ORIGINAL PAPER
Comparative Effectiveness Analysis of Amlodipine Renin-Angiotensin
System Blocker Combinations
C. Venkata S. Ram, MD, MACP;1,2 Joseph Vasey, PhD;3 Sumeet Panjabi, PhD;4 Chunlin Qian, PhD;4 Ruth Quah, MPH3
From the Texas Blood Pressure Institute, Dallas, TX;1 the MediCiti Institute of Medical Science, Medchal Hyderabad, India;2 GE Healthcare,
Princeton, NJ;3 and Daiichi Sankyo, Parsippany, NJ4
A comparative effectiveness analysis of antihypertensive
therapy amlodipine (AML) and angiotensin receptor blocker
(ARB) fixed- and loose-dose combinations (FDCs and
LDCs) in achieving blood pressure (BP) reduction and
Seventh Report of the Joint National Committee on Pre-
vention, Detection, Evaluation and Treatment of High
Blood Pressure (JNC 7) goal attainment was made using
retrospective electronic medical record (EMR) data. Treat-
ment goal rates ranged from 35.0% for LDC AML losartan
to 45.7% for FDC AML olmesartan (OM). FDC AML OM
achieved significantly greater reductions in systolic BP
than FDC AML benazepril (BEN), FDC AML valsartan
(VAL), and LDC AML ARBs, respectively, and significantly
Nearly 33.5% of US adults have high blood pressure
(BP),1 and the prevalence is expected to increase by
9.9% over the next 2 decades, reaching 37.3% by the
year 2030.2 Untreated or undertreated hypertension is
associated with significant cardiovascular morbidity
and mortality1,3 and is a precursor to first stroke, first
heart attack, or heart failure (HF) in approximately
75% of individuals.1
The Seventh Report of the Joint National Commit-
tee on Prevention, Detection, Evaluation and Treat-
ment of High Blood Pressure (JNC 7) recommends
treatment to a BP <140 90 mm Hg for nondiabetic
hypertensive persons and <130 80 mm Hg for those
with diabetes or chronic kidney disease (CKD).4 How-
ever, despite recent improvements in BP control rates,
hypertension remains inadequately managed in
approximately 50% of all patients.5 About two thirds
of the diagnosed hypertensive population will require
combination therapy in order to achieve BP goals.68
Therapy using multiple antihypertensive agents from
different therapeutic classes treats the disease through
multiple physiologic pathways.7,9 JNC 7 guidelines
recommend initial combination therapy for patients
presenting with systolic BP (SBP) >20 mm Hg above
goal or diastolic BP (DBP) >10 mm Hg above goal,
since combination therapy increases the probability
of achieving BP goals within a shorter period than
single-drug therapy.4
Address for correspondence: Chunlin Qian, PhD, Daiichi Sankyo,
2 Hilton Court, Parsippany, NJ 07054
E-mail: cqian@dsi.com
Manuscript received: March 13, 2012; revised: May 31, 2012;
accepted: June 12, 2012
DOI: 10.1111/j.1751-7176.2012.00695.x
Official Journal of the American Society of Hypertension, Inc.
greater reductions in diastolic BP than FDC AML VAL and
LDC therapy, respectively. Compared with patients treated
with AML OM, patients prescribed AML VAL and LDC
AML ARB were significantly less likely to attain JNC 7 BP
goal. Among subpopulations, AML OM yielded higher
rates of goal attainment among both African Americans
and obese overweight patients relative to AML VAL and
combined LDCs. Switchers from monotherapy with AML,
OM, or VAL to AML OM were significantly more likely to
attain JNC 7 goals than those switching to AML VAL or
AML BEN. J Clin Hypertens (Greenwich). 2012;14:601
610. 2012 Wiley Periodicals, Inc.
A combination regimen of a calcium channel
blocker (CCB) and angiotensin receptor blocker (ARB)
benefits from the complementary mechanisms of
action of these two classes. Dihydropyridine CCBs
(DHP-CCBs) decrease the BP by promoting vasodila-
tion, which may lead to activation of the sympathetic
nervous system (SNS) and the renin angiotensin-aldo-
sterone system (RAAS).1012 This activation of SNS
causes tachycardia and vasoconstriction, reducing the
antihypertensive efficacy of the CCB; however, ARBs
attenuate this counter-regulatory response.1012 Fur-
thermore, the addition of an ARB to a CCB signifi-
cantly improves tolerability.11,12 CCBs produce
arteriolar dilation, which leads to peripheral edema, a
major side effect of CCB therapy,1013 while ARBs
cause venodilation, thereby decreasing the transcapil-
lary gradient and ameliorating ankle edema.1013
Moreover, the availability of ARB CCB fixed-dose
combinations (FDCs) lowers the pill burden to patients
and is associated with improved adherence to therapy,
and thus better treatment outcomes may be expected
than observed with loose-dose combinations
(LDCs).14,15 Two ARB CCB FDCs, amlodipine olme-
sartan (AML OM) and amlodipine valsartan (AML
VAL), are currently available in the US market.
The primary purpose of this study was to evaluate
the comparative effectiveness of FDCs of AML OM,
AML VAL, amlodipine benazepril (AML BEN), and
LDCs of amlodipine and ARBs (olmesartan, valsartan,
losartan [LOS], and irbesartan [IRB]) in real-world
clinical practice. Secondary objectives included the
evaluation of BP reduction among patient subgroups,
including African Americans, diabetic patients, over-
weight and obese patients, and patients with chronic
kidney disease (CKD).
The Journal of Clinical Hypertension Vol 14 | No 9 | September 2012 601
Comparative Effectiveness Analysis of Amlodipine
METHODS
Data Source
The datasource used in the study was the GE Centric-
ity EMR database (GE Healthcare, Waukesha, WI).
This database is populated at the point of care by
clinical staff and all patient records are anonymized.
Database content includes patient demographic infor-
mation (such as age, sex, and race), as well as longitu-
dinal clinical information (diagnoses, vital signs
including BP measurements, body mass index [BMI],
prescribed medications, clinical observations, and lab-
oratory test results). As of December 2010, the data-
base contained ambulatory electronic health record
data for >18 million patients. These data were entered
by >6000 physicians, 63% of whom were in primary
care practice.
Study Population
Data for the time period of January 1, 2005, through
December 31, 2010 were utilized for this study.
Patient index date was defined as the earliest start date
for one of the study medications on or after July 1,
2005, and prior to December 31, 2009, to ensure at
least 6 months of baseline and 1 year of follow-up
data for each patient. The FDC cohort included
patients taking CCB ARB FDCs AML OM and
AML VAL, and CCB ACE inhibitor FDC AML BEN.
The earliest instance of a prescription for an FDC was
used for patients prescribed >1 FDC drug. Adult
patients 18 years or older at the index date were eligi-
ble if they received a prescription for one of the study
drugs during the timeframe defined above, with an
available baseline BP that exceeded JNC 7 goal
(140 90 mm Hg or 130 80 mm Hg for patients
with diabetes or CKD).
Patients taking fixed-dose triple combination drugs
such as AML OM hydrochlorothiazide (HCTZ) or
AML VAL HCTZ were excluded, since the US launch
dates for these drugs was too recent to allow for suffi-
cient patient count based on the study identification
period. Index date for LDC was based on the prescrip-
tion date of the second drug in the sequence. LDC am-
lodipine and ARB combination cohorts were identified
based on any of the following prescription permuta-
tions: ARB and AML, ARB HCTZ and AML, AML
and ARB, or AML and ARB HCTZ without a pre-
scription for any other study drug of interest in
between the ARB and amlodipine.
The eligibility criteria for the study were as
follows: age 18 years or older at index date and
available baseline BP that exceeded the JNC 7 goal
(140 90 mm Hg or 130 80 mm Hg for patients
with diabetes or CKD).
No statistical adjustments were made to adjust for
prior treatment status. However, the use of ARB or
AML prior to the study index drug was captured as a
variable for subgroup analyses. Based on International
Statistical Classification of Diseases and Related
602 The Journal of Clinical Hypertension Vol 14 | No 9 | September 2012
| Ram et al.
Health ProblemsNinth Revision (ICD-9) codes, the
presence of diabetes (ICD-9-Clinical Modification
250.xx), and or CKD (ICD-9-Clinical Modification
585.xx) during the 6-month period preceding
the index date was identified. The baseline BP on the
study index date was obtained or, if missing,
the last record within )30 days and +1 day of the
index date was recorded. For each patient identified
on the basis of the index study medication, all demo-
graphic information at baseline (age, race, sex, first
and last activity dates, and BMI) was obtained.
Pre-index and post-index BP data, records of pre-
scribed antihypertensive medications, and comorbidity
information based on selected ICD-9 codes were
abstracted.
Outcome Measures
The primary study objective was to ascertain the effec-
tiveness of AML OM in BP reduction and JNC 7 BP
goal attainment relative to the following: AML VAL;
AML BEN; individual LDC AML+ARB combinations,
namely AML+OM, AML+VAL, AML+IRB, and
AML+LOS; and finally the AML ARB LDC combined
group. As randomized clinical trials have found that
OM and IRB provide the greatest reduction in BP,
followed by VAL and LOS,16,17 and previous retro-
spective, real-world studies have found improved BP
lowering with OM as compared with IRB, LOS, and
VAL,18,19 AML OM was chosen as the reference
group for all comparisons.
Primary outcomes of interest were systolic and dia-
stolic BP change, calculated as the difference between
the baseline value and the average follow-up value
obtained over a 1-year period post-index. The follow-
up value was calculated as an average of the quarterly
post-index BP measures for each patient. Achievement
of JNC 7 BP goal attainment was determined based on
the average follow-up systolic and diastolic BP values.
Secondary objectives included the evaluation of goal
attainment among the following 5 important sub-
populations of interest: African Americans, diabetic
patients, patients with BMI indicative of overweight
(25 to <30) or obesity (30), and patients with CKD.
Another objective was to compare goal attainment
among patients who switched to AML OM, AML -
VAL, and AML BEN from (1) monotherapy (OM,
VAL, or AML) and (2) LDC AML and ARBs.
Statistical Methods
The longitudinal BP records of all eligible patients
were included in the analysis. Daily average BP was
calculated where multiple BP records existed in a
single day. Day 6 to day 365 subsequent to the index
date were used for follow-up BP data. The 1-year
interval (day 6 to day 365) was divided into 4 equal
quarters of 90 days each. Quarterly average BPs were
calculated based on the average daily BPs. Finally,
the average of the 4 quarterly BPs was used as the
follow-up BP.
Official Journal of the American Society of Hypertension, Inc.

Treatment cohorts were compared on the basis of
the difference in the mean change in SBP and DBP
between baseline and follow-up, as well as on the
basis of JNC 7 goal attainment using multivariate
regression models. Analysis of covariance was used to
estimate the difference in mean SBP and DBP change
between cohorts. Logistic regression models were used
to estimate the likelihood of attaining JNC 7 goal with
the comparators relative to AML OM. The following
covariates were included in the regression models: age,
sex, race, BMI, concomitant medication use (ie,
number of non-ARB antihypertensive classes used at
baseline), baseline comorbidities, year of index date,
starting dose category (low, medium, high), baseline
SBP and DBP, and propensity score. The assignment
of dose categories was based on both contributing
medications with the following logic: dose was consid-
ered low if both components of the combination were
at a low dose (AML 2.5 5 mg, OM 20 mg, VAL
80 160 mg, LOS 50 mg, IRB 150 mg, BEN 10 mg);
dose was considered high if both drugs were at a high
dose (AML 10 mg, OM 40 mg, VAL 320 mg, LOS
100 mg, IRB 300 mg, BEN 40 mg); dose was consid-
ered medium if one component in the combination
was high dose and the other was low dose, except in
the case of benazepril (20-mg dose was considered
medium).
Assessed for eligibility in GE
Centricity EMR Database 2005-
2010
(n = 1,833,727)
Enrollment
Hypertensive study
cohort (n = 46,706)
Treatment
FDC (n= 32,807)
AML/OM (n= 4699)
AML/VAL (n= 6673)
AML/BEN (n= 21,435)
FIGURE 1. Study inclusion and exclusion criteria: consort diagram. See text for abbreviations.
Official Journal of the American Society of Hypertension, Inc.
Comparative Effectiveness Analysis of Amlodipine | Ram et al.
The propensity score is the conditional probability
of each patient receiving a particular treatment based
on study baseline variables. Using the LOGISTIC pro-
cedure, propensity scores were calculated as the proba-
bility of being prescribed a treatment regimen based
on the following patient baseline characteristics: sex,
race, age group, existence of comorbidities (ischemic
heart disease, nephritis, cardiovascular disease, diabe-
tes mellitus, CKD, chronic HF [CHF]), body mass cat-
egory, and baseline BP (SBP, DBP). Two propensity
scores were calculated: (1) to reflect patients assign-
ment to each of the seven treatment groups, and (2) to
estimate the likelihood of treatment with AML OM
relative to the combined LDC group.
RESULTS
Based on the study inclusion criteria, the final dataset
consisted of 46,706 patients. The Figure 1 includes a
consort diagram that outlines the study cohort identifi-
cation algorithm. Table I includes the distribution of
patients by treatment cohorts and associated baseline
characteristics. The LDC study groups had more
patients in the older age category, had higher rates of
comorbidities, and had greater use of other concomi-
tant antihypertensive medications compared with the
FDC study groups. BMI and baseline BP values were
similar across all study groups.
Excluded (n =1,787,021)
Not meeting age, diagnosis,
medication, and data
availability inclusion criteria
(n = 1,742,012)
Baseline BP exceeded study
inclusion threshold (n=41,126)
Not meeting follow-up BP
data criteria (n =3883)
LDC (n= 13,899)
AML + OM (n=3305)
AML + VAL (n=5481)
AML + IRB (n=1860)
AML + LOS (n=3253)
The Journal of Clinical Hypertension Vol 14 | No 9 | September 2012 603
604
TABLE I. Baseline Patient Characteristics: Demographics and Comorbiditiesa
Fixed-Dose Combination Drugs Loose-Dose Combination of ARB With AML

AML VAL AML BEN OM VAL IRB LOS Combined LDC

AML OM (n=6673), (n=21,435), (n=3305), (n=5481) (n=1860), (n=3253), (n=13,899),
(n=4699), No. (%) No. (%) No. (%) No. (%) No. (%) No. (%) No. (%) No. (%)

ARB as single agent 1926 (58.3) 3268 (59.6) 1178 (63.3) 2126 (65.4) 8498 (61.1)
ARB+HCTZ 1379 (41.7) 2213 (40.4) 682 (36.7) 1127 (34.6) 5401 (38.9)

The Journal of Clinical Hypertension

Age, y
1840 339 (7.2) 483 (7.2) 1709 (8.0) 117 (3.5) 213 (3.9) 52 (2.8) 86 (2.6) 468 (3.4)
4164 2382 (50.7) 3314 (49.7) 10,860 (50.7) 1324 (40.1) 2134 (38.9) 712 (38.3) 1247 (38.3) 5417 (39.0)
Comparative Effectiveness Analysis of Amlodipine

65+ 1978 (42.1) 2876 (43.1) 8866 (41.4) 1864 (56.4) 3134 (57.2) 1096 (58.9) 1920 (59.0) 8014 (57.7)
|

Sex
Male 1673 (35.6) 2357 (35.3) 7318 (34.1) 1223 (37.0) 2002 (36.5) 754 (40.5) 1222 (37.6) 5201 (37.4)
Race
White 1673 (35.6) 2357 (35.3) 7318 (34.1) 1198 (36.3) 1976 (36.1) 774 (41.6) 1096 (33.7) 5044 (36.3)
Ram et al.

African American 516 (11.0) 862 (12.9) 2513 (11.7) 288 (8.7) 710 (13.0) 189 (10.2) 435 (13.4) 1622 (11.7)

Vol 14 | No 9 | September 2012

Other 112 (2.4) 223 (3.3) 575 (2.7) 93 (2.8) 195 (3.6) 50 (2.7) 125 (3.8) 463 (3.3)
Missing 2398 (51.0) 3231 (48.4) 11,029 (51.5) 1726 (52.2) 2600 (47.4) 847 (45.5) 1597 (49.1) 6770 (48.7)
BMI
Underweight (<18.5) 22 (0.5) 42 (0.6) 128 (0.6) 17 (0.5) 31 (0.6) 18 (1.0) 19 (0.6) 85 (0.6)
Normal (18.524.9) 544 (11.6) 813 (12.2) 2714 (12.7) 450 (13.6) 690 (12.6) 262 (14.1) 434 (13.3) 1836 (13.2)
Overweight (2529.9) 1218 (25.9) 1674 (25.1) 5544 (25.9) 877 (26.5) 1474 (26.9) 490 (26.3) 843 (25.9) 3684 (26.5)
Obese (30) 2358 (50.2) 3409 (51.1) 10,159 (47.4) 1672 (50.6) 2802 (51.1) 926 (49.8) 1699 (52.2) 7099 (51.1)
Missing 557 (11.9) 735 (11.9) 2890 (11.0) 289 (8.7) 484 (8.8) 164 (8.8) 258 (7.9) 1195 (8.6)
Baseline BP
SBP, mean (SD) 158 (17.9) 157 (17.6) 156 (16.7) 156 (17.2) 156 (17.0) 156 (17.2) 156 (16.9) 156 (17.0)
DBP, mean (SD) 89 (13.3) 89 (13.2) 88 (13.0) 85 (12.7) 85 (12.7) 84 (12.4) 84 (12.9) 85 (12.7)
Comorbiditiesa
Ischemic heart disease 617 (13.1) 960 (14.4) 2359 (11.0) 577 (17.5) 1015 (18.5) 353 (19.0) 634 (19.5) 2579 (18.6)
Nephritis 442 (9.4) 767 (11.5) 1661 (7.8) 494 (15.0) 857 (15.6) 296 (15.9) 577 (17.7) 2224 (16.0)
Cardiovascular disease 358 (7.6) 575 (8.6) 1511 (7.1) 383 (11.6) 653 (11.9) 212 (11.4) 400 (12.3) 1648 (11.9)
Diabetes 1406 (29.9) 2172 (32.6) 6279 (29.3) 1218 (36.9) 2151 (39.2) 851 (45.8) 1407 (43.3) 5627 (40.5)
Chronic kidney disease 293 (6.2) 607 (9.1) 1104 (5.2) 322 (9.7) 583 (10.6) 206 (11.1) 407 (12.5) 1518 (10.9)
Heart failure 168 (3.6) 257 (3.9) 611 (2.9) 193 (5.8) 346 (6.3) 102 (5.5) 231 (7.1) 872 (6.3)
See text for abbreviations. aComorbid conditions defined by the presence of International Statistical Classification of Diseases and Related Health ProblemsNinth RevisionClinical Modifica-
tion codes during the 6-month period prior to study index date.

Official Journal of the American Society of Hypertension, Inc.


Overall, the proportion of patients taking concomi-
tant medications tended to remain unchanged or
slightly lower from baseline to follow-up. The propor-
tion of patients who took a concomitant ACE inhibitor
during the baseline period and the end of follow-up
was lowest for AML VAL (21.8% and 18.8%) fol-
lowed by AML OM (23.5% and 20.8%), the com-
bined LDC cohort (24.6% and 20.1%), and
AML BEN cohort (31.9% and 29.3%). Concomitant
diuretics declined slightly from baseline to follow-up
and were most frequent in the LDC cohort
(27.925.7%) followed by the AML BEN cohort
(24.022.1%), the AML VAL cohort (22.420.9%),
and the AML OM cohort (22.420.7%). a-Blocker use
was higher among patients taking ARB combinations
at baseline and follow-up: LDC cohort (7.3% and
6.5%), AML VAL (6.6% and 6.6%), and AML OM
cohort (5.8% and 5.8%), respectively. a-Blocker use in
the AML BEN cohort was 3.6% and 4.0% at baseline
and follow-up, respectively. Concomitant direct rennin
inhibitor use at baseline and follow-up was most com-
mon with the ARB FDCs, namely AML VAL (3.8%
and 4.1%) and AML OM (2.9% and 3.1%) and was
less frequent in the LDC cohort (1.1% and 1.0%) and
among AML BEN (0.3% and 0.6%).
Consistency in dosing was observed during the study
follow-up period. Patients prescribed AML OM,
AML VAL, or AML BEN exhibited a high degree of
consistency in that their initial dosage level (character-
ized as low, medium, or high) tended to (0.60 mm Hg, P<.01) cohort. The absolute rate of
remain unchanged among >70% of patients.
Table II details treatment comparisons of 1-year aver-
age BP changes, mean differences in SBP and DBP
changes between comparators, and JNC 7 goal attain-
ment rates for the entire sample. Patients in the
AML OM cohort experienced significantly greater
regression-adjusted reductions in SBP compared with all
other study groups. The mean regression-adjusted
difference in SBP change from baseline to follow-up was
significantly greater with AML OM compared
with AML VAL (1.14 mm Hg, P<.001), AML BEN
(1.03 mm Hg, P=.0283), and combined LDC
AML ARB (1.73 mm Hg, P<.001). Similarly, regres-
sion-adjusted mean differences in DBP were signifi-
cantly greater in the AML OM cohort compared with
all other study cohorts except AML BEN. The mean
regression-adjusted difference in DBP change from base-
line to follow-up was significantly greater in the
AML OM cohort by 0.61 mm Hg (P<.001) vs AML
VAL, and by 0.68 mm Hg (P<.001) vs the combined
LDC cohort. The absolute rate of JNC 7 BP goal attain-
ment over the 1-year follow-up was the highest in the
AML OM cohort (45.7%). Attainment of JNC 7 BP
goal was significantly less likely among patients treated
with AML VAL (odds ratio [OR]=0.86, P=.0004) and
the combined LDC cohort (OR=0.76, P<.0001).
A general consistency in dosing was observed from
index date to last follow-up date. Patients taking
AML OM, AML VAL, and AML BEN exhibited a
Official Journal of the American Society of Hypertension, Inc.
Comparative Effectiveness Analysis of Amlodipine | Ram et al.
high degree of consistency in that >70% of patients
had their initial dosage level maintained. For patients
taking LDC therapy, OM patients initially prescribed
medium or high dosages tended to end the observation
period at a lower dosage; 80% of LDC AML OM
patients who started at medium dosage finished at low
dosage, and 43.6% who started at high dosage
finished at medium dosage.
Table III presents mean differences in SBP and DBP
changes between comparators and JNC 7 goal attain-
ment rates for important subgroups. Among African
Americans, the mean regression-adjusted difference in
SBP change was significantly greater in the AML OM
cohort vs the AML VAL cohort (1.33 mm Hg, P=.04).
There were no statistically significant differences
between FDC AML OM and AML BEN and LDC
cohorts in terms of SBP change within this subgroup.
Among African Americans, patients prescribed AML -
VAL (OR=0.66, P<.01) and the combined LDC
cohort (OR=0.72, P=.03) were significantly less likely
to attain JNC 7 BP goal relative to patients prescribed
AML OM. Among diabetic patients, the mean regres-
sion-adjusted difference in SBP change was signifi-
cantly greater for patients in the AML OM cohort
relative to the AML VAL (1.23 mm Hg, P<.01) and
combined LDC AML ARB (0.94 mm Hg, P=.04)
cohorts. The mean regression-adjusted difference in
DBP change was significantly greater for patients in
the AML OM cohort relative to the AML VAL
JNC 7 goal attainment was lower by nearly 50%
among patients with diabetes relative to the overall
sample. Diabetic patients in the combined LDC
AML ARB cohort (OR=0.78, P<.01) were less likely
to attain JNC 7 BP goal relative to patients prescribed
AML OM.
For the subgroup of patients who were identified as
obese, the mean regression-adjusted difference in
SBP DBP change was significantly greater in the
AML OM cohort vs the AML VAL (1.49 0.68 mm Hg,
P<.01), AML BEN (2.01 1.10 mm Hg, P<.01), and
combined LDC AML ARB (1.57 0.50 mm Hg, P<.01
and P=.02, respectively) cohort. Among obese patients,
the likelihood of JNC 7 goal attainment was significantly
lower with AML VAL (OR=0.87, P=.03), AML BEN
(OR=0.78, P=.04), and the combined LDC cohort
(OR=0.79, P<.01) relative to patients taking
AML OM.
For the subgroup of patients who were identified as
overweight, the mean regression-adjusted difference
in SBP DBP change was significantly greater in the
AML OM cohort compared with the combined LDC
AML ARB cohort (2.05 0.89 mm Hg, P<.01). Rela-
tive to the AML OM cohort, patients in the LDC
AML ARB cohort were significantly less likely to
attain JNC 7 BP goal (OR=0.70, P<.01).
Among patients with CKD, the mean regression-
adjusted difference in SBP change was significantly
greater in the AML OM cohort compared with the
The Journal of Clinical Hypertension Vol 14 | No 9 | September 2012 605
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The Journal of Clinical Hypertension
TABLE II. Treatment Comparisons of 1-Year Average BP Changes and 1-Year JNC 7 Goal Attainment for All Patients in Study
Mean BP Decrease From Baseline 1-Y JNC 7 Goal Attainment

SBP DBP
Comparative Effectiveness Analysis of Amlodipine
|

Unadjusted Mean (SD) Regression-Adjusted Unadjusted Mean (SD) Regression-Adjusted

Difference
Decrease Diff in Change Decrease in Change
From Relative to From Relative to
Ram et al.

Baseline AML OM Baseline AML OM

Vol 14 | No 9 | September 2012

Odds Ratio
Mean Mean P At Relative to P
Index ARB, No. Baseline Decrease Mean 95% CI Mean P Value Baseline Decrease Mean 95% CI Mean Value Goal, % AML OM 95% CI Value
AML OM (4699) 158.14 (17.9) 20.15 (18.5) 18.91 18.3619.47 89.39 (13.3) 9.78 (11.2) 8.73 8.419.05 45.7
AML VAL (6673) 157.49 (17.7) 18.58 (18.4) 17.77 17.3218.21 1.14 <.0001 88.76 (13.2) 8.87 (10.6) 8.12 7.868.37 0.61 <.0001 41.6 0.86 0.790.93 .0004
AML BEN (21,435) 155.52 (16.7) 17.83 (17.7) 17.88 17.4118.34 1.03 .0283 88.22 (13.0) 8.58 (10.7) 8.24 7.978.51 0.49 .0740 45.2 0.93 0.791.09 .3655
LDC OM+AML (3305) 156.15 (17.2) 16.76 (18.5) 17.33 16.7017.95 1.58 <.0001 85.14 (12.7) 7.11 (10.3) 8.00 7.648.36 0.73 <.0001 38.9 0.77 0.690.85 <.0001
LDC VAL+AML (5481) 156.15 (17.0) 16.42 (18.3) 16.96 16.4717.44 1.95 <.0001 84.64 (12.7) 6.98 (10.3) 8.19 7.918.57 0.54 .0014 38.1 0.78 0.700.86 <.0001
LDC IRB+AML (1860) 156.08 (17.2) 16.32 (18.2) 17.21 16.4417.99 1.70 <.0001 83.85 (12.4) 6.45 (9.9) 8.05 7.608.50 0.68 .0019 36.1 0.78 0.680.88 .0001
LDC LOS+AML (3253) 155.63 (16.9) 15.31 (17.7) 16.48 15.8617.09 2.43 <.0001 84.05 (12.9) 6.43 (10.1) 7.92 7.578.28 0.81 <.0001 35.0 0.72 0.640.80 <.0001
AML OM (4699) 158.14 (17.9) 20.15 (18.5) 18.51 18.0718.91 89.39 (13.3) 9.78 (11.2) 8.07 7.838.32 45.7
Combined LDC (13,899) 156.02 (17.0) 16.23 (18.2) 16.78 16.5517.01 1.73 <.0001 84.52 (12.7) 6.81 (10.2) 7.39 7.267.52 0.68 <.0001 37.3 0.82 0.750.89 <.0001
See text for abbreviations.

Official Journal of the American Society of Hypertension, Inc.

 TABLE III. Blood Pressure Change and Goal Attainment in Important Subgroups
Baseline Regression-Adjusted Baseline Regression-Adjusted 1-Y JNC 7
Systolic Decrease From Diastolic Decrease From Goal Attainment
Baseline Systolic Baseline Diastolic

P Value Odds Ratio

Relative to Relative to

Official Journal of the American Society of Hypertension, Inc.

Race Drug Mean (SD) Mean 95% CI Mean (SD) Mean 95% CI Goal (%) AML OM AML OM P Value

African American AML OM (516) 158.98 (18.83) 17.25 14.1720.33 93.41 (13.15) 7.39 5.619.18 35.27
AML VAL (862) 157.76 (18.87) 15.92 12.9318.91 91.72 (12.92) 7.20 5.468.93 28.42 .0078 0.66 <.01
AML BEN (2513) 155.91 (17.31) 16.52 13.5619.49 91.28 (12.65) 7.49 5.779.21 33.78 .5161
Combined LDC 156.70 (18.32) 14.68 13.9615.39 88.72 (13.01) 7.49 7.097.89 26.02 .82 0.72 .033
Diabetes AML OM (1406) 154.42 (18.75) 18.32 15.3721.26 84.63 (13.02) 9.30 7.6011.01 21.55
AML VAL (2712) 154.12 (18.45) 17.10 14.1920.01 84.37 (12.69) 8.70 7.0110.38 19.89 .2061
AML BEN (6279) 151.71 (17.35) 17.79 14.8720.72 83.50 (12.21) 9.28 7.5910.98 21.79 .846
Combined LDC 152.82 (17.52) 13.60 13.2613.95 81.07 (12.26) 5.57 5.375.77 19.51 .84 0.78 <.01
Obese AML OM (2355) 156.62 (17.73) 19.04 16.1221.96 90.18 (12.99) 8.78 7.0810.47 42.38
AML VAL (3408) 155.91 (17.14) 17.66 14.7620.56 90.05 (13.04) 8.18 6.509.86 38.85 .0073 0.79 .03
AML BEN (10,145) 154.08 (16.31) 17.80 14.8820.73 89.67 (12.68) 8.23 6.549.93 41.79 .6049 0.78 .04
Combined LDC 154.56 (16.61) 15.36 15.0615.67 85.67 (12.56) 7.22 7.047.41 33.74 .02 0.79 <.01
Overweight AML OM (1221) 158.98 (17.70) 19.89 16.9222.86 88.57 (13.44) 9.65 7.9211.37 50.45
AML VAL (1675) 158.39 (17.49) 19.01 16.0721.94 87.31 (12.78) 8.96 7.2610.66 45.79 .0132
AML BEN (5558) 155.75 (16.29) 19.01 16.0721.95 86.98 (12.84) 9.24 7.5410.94 50.59 .9277
Combined LDC 156.72 (16.99) 17.88 17.4318.34 83.40 (12.62) 7.55 7.307.80 40.77 <.01 0.70 <.01
CKD AML OM (293) 156.07 (18.76) 20.19 16.9523.42 82.24 (14.72) 10.00 8.1211.87 25.60

The Journal of Clinical Hypertension

AML VAL (607) 154.92 (18.4) 18.10 15.0521.14 81.11 (13.10) 9.07 7.3010.83 24.38 .6924
AML BEN (1104) 152.24 (18.36) 18.79 15.8021.77 80.53 (12.99) 9.07 7.3410.80 28.08 .3979
Combined LDC 153.91 (18.10) 14.99 14.3315.66 80.02 (12.66) 5.77 5.396.16 23.45 .03 0.67 .03
Abbreviations: CI, confidence interval; SD, standard deviation. See text for all other abbreviations.
Comparative Effectiveness Analysis of Amlodipine
|

Vol 14 | No 9 | September 2012

Ram et al.

607
Comparative Effectiveness Analysis of Amlodipine | Ram et al.

tices in a community-based setting. All combinations

TABLE IV. Treatment Comparisons of JNC Goal
of ARBs and amlodipine studied were effective in low-
Attainment Rates for Patients Experiencing
ering BP and these reductions were sustained in the
Treatment Switching
study. Crude goal attainment rates ranged from
Patients Who Switched Treatments 35.0% for the AML LOS LDC cohort to 45.7% for
AML OM AML VAL AML BEN the AML OM cohort. Patients prescribed AML OM
attained significantly greater reductions in SBP com-
Switchers from monotherapy N=1538 N=2174 N=4317
pared with patients prescribed AML BEN, AML VAL,
(OM, VAL, AML) or FDC
and LDC therapy with AML ARBs, as well as signifi-
(OM HCTZ, VAL HCTZ)
cantly greater reductions in DBP compared with
not at goal at switcha
patients prescribed AML VAL and LDC AML ARB
JNC 7 goal attainment (post-switch) therapy. Compared with AML OM, patients pre-
Yes, % 49.15 46.73 48.23 scribed AML VAL and LDC AML ARB therapy were
No, % 50.85 53.27 51.77 significantly less likely to attain JNC 7 BP goal.
Odds ratio (95% confidence 0.94 0.86
These findings may have clinical relevance to hyper-
interval) of attaining goal (0.811.08) (0.740.99)
tensive patients and their providers. Incremental reduc-
relative to AML OM P=.37 P=.03
tions in SBP of between 2.0 mm Hg and 15 mm Hg
Switchers from n=324 n=551 n=560 have been reported to produce significant reductions in
LDC AML ARBb cardiovascular outcomes including myocardial infarc-
JNC 7 goal attainment (post-switch) tion, cardiovascular mortality, and stroke.20 Risk of
Yes, % 41.05 36.84 37.32 incident atrial fibrillation also increases with increasing
No, % 58.95 63.16 62.68 SBP. Patients with SBP >140 mm Hg account for
Odds ratio (95% confidence 0.85 0.85 >82% of the increase in incident atrial fibrillation.20
interval) of attaining goal (0.621.16) (0.601.20) In addition to various individual criteria, superior out-
relative to AML OM P=.30 P=.34 comes in terms of JNC 7 goal attainment may be con-
See text for abbreviations. Covariates for logistic regression models: sidered as a parameter in guiding treatment decisions.
treatment group propensity score, hydrochlorothiazide use, baseline The results in this study suggest that, at comparable
blood pressure, sex, age, race, body mass index (overweight, obese,
undetermined), comorbidities (IHD, nephritis, CVD, DM, CKD, CHF),
doses and baseline BP levels, treatment with FDC
baseline hypertensive medicine count, baseline dosage indicator therapy vs LDC therapy is associated with increased
(low, high). aPatients switching from monotherapy to combination likelihood for patients to attain JNC 7 goal. It was
therapy. bPatients switching from LDC therapy to combination
therapy. observed that in general, goal attainment rates and
reductions in SBP and DBP were greater in the FDC
therapy cohorts (AML OM, AML VAL, AML VAL)
AML VAL (2.41, P=.02) and combined LDC compared with the combined LDC cohort.
AML ARB cohorts (2.42 mm Hg, P=.01). Relative to Several studies have demonstrated that the benefits
the AML OM cohort, patients in the LDC AML ARB of FDCs in a single tablet are associated with greater
cohort were significantly less likely to attain JNC 7 BP adherence, superior BP outcomes, and lower health
goal (OR=0.67, P=.03). care costs compared wtih the corresponding free-drug
Table IV presents the treatment comparisons of components given separately. A recent meta-analysis
JNC 7 goal attainment rates for patients who were compared health care costs, adherence, and persistence
identified as being not at goal and switched from between groups of patients taking antihypertensives
monotherapy and LDC therapy to FDC therapy. as single-pill combinations (SPCs) with free-equiva-
Among monotherapy switchers, 1538 switched to lent components.21 Combined total annual hyperten-
AML OM, 2174 to AML VAL, and 4317 to AML sion-related and all-cause health care costs were
BEN. Monotherapy switchers to AML BEN had a nearly $1350 lower for SPC than for free-equivalent
lower likelihood (OR=0.86, P=0.03) of getting to JNC component groups, and both adherence and persis-
7 goal relative to AML OM. The likelihood of JNC 7 tence were greater for patients prescribed SPCs.
goal attainment for switchers from LDC was not sig- Another meta-analysis found that, compared with
nificantly different between AML OM and AML VAL free-drug combinations, FDCs of antihypertensive
or AML OM and AML BEN. agents were associated with a significant improvement
in compliance and with nonsignificant beneficial trends
DISCUSSION in BP and adverse effects.22
The primary objective of this study was to analyze the Bangalore and colleagues23 compared patient com-
comparative effectiveness of CCB (amlodipine) and pliance in 4 studies that involved FDC vs free-drug
ARB FDCs and LDCs in achieving BP reduction and components of the same antihypertensive regimen given
JNC 7 goal attainment using EMR data from real- separately. FDC (pooled relative risk, 0.76; 95% confi-
world clinical practice; while the EMR-derived data dence interval, 0.710.81; P<.0001) decreased the risk
are retrospective in nature with uneven baseline of medication noncompliance by 24% compared with
parameters, they reflect real-world therapeutic prac- LDC regimens (N=5750). Furthermore, improved

608 The Journal of Clinical Hypertension Vol 14 | No 9 | September 2012 Official Journal of the American Society of Hypertension, Inc.

adherence has been associated with a lower risk of car-
diovascular events. In a study of patients newly treated
with antihypertensive agents between 1999 and 2002
and followed-up for a 3-year period, it was found that
patients with low adherence were more likely to have
coronary disease, cerebrovascular events, and CHF
within the 3-year follow-up period.24
Subgroup Analyses
This study confirms previous findings that goal attain-
ment among African Americans, patients with diabetes
and CKD, and obese patients is more difficult than for
the general population.18 The results in the subgroups
mirror the differences seen in the overall sample; treat-
ment with AML OM was associated with higher rates
of JNC 7 goal attainment among African Americans
and obese and overweight patients, relative to AML
VAL and the combined LDC cohort. Statistically
significant differences were not observed between
treatment cohorts in diabetic and CKD subgroups.
The efficacy of the AML OM combination has been
well established in difficult-to-treat subpopulations
through prospective clinical trials, including African
Americans, diabetic hypertensive patients, and obese
patients.2527
Data from previous randomized clinical trials compar-
ing these ARBs suggest that OM and IRB offer the great-
est reduction in BP, followed by VAL and LOS.16,17 In a
previous, large (N=73,012) real-world retrospective
analysis that utilized EMR data representative of ambu-
latory patients over 13 months, Ram and colleagues
found that adjusting for covariates, overall BP reductions
with OM, and OM HCTZ were 1.88 0.86 mm Hg,
1.21 0.52 mm Hg, and 0.89 0.51 mm Hg greater than
for LOS and LOS HCTZ, VAL and VAL HCTZ,
and IRB and IRB HCTZ, respectively.18 Addition-
ally, mean differences were higher for monothera-
py: 2.43 1.16 mm Hg, 2.18 0.93 mm Hg, and 1.44
0.91 mm Hg, respectively (all P values <.0001).
In another analysis using medical charts (N=1293)
and claims data, Miller and associates concluded that
treatment with OM was associated with the highest
proportion of patients achieving JNC 7 goal relative to
VAL, LOS, and IRB.19 Additionally, an analysis that
utilized real-world, retrospective claims data from a
large, national managed care plan showed that during
an average follow-up of 2.5 years among patients with
newly initiated ARB therapy (N=65,579), treatment
with OM was associated with lower risk of cardiac
events and lower healthcare resource utilization vs
VAL, LOS, and IRB.28
EFFECT OF SWITCHING THE TREATMENT
Patients who were not at BP goal on monotherapy with
AML, OM, or OM HCTZ, and VAL or VAL HCTZ,
and switched to FDC therapy, were significantly more
likely to attain recommended BP goals when switched
to AML OM than to AML BEN. For switchers from
LDC therapy to FDC therapy, statistically significant
Official Journal of the American Society of Hypertension, Inc.
Comparative Effectiveness Analysis of Amlodipine | Ram et al.
differences were not observed between the three FDCs
therapies. These observations are in line with the find-
ings of the prospective, open-label, titrate-to-goal Blood
Pressure Control in All Subgroups With Hypertension
(BP-CRUSH) study, in which 999 patients with hyper-
tension uncontrolled on monotherapy were switched to
fixed-dose AML OM and uptitrated in terms of dose
and or addition of HCTZ as triple therapy.29 The
cumulative percentage of patients achieving seated sys-
tolic BP <140 mm Hg (<130 mm Hg for patients with
diabetes) by week 12 was 75.8% and by week 20 the
cumulative BP threshold of <140 90 mm Hg was
achieved by 90.3% of patients.
Study Limitations
Since our study employed a retrospective observational
design, patient assignment to treatment group was
dependent on clinical assessment by the individuals
physician. This was a study limitation due to differences
in the indications for the different ARBs. It was also
possible that a patient received an antihypertensive pre-
scription from another physician that was not recorded
in the EMR database. We employed propensity scoring
to minimize the selection bias inherent in retrospective
database studies. However, it is possible that some vari-
ables were not available for analysis and inclusion in the
propensity score calculation, and it is difficult to know
whether this may have impacted our studys results.
It is possible that certain comorbidities such as CKD
or diabetes may have been under-reported in the data-
base; furthermore, ICD-9-Clinical Modification codes
were solely used to identify these conditions, and bet-
ter sensitivity may have resulted from the use of labo-
ratory data (CKD) and or antidiabetic medication use
(diabetes). Additionally, information regarding race
was not always present, and other socioeconomic and
clinical patient characteristics, such as insurance type,
income, and duration of hypertension, were not
included in the analysis. In addition, since our study
was retrospective in nature, BP measurements were
not standardized and we cannot rule out measure-
ment error in our study. However, as reported in an
earlier study using the EMR database,18 it is unlikely
that these omissions or that BP measurement errors
systematically biased the findings in one treatment
cohort over another. Another limitation of these data is
the inability to extract meaningful safety information.
Details regarding prescription refills and medication
compliance and persistence were not available, but
given their similar tolerability profiles, compliance and
persistence between different ARBs would be expected
to be similar. Despite these limitations, this study has
considerable implications in terms of the real-world
data clinical practice trends.
CONCLUSIONS
Comparative effectiveness research, as carried out in
this study, provides a practical and cost-effective
way to complement randomized clinical trial data on
The Journal of Clinical Hypertension Vol 14 | No 9 | September 2012 609
Comparative Effectiveness Analysis of Amlodipine | Ram et al.
treatment of hypertension. In this way, the effect of
FDC and LDC therapy on BP reduction and goal
attainment has been compared in the real-life clinical
setting and provides an insight into treatment effec-
tiveness in traditionally hard-to-treat populations,
including African Americans, patients with diabetes,
overweight and obese patients, and patients with
CKD. A CCB ARB combination regimen has been
found to be a rational choice based on the comple-
mentary mechanisms of action of these two classes.
The finding that goal attainment rates and reductions
in SBP and DBP were, in general, numerically greater
in the FDC treatment groups compared with the LDC
groups indicates the potential benefits of improved
adherence using a FDC therapy such as AML and
OM. Given the potential long-term health benefits of
even modest improvements in BP control, consider-
ation of FDC therapy with the greatest real-world
effectiveness could play an important role in hyperten-
sion management, particularly in hard-to-treat patient
subgroups. Among the two ARB-based fixed-dose
options studied, AML OM demonstrated better goal
attainment in the subgroups of African Americans and
obese and overweight patients relative to AML VAL.
Finally, this studys findings highlight the value of
EMR databases in the evaluation of treatment-to-
guideline recommendations in primary care settings.
Acknowledgments and disclosures: CER & Outcomes writing support was
provided by Poornima Whomsley, PhD. This analytical research project was
supported by funds from Daiichi Sankyo USA. All authors declared no
competing interests.
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