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Background The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of
High Blood Pressure recommends that clinicians consider the use of multidrug therapy to increase likelihood of achieving blood
pressure goal. Little is known about recent patterns of combination antihypertensive therapy use in patients being initiated on
hypertension treatment.
Methods
We investigated combination antihypertensive therapy use in newly diagnosed hypertensive patients from the
Cardiovascular Research Network Hypertension Registry. Multivariable logistic regression was used to assess the relationship
between combination antihypertensive therapy and 12-month blood pressure control.
Results
Between 2002 and 2007, a total of 161,585 patients met criteria for incident hypertension and were initiated on
treatment. During the study period, an increasing proportion of patients were treated initially with combination rather than with
single-agent therapy (20.7% in 2002 compared with 35.8% in 2007, P b .001). This increase in combination therapy use was
more pronounced in patients with stage 2 hypertension, whose combination therapy use increased from 21.6% in 2002 to
44.5% in 2007. Nearly 90% of initial combination therapy was accounted for by 2 combinations, a thiazide and a potassiumsparing diuretic (47.6%) and a thiazide and an angiotensin-converting enzyme inhibitor (41.4%). After controlling for relevant
clinical factors, including subsequent intensification of treatment and medication adherence, combination therapy was
associated with increased odds of blood pressure control at 12 months (odds ratio compared with single-drug initial therapy
1.20; 95% CI 1.15-1.24, P b .001).
Conclusions Initial treatment of hypertension with combination therapy is increasingly common and is associated with
better long-term blood pressure control. (Am Heart J 2011;162:340-6.)
Methods
Definition of the hypertensive cohort
This study was conducted within the CVRN, a consortium of
research organizations affiliated with the Health Maintenance
Organization Research Network and sponsored by the National
Heart, Lung, and Blood Institute. The CVRN Hypertension
Registry includes all adult patients with hypertension at 3 large
integrated health care delivery systems, HealthPartners of
Minnesota, Kaiser Permanente Colorado, and Kaiser Permanente Northern California. The algorithm for entry into the
cohort has been described previously.8 Briefly, patients entered
into the registry upon meeting 1 of the following criteria: (1)
at least 2 consecutive elevated BP measurements (ie, 140 mm
Hg systolic and/or 90 mm Hg diastolic or 130/80 mm Hg in
the presence of diabetes mellitus or chronic kidney disease);
(2) 2 diagnostic codes for hypertension (International
Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes: 401.x to 405.x) recorded on separate
dates; (3) 1 diagnostic code for hypertension plus prescription
for an antihypertensive medication; or (4) 1 elevated BP
measurement plus 1 diagnostic code for hypertension.
The current analysis included 161,585 patients with incident
hypertension between 2002 and 2007 who were started on
therapy with antihypertensive medications. Incident hypertension was defined as having 1 year or longer health plan
membership with drug coverage before meeting hypertension
registry entry criteria, without a prior hypertension diagnosis,
and without prior pharmacy dispensing or claims filed for
antihypertensive medications. Individuals who qualified for
entry into the cohort but whose initial BP upon cohort entry was
normal (n = 16,038) or missing (n = 41,473) were excluded. We
excluded patients whose initial BP upon entry into the cohort
was normal to help ensure that the patients included in the
analysis did indeed have as-yet-untreated incident hypertension.
Only individuals with at least 180 days of health plan
membership with drug coverage after entry into the cohort
were included in the current analysis. Baseline BP was defined
as the BP closest to the date of entry into the cohort and could
include BP measurements up to 90 days before cohort entry
date. In addition, the 1.4% of patients prescribed 3 or medication classes as initial treatment for a new diagnosis of hypertension were not included in the analysis because these patients
may have prevalent rather than incident hypertension.
Byrd et al 341
Combination therapy
Combination antihypertensive therapy, the primary exposure of interest, was defined as treatment initiation with 2
antihypertensive medications for patients with incident hypertension. Treatment initiation was defined as the first prescription or set of prescriptions filled after entry in the hypertension
registry in patients without prior diagnosis of hypertension.
Initiation of medication was determined using pharmacy
dispensing data, which include all medications dispensed
from health plan outpatient pharmacies, or claims filed
for medications.
Statistical analysis
The BP levels, stage of hypertension, and treatment with
either combination or single-agent therapy as well as the
specific combination were described for patients with incident
hypertension being started on treatment during the study
period. Student's t and 2 tests were used to compare baseline
variables in patients treated with combination versus singleagent therapy. Multivariable logistic regression assessed demographic and clinical factors associated with initial combination antihypertensive drug therapy. The model included site of
care, gender, race, smoking status, year of entry into the
cohort, and comorbid compelling indications for particular
antihypertensive drug classes (eg, diabetes, myocardial infarction, heart failure, chronic kidney disease, or stroke). International Classification of Diseases, Ninth Revision, Clinical
Modification codes were used to define myocardial infarction
(410.), congestive heart failure (428.), and ischemic stroke
(433., 434., and 436). Diabetes mellitus was defined by the
following: (1) 2 outpatient diagnoses or 1 primary inpatient
discharge diagnosis of diabetes mellitus (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 mellitus, or (4) hemoglobin A1c value N7% or 2 fasting plasma
glucose values N7 mmol/L (126 mg/dL) on separate dates.
Chronic kidney disease was defined as 2 consecutive serum
creatinine values that yield estimated glomerular filtration
rates b60 mL/min when the Modification of Diet in Renal
Disease equation is applied or by an ICD-9-CM diagnostic code
for chronic kidney disease (codes 585.1-585.9). To assess the
association between combination therapy and BP control at
12 months, multivariable logistic regression models were
constructed adjusting for these variables, as well as BP stage
and combination antihypertensive agent use. Data from
patients who died or who were missing a BP measurement
within a 6-month window around the 12-month time point
were censored.
342 Byrd et al
Figure 1
Figure 2
manuscript, and its final contents. Funding for the study was
provided by the National Institutes of Health.
Results
Baseline characteristics of patients with
incident hypertension
Among 161,585 patients with incident hypertension
being initiated on therapy during the study period, there
was a decline in the proportion of individuals entering
the cohort with stage 2 hypertension (defined as initial
SBP 160 mm Hg or DBP 100 mm Hg), from 58.7% in
2002 to 40.0% in 2007 (P b .001) (Figure 1). There was a
corresponding decrease in SBP during the same period
from a mean SBP of 158.1 mm Hg for those entering the
cohort in 2002 to a mean of 152.3 mm Hg for those
entering in 2007 (Figure 2). The mean DBP for those
entering the cohort in 2002 was 91.3 mm Hg. By 2004,
the mean DBP decreased to 89.1 mm Hg, subsequently
increasing slightly to 89.6 mm Hg in 2007.
Initial combination therapy for incident hypertension
In both stage 1 and stage 2 hypertensive patients, the
proportion initially treated with 2 drugs increased from
2002 to 2007. This increase was larger in patients with
stage 2 hypertension. Among patients newly diagnosed
with stage 2 hypertension, the proportion initially treated
with 2 drugs rose from 21.6% in 2002 to 44.5% in 2007
(Figure 3). Nearly 90% of initial combination therapy was
accounted for by 2 combinations of classes. A combination of a thiazide and a potassium-sparing diuretic
accounted for 47.6% of initial combination therapy, and
a combination of a thiazide and an ACE inhibitor
Figure 3
Byrd et al 343
Discussion
The objectives of this study were to assess trends in the
use of combination versus single-agent therapy as initial
treatment for patients with incident hypertension and to
evaluate the use of combination therapy and BP control.
We found that initial therapy with 2 drugs for new-onset
hypertension was associated with better BP control at 12
months compared with single-agent therapy even after
adjusting for, among other factors, subsequent therapy
intensification and medication adherence. The association between 2-drug initial therapy for hypertension and
better 12-month BP control was found irrespective of use
344 Byrd et al
Table I. Characteristics of the cohort by type of initial antihypertensive therapy (single vs combination)
Characteristic
Single; n = 122662
Combination; n = 38923
55.8 13.5
29.9 6.5
153.6 14.7
89.1 12.1
55.1 12.9
30.5 6.6
156.8 15.7
91.8 12.1
b.001
b.001
b.001
b.001
62,738 (51.2)
20,348 (52.3)
b.001
8438
12299
15003
61282
25640
(6.9)
(10.0)
(12.2)
(50.0)
(20.9)
3068 (7.9)
3569 (9.2)
4213 (10.8)
18578 (47.7)
9495 (24.4)
b.001
68483 (55.8)
17990 (46.2)
b.001
500 (0.4)
267 (0.7)
b.001
1877 (1.5)
392 (1.0)
b.001
732 (0.6)
362 (0.9)
b.001
19287 (15.7)
3054 (7.9)
b.001
4924 (4.0)
0.78 0.28
1147 (3.0)
0.76 0.28
b.001
b.001
92008 (75.0)
24439 (19.9)
6215 (5.1)
29342 (75.4)
7633 (19.6)
1948 (5.0)
.33
76735 (62.6)
34042 (27.8)
11885 (9.7)
26383 (67.8)
9740 (25.0)
2800 (7.2)
b.001
Byrd et al 345
OR
95% CI
1.00
1.11
1.02
1.08
2.11
2.40
1.15
1.14
Reference
1.05-1.18
0.96-1.08
1.02-1.15
1.98-2.24
2.25-2.56
1.14-1.16
1.13-1.16
1.00
1.20
0.77
1.04
1.01
Reference
1.15-1.25
0.71-0.83
1.03-1.06
0.98-1.04
1.00
1.21
1.03
1.05
1.16
Reference
1.14-1.27
0.99-1.08
1.01-1.10
1.12-1.20
1.00
0.86
0.91
0.91
1.10
1.09
1.74
0.58
2.07
0.77
0.77
Reference
0.80-0.93
0.87-0.94
0.83-0.99
1.01-1.20
1.08-1.11
1.50-2.03
0.55-0.61
1.74-2.47
0.68-0.87
0.71-0.83
346 Byrd et al
Disclosures
Conflicts of Interest/Disclosure(s): P. M. H. serves as a
consultant for Wellpoint, Inc.
References
1. Chobanian AV, Bakris GL, Black HR, et al. Seventh Report of the Joint
National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure. Hypertension 2003;42:1206-52.
2. Black HR, Elliott WJ, Grandits G, et al. Principal results of the
Controlled Onset Verapamil Investigation of Cardiovascular End
Points (CONVINCE) trial. JAMA 2003;289:2073-82.
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