978)
Matched on Propensity Score
(n = 22 352)
Atenolol
(n = 109 798)
Metoprolol Tartrate
(n = 11 180)
Atenolol
(n = 11 176)
Metoprolol Tartrate
(n = 11 176)
Year of BB therapy initiation
2000 14 10 87 10
2001 11 6 7 6
2002 15 9 9 9
2003 15 10 10 10
2004 14 12 12 12
2005 12 15 16 15
2006 10 16 16 16
2007 8 14 14 14
2008 2 5 5 5
2009 2 4 4 4
Age, mean (SD), y 60.8 (13.0) 65.1 (13.6) 65.0 (13.4) 65.2 (13.6)
Age category, y
50 20 13 14 13
50-59 27 21 20 21
60-69 25 25 25 25
70-79 20 26 26 26
80 7 15 15 15
Male 43 44 43 44
Race/ethnicity
White 62 66 63 66
African American 10 11 12 11
Asian 9 7 8 8
Nonwhite Hispanic 1 1 1 1
Other/multiple/unknown 19 14 15 14
Median ambulatory visits in prior year 5.0 7.0 7.0 7.0
Insurance payer
Commercial 79 71 70 71
Government 21 29 28 29
SBP at start of BB therapy, mean (SD), mm Hg 148.5 (20.2) 144.0 (21.5) 144.8 (20.4) 144.0 (21.5)
DBP at start of BB therapy, mean (SD), mm Hg 84.5 (13.2) 82 (12.5) 82.1 (12.6) 80.9 (12.9)
Lipid disorder
b
32 42 47 42
Diabetes mellitus
c
21 31 30 30
Chronic kidney disease
d
12 28 28 28
ACE inhibitor or ARB use within 6 mo prior
to BB therapy initiation
36 46 47 46
CCB use within 6 mo prior to BB therapy initiation 14 23 17 23
Diuretic use within 6 mo prior to BB therapy initiation 51 49 54 49
Other antihypertensive medication use within 6 mo
prior to BB therapy initiation
7 13 9 13
Antihypertensive medications within 6 mo prior
to BB therapy initiation, No.
0 32 26 26 26
1 26 31 32 31
2 26 30 32 30
3 6 11 8 11
4 1 2 1 2
Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; CVRN, the Cardiovascular Research
Network.
a
Data are given as percentage of patients unless otherwise indicated. Percentages may not add to 100 because of rounding.
b
Lipid disorders were identified by International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes 272.x.
c
Diabetes mellitus was defined by (1) 2 outpatient diagnoses or 1 primary inpatient discharge diagnosis of diabetes (ICD-9-CM code 250.x); (2) prescription
for any antidiabetic medication other than metformin or thiazolidinediones; (3) prescription for metformin or a thiazolidinedione plus a diagnosis of diabetes; or
(4) hemoglobin A
1c
value higher than 7% or 2 fasting plasma glucose values of 126 mg/dL or higher (to convert to millimoles per liter, multiply by 0.0555)
on separate dates.
d
Chronic kidney disease was defined by (1) 2 consecutive serum creatinine values that yield estimated glomerular filtration rates lower than 60 mL/min when
the Modification of Diet in Renal Disease equation
22
is applied or (2) an International Classification of Diseases, Ninth Revision (ICD-9) diagnostic code for chronic
kidney disease (ICD-9-CM codes 585.1-585.9).
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compared with other treatments for total mortality, coro-
nary heart disease, and stroke.
6,7,28
Meta-analyses and a
Cochrane review of recent trials that looked specifically
at -blockers usedas monotherapy or as the first-line drug
in a stepped care approach concluded that the evidence
did not support use of -blockers as a first-line therapy.
11
Based on these findings, recently issued guidelines have
relegated -blockers to third- or fourth-line treatment for
uncomplicated hypertension.
29
-blockers differ in selectivity for the
1
- and
2
- and
-adrenergic receptors, lipophilicity, penetration across
the blood-brain barrier, duration of action, vasodilation
properties, and type 3 antiarrhythmic activity.
14,15,30
Dif-
ferent types of -blockers may be indicated depending
on patient profiles and tolerances. Given that most of the
evidence comes from trials where atenolol was the
-blocker used,
11
it is unclear if the observed effects of
-blockers in comparison with other antihypertensive
medications are due to properties of atenolol or the en-
tire class of -blockers. However, there have beenno trials
comparing the different subtypes of -blockers. While
both atenolol and metoprolol tartrate are both
1
-
adrenergic receptors, they differ in lipophilicity, bioavail-
ability, and metabolism.
10,11,31
Metoprolol is lipid soluble
andtends tohave highly variable bioavailability anda short
plasma half-life. Incontrast, atenolol is more water soluble,
shows less variance in bioavailability, and has a longer
plasma half-life. Despite these differences, bothdrugs have
the effect of increasing vagal tone and causing a reduc-
tion in sympathetic outflow, likely via peripheral -ad-
renergic blockade.
32,33
Our findings that there are no dif-
ferences betweenatenolol and metoprolol tartrate inevent
rates and effectiveness at BP lowering in a cohort of adults
without prior CVevents suggest that the unfavorable trial
data with atenolol may also apply to other -blockers.
As with any observational study, there are potential
limitations and caveats. We were unable to compare aten-
olol with any -blocker other than metoprolol tartrate
because of the lowuse of other agents in our study popu-
lation during the years of observation. The use of meto-
prolol succinate, a once-daily drug that may have better
adherence rates compared with twice-daily metoprolol
tartrate, has been increasing owing to the availability of
generic versions in recent years, but the shift away from
-blockers after 2007 may make comparative effective-
ness analyses more difficult.
Most importantly, patients were not randomly as-
signed to treatment witheither atenolol or metoprolol tar-
Table 2. Incident Cardiovascular (CV) Events Associated With Metoprolol Tartrate Compared With Atenolol
Variable
Multivariable
a
Cox Proportional Hazards Regression Propensity ScoreMatched
b
Cox Proportional Hazards Model
No. of Events Person-years Hazard Ratio (95% CI) No. of Events Person-years Hazard Ratio (95% CI)
MI 3517 631 403 0.99 (0.97-1.01) 712 94 261 0.99 (0.97-1.02)
HF 3272 633 987 0.99 (0.97-1.01) 831 94 257 0.99 (0.96-1.01)
Stroke 3664 632 386 0.99 (0.97-1.01) 773 94 346 0.99 (0.97-1.02)
Any CV event 9353 616 028 0.98 (0.99-1.00) 2064 91 191 0.98 (0.95-1.00)
Abbreviations: HF, heart failure; MI, myocardial infarction.
a
Multivariable model adjusted for year of -blocker therapy initiation, age, sex, number of visits in prior year, systolic blood pressure at start of -blocker
therapy, lipid disorder, diabetes mellitus, chronic kidney disease, and if using other antihypertensive medications.
b
Matched on propensity score. Propensity score adjusted for year of -blocker therapy initiation, age, sex, number of visits in prior year, systolic blood
pressure at start of -blocker therapy, lipid disorder, diabetes, chronic kidney disease mellitus, and if using other antihypertensive medications.
Table 3. Comparison of Blood Pressure (BP)-Lowering Effects at 6 Months in New -Blocker Users
Variable
Multivariable
a
Linear Regression Propensity ScoreMatched
b
Linear Regression
BP Estimate (SE), mm Hg
P Value
BP Estimate (SE), mm Hg
P Value
Atenolol
(n = 61 869)
Metoprolol Tartrate
(n = 7013)
Atenolol
(n = 6907)
Metoprolol Tartrate
(n = 7010)
Baseline SBP and DBP
SBP 148.5 (0.25) 145.4 (0.33) .001 144.2 (0.25) 143.3 (0.25) .007
DBP 84.2 (0.15) 82.5 (0.20) .001 81.3 (0.15) 80.2 (0.15) .001
SBP and DBP at 6 mo after
-blocker therapy initiation
SBP 137.4 (0.23) 137.5 (0.30) .82 136.5 (0.23) 136.6 (0.23) .85
DBP 77.3 (0.13) 77.7 (0.17) .005 76.6 (0.13) 76.7 (0.13) .41
Change in SBP and DBP over
the 6 mo follow-up
SBP 9.8 (0.23) 9.8 (0.30) .82 7.7 (0.29) 6.7 (0.29) .02
DBP 5.9 (0.13) 5.5 (0.17) .005 4.7 (0.16) 3.4 (0.16) .001
Abbreviations: DBP, diastolic BP; SBP, systolic BP.
a
Multivariable model adjusted for year of -blocker therapy initiation, age, sex, number of visits in prior year, SBP at start of -blocker therapy, lipid disorder,
diabetes mellitus, chronic kidney disease, and if using other antihypertensive medications.
b
Matched on propensity score. Propensity score adjusted for year of -blocker therapy initiation, age, sex, number of visits in prior year, SBP at -blocker
therapy initiation, lipid disorder, diabetes mellitus, chronic kidney disease, and if using other antihypertensive medications.
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trate. The decision on the part of the clinician to choose
one drug over another may be related to patient charac-
teristics associated with BP control or CV risk or physi-
cian characteristics associated with differences in quality
of care. To reduce the potential bias related to confound-
ing by indication, we took 2 approaches: (1) we used a
newuser design
21,34
and restricted the sample to those pa-
tients with no evidence of diagnosed or suspected CVD
34
and (2) we used propensity score matching to ensure that
patients were comparable with regard to baseline covari-
ates and the probability of receiving each treatment.
Despite these robust methods, no observational study
can rule out the impact of unmeasured confounding. If
unmeasured variables associated with poorer prognosis
were more commoninpatients prescribed metoprolol tar-
trate, it could mask a beneficial effect of metoprolol. We
excluded patients who had seen a cardiologist in the 12
months prior to the initiation of -blocker therapy, but
this strategy may have been insufficient to rule out sus-
pected CVD. However, in a recent study using data from
one of the study sites, we found no evidence of sus-
pected heart disease in audits of physician medical chart
notes in240 patients lacking specific ICD-9 codes for heart
disease (410-414 and 420-429).
35
Other important po-
tential unmeasured confounders that are not available in
electronic medical records include behavioral or envi-
ronmental risk factors, such as poor diet, low level of
physical activity, or exposure to second-hand smoke, al-
though we have no reason to believe that patients with
these risk factors would be more likely to be prescribed
metoprolol tartrate rather than atenolol.
In conclusion, we found no differences in CV event
rates when comparing patients without a history of CV
events who were initiating treatment with either ateno-
lol or metoprolol tartrate. These findings suggest that hy-
pertension trial outcomes with atenolol may not relate
tounfavorable characteristics of this particular drug. These
results should be interpreted cautiously, since there have
been no trials comparing these 2 -blockers directly.
Accepted for Publication: June 11, 2012.
Published Online: August 27, 2012. doi:10.1001
/archinternmed.2012.4276
Correspondence: Emily D. Parker, MPH, PhD, Health-
Partners Institute for Education and Research, Box 1524,
Mail Stop 21111R, Minneapolis, MN55440-1524 (Emily
.D.Parker@Healthpartners.com).
Author Contributions: Study concept and design: Parker,
Margolis, and OConnor. Acquisition of data: Margolis,
Trower, Magid, Tavel, Shetterly, Swain, and OConnor.
Analysis and interpretation of data: Parker, Margolis, Ho,
and OConnor. Drafting of the manuscript: Parker, Mar-
golis, Trower, Swain, and OConnor. Critical revision of
the manuscript for important intellectual content: Parker,
Magid, Tavel, Shetterly, andHo. Statistical analysis: Parker
andTrower. Obtained funding: MagidandOConnor. Study
supervision: Margolis.
Financial Disclosure: None reported.
Funding/Support: This project was funded by grant NIH/
NHLBI/U19 HL091179 from the National Heart, Lung,
and Blood Institute and subcontract to HealthPartners
Institute for Education and Research.
REFERENCES
1. Turnbull F; Blood Pressure Lowering Treatment Trialists Collaboration. Effects
of different blood-pressure-lowering regimens on major cardiovascular events:
results of prospectively-designed overviews of randomised trials. Lancet. 2003;
362(9395):1527-1535.
2. Psaty BM, Smith NL, Siscovick DS, et al. Health outcomes associated with an-
tihypertensive therapies used as first-line agents: a systematic review and
meta-analysis. JAMA. 1997;277(9):739-745.
3. Messerli FH, Grossman E, Goldbourt U. Are -blockers efficacious as first-line
therapy for hypertension in the elderly? a systematic review. JAMA. 1998;279
(23):1903-1907.
4. Mancia G, De Backer G, Dominiczak A, et al; The task force for the management
of arterial hypertension of the European Society of Hypertension; The task force
for the management of arterial hypertension of the European Society of Cardi-
ology. 2007 Guidelines for the management of arterial hypertension. Eur Heart
J. 2007;28(12):1462-1536.
5. Chobanian AV, Bakris GL, Black HR, et al; National Heart, Lung, and Blood In-
stitute Joint National Committee on Prevention, Detection, Evaluation, and Treat-
ment of High Blood Pressure; National High Blood Pressure Education Program
Coordinating Committee. The Seventh Report of the Joint National Committee
on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the
JNC 7 report. JAMA. 2003;289(19):2560-2572.
6. Dahlof B, Devereux RB, Kjeldsen SE, et al; LIFE Study Group. Cardiovascular mor-
bidity and mortality in the Losartan Intervention For Endpoint reduction in hy-
pertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;
359(9311):995-1003.
7. Dahlof B, Sever PS, Poulter NR, et al; ASCOT Investigators. Prevention of car-
diovascular events with an antihypertensive regimen of amlodipine adding per-
indopril as required versus atenolol adding bendroflumethiazide as required, in
the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm
(ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005;366
(9489):895-906.
8. Messerli FH, Beevers DG, Franklin SS, Pickering TG. beta-Blockers in hypertension-
the emperor has no clothes: an open letter to present and prospective drafters
of new guidelines for the treatment of hypertension. Am J Hypertens. 2003;
16(10):870-873.
9. LindholmLH, Carlberg B, Samuelsson O. Should beta blockers remain first choice
in the treatment of primary hypertension? a meta-analysis. Lancet. 2005;366
(9496):1545-1553.
10. Ong HT. Beta blockers in hypertension and cardiovascular disease. BMJ. 2007;
334(7600):946-949.
11. Wiysonge CS, Bradley H, Mayosi BM, et al. Beta-blockers for hypertension. Coch-
rane Database Syst Rev. 2007;(1):CD002003.
12. Beevers DG. The end of beta blockers for uncomplicated hypertension? Lancet.
2005;366(9496):1510-1512.
13. Massie BM. Review: available evidence does not support the use of beta block-
ers as first line treatment for hypertension. Evid Based Med. 2007;12(4):112.
14. Reid JL. Optimal features of a new beta-blocker. Am Heart J. 1988;116(5, pt 2):
1400-1404.
15. Drayer DE. Lipophilicity, hydrophilicity, and the central nervous system side ef-
fects of beta blockers. Pharmacotherapy. 1987;7(4):87-91.
16. Ho PM, Zeng C, Tavel HM, et al. Trends in first-line therapy for hypertension in
the Cardiovascular Research Network Hypertension Registry, 2002-2007. Arch
Intern Med. 2010;170(10):912-913.
17. Magid DJ, Shetterly SM, Margolis KL, et al. Comparative effectiveness of angio-
tensin-converting enzyme inhibitors versus beta-blockers as second-line therapy
for hypertension. Circ Cardiovasc Qual Outcomes. 2010;3(5):453-458.
18. Schmittdiel J, Selby JV, Swain B, et al. Missed opportunities in cardiovascular
disease prevention? low rates of hypertension recognition for women at medi-
cine and obstetrics-gynecology clinics. Hypertension. 2011;57(4):717-722.
19. Selby JV, Lee J, Swain BE, et al. Trends in time to confirmation and recognition
of new-onset hypertension, 2002-2006. Hypertension. 2010;56(4):605-611.
20. Selby JV, Peng T, Karter AJ, et al. High rates of co-occurrence of hypertension,
elevated low-density lipoprotein cholesterol, and diabetes mellitus in a large man-
aged care population. Am J Manag Care. 2004;10(2, pt 2):163-170.
21. Ray WA. Evaluating medication effects outside of clinical trials: new-user designs.
Am J Epidemiol. 2003;158(9):915-920.
22. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kid-
ney disease: evaluation, classification, and stratification. AmJ Kidney Dis. 2002;
39(2)(suppl 1):S1-S266.
23. Parsons L. Reducing bias in a propensity score matched-pair sample using greedy
matching techniques. In: Proceedings of the Twenty-sixth Annual SASUsers Group
International Conference. Cary, NC: SAS Institute Inc; 2001:214-226.
ARCH INTERN MED/ VOL 172 (NO. 18), OCT 8, 2012 WWW.ARCHINTERNMED.COM
1411
2012 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ on 08/10/2014
24. Neal B, MacMahon S, Chapman N; Blood Pressure Lowering Treatment Trial-
ists Collaboration. Effects of ACE inhibitors, calciumantagonists, and other blood-
pressure-lowering drugs: results of prospectively designed overviews of ran-
domised trials. Blood Pressure Lowering Treatment Trialists Collaboration. Lancet.
2000;356(9246):1955-1964.
25. Coope J, Warrender TS. Randomised trial of treatment of hypertension in el-
derly patients in primary care. Br Med J (Clin Res Ed). 1986;293(6555):1145-
1151.
26. Medical Research Council Working Party. MRC trial of treatment of mild hyper-
tension: principal results. Br Med J (Clin Res Ed). 1985;291(6488):97-
104.
27. The IPPPSH Collaborative Group. Cardiovascular risk and risk factors in a ran-
domized trial of treatment based on the beta-blocker oxprenolol: the Interna-
tional Prospective Primary Prevention Study in Hypertension (IPPPSH).
J Hypertens. 1985;3(4):379-392.
28. MRC Working Party. Medical Research Council trial of treatment of hyper-
tension in older adults: principal results. BMJ. 1992;304(6824):405-
412.
29. National Institute for Health and Clinical Excellence. Hypertension: Clinical Man-
agement of Primary Hypertension in Adults. London, England: National Institute
for Health and Clinical Excellence; 2011. NICE Clinical Guideline 127.
30. Weber MA. The role of the newbeta-blockers in treating cardiovascular disease.
Am J Hypertens. 2005;18(12, pt 2):169S-176S.
31. Wikstrand J, Kendall M. The role of beta receptor blockade in preventing sudden
death. Eur Heart J. 1992;13(suppl D):111-120.
32. Sandrone G, Mortara A, Torzillo D, La Rovere MT, Malliani A, Lombardi F. Ef-
fects of beta blockers (atenolol or metoprolol) on heart rate variability after acute
myocardial infarction. Am J Cardiol. 1994;74(4):340-345.
33. Tuininga YS, Crijns HJ, Brouwer J, et al. Evaluation of importance of central ef-
fects of atenolol and metoprolol measured by heart rate variability during men-
tal performance tasks, physical exercise, and daily life in stable postinfarct patients.
Circulation. 1995;92(12):3415-3423.
34. Psaty BM, Siscovick DS. Minimizing bias due to confounding by indication in
comparative effectiveness research: the importance of restriction. JAMA. 2010;
304(8):897-898.
35. Kottke T, Baechler C, Parker E. The accuracy of heart disease prevalence esti-
mated fromclaims data compared to electronic health record. Prev Chronic Dis.
2012;9:E141.
INVITED COMMENTARY
Observational Comparative Effectiveness Studies
of Drug Therapies
High-Quality Answers or Important Clinical Questions?
F
or the prevention of cardiovascular disease
(CVD), -blockers are among the most widely
used therapies. Multiple clinical trials have
established their efficacy in preventing death after
myocardial infarction (MI) and in treating congestive
heart failure (CHF) due to systolic dysfunction.
1,2
-Blockers have also long been used to treat hyperten-
sion. Although low-dose diuretics are the recom-
mended first-line agent for pharmacologic therapy for
uncomplicated high blood pressure,
3
several large
trials funded by the pharmaceutical industry have
used -blockers as the active-comparison control
treatment,
4
and the results of these trials suggest that
other therapies are more effective than atenolol in pre-
venting cardiovascular events, particularly stroke.
5,6
Because no primary prevention trial among hyperten-
sive patients has compared atenolol head to head with
other -blockers, their comparative effectiveness in
this setting remains unknown.
To address this question, Parker and colleagues
7
conducted an observational study that compared the
new use of atenolol and metoprolol tartrate, 2 widely
used -blockers in the United States, for the prevention
of MI, stroke, and CHF in patients with treated hyper-
tension. This study was nested within the hypertension
registry of the Cardiovascular Research Network
(CVRN), which includes all adult patients with hyper-
tension enrolled in 3 large integrated health care plans
from 2000 to 2009. Most -blocker use was in combi-
nation with other therapies, and half of the study popu-
lation used diuretics within 6 months prior to starting a
-blocker. For all outcomes, the relative risk estimates
were null, and the 95% confidence intervals excluded a
greater than 2%increased risk associated with metopro-
lol use compared with atenolol.
This study has several strengths. The validation of en-
try criteria inthe hypertensionregistry and the use of elec-
tronic prescriptions records allowed for a new-user study
design, which compares users of different treatments at
a similar point in the natural history of hypertensive dis-
ease and avoids some sources of bias that are common
in studies that include prevalent users of medications.
8
Because of the careful use of restriction to exclude per-
sons with known prevalent CVD and even persons re-
ferred to a cardiologist, who may be more likely than non-
referred patients to have undocumented or suspected but
undiagnosed CVD, the observed cardiovascular events
likely reflect incident disease.
The authors used several analytic methods to mini-
mize confounding bias. In one set of analyses, factors as-
sociated with both the choice of -blocker and the risk
of outcomes were adjusted for. In another, propensity
scores were used to make comparisons among a subset
of the study population with similar probabilities of treat-
ment based on known risk factors. Furthermore, ateno-
lol and metoprolol, which are both cardioselective
1
-
adrenergic receptor blockers, have similar pharmacologic
properties and similar indications.
9
The relative risk es-
timates fromthe 2 analytic approaches were similar, and
because of large sample sizes, the 95% confidence inter-
vals were narrow.
The study by Parker and colleagues
7
also shares the
traditional and persistent weaknesses of observational
studies, particularly those that rely onadministrative data.
Some potential confounding variables are not well cap-
tured by administrative codes, and information on oth-
ARCH INTERN MED/ VOL 172 (NO. 18), OCT 8, 2012 WWW.ARCHINTERNMED.COM
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2012 American Medical Association. All rights reserved.
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