Initial Combination Therapy Reduces the Risk of
Cardiovascular Events in Hypertensive Patients
A Matched Cohort Study
Alan H. Gradman, Hélène Parisé, Patrick Lefebvre, Heather Falvey,
Marie-Hélène Lafeuille, Mei Sheng Duh
Downloaded from http://hyper.ahajournals.org/ by guest on July 28, 2017
Abstract—This study evaluated the effects of initial versus delayed treatment with a drug combination on blood pressure
(BP) control and the risk of cardiovascular (CV) events in hypertensive patients. Clinical trials suggest that the time to BP
control is an important determinant of long-term outcomes, but real-world evidence is scarce. Using electronic medical
charts (2005–2009), we retrospectively analyzed 1762 adult patients with BP elevation initiating combination therapy
matched 1:1 with similar patients initiating monotherapy and later switched to combination therapy. Incidence rate ratios
of CV events (myocardial infarction, stroke/transient ischemic attack, or hospitalization for heart failure) or all-cause death
and Kaplan-Meier analyses of time to BP control were compared between cohorts. Hazard ratios indicating the effects
of initial treatment on CV events and BP control were estimated using time-varying Cox proportional hazard models.
Initial combination therapy was associated with a significant reduction in the risk of CV events or death (incidence rate
ratio, 0.66 [95% confidence interval, 0.52–0.84]; P=0.0008). After 6 months of therapy, 40.3% and 32.6% of patients
with initial versus delayed combination treatment reached BP control, respectively. Achieving target BP was associated
with a statistically significant risk reduction of 23% for CV events or death (hazard ratio, 0.77 [95% confidence interval,
0.61–0.96]; P=0.0223); the residual effect of initial combination therapy did not reach statistical significance (hazard
ratio, 0.84 [95% confidence interval, 0.68–1.03]; P=0.0935). Initial combination therapy was associated with a significant
risk reduction of cardiovascular events. More rapid achievement of target BP was found to be the main contributor to the
estimated risk reduction. (Hypertension. 2013;61:309-318.)
Key Words: combination therapy ■ monotherapy ■ blood pressure goal attainment ■ cardiovascular events
■ matched cohort study ■ healthcare resource utilization ■ hypertension
C
varies, however, and the majority of patients including those
with stage 2 hypertension receive initial monotherapy.7,8
Clinical trials and observational studies indicate that
initiating treatment with a 2-drug combination results in
more rapid achievement of target BP compared with initial
monotherapy.9–12 Retrospective analysis of data from the
VALUE (Valsartan Antihypertensive Long-term Use
Evaluation) trial comparing valsartan- and amlodipine-based
antihypertensive treatment reported that early BP control
translated into a significant reduction in 5-year CV risk
regardless of drug assignment.13 Definitive studies have not
been conducted, however, and the most advantageous time
frame for achieving target BP in clinical practice has never
been defined. In this study, a retrospective analysis of electronic
medical charts was performed to evaluate the impact of initial
combination therapy on CV event rates and its relationship to
ardiovascular (CV) disease is the leading cause of mortality in the United States, accounting for 1.0 of every 2.9
deaths in 2007.1 Hypertension is one of the most important
risk factors for CV disease,2 with ≈54% of stroke and 47% of
ischemic heart disease worldwide attributable to high blood
pressure (BP) according to a 2008 International Society of
Hypertension report.3 It has been estimated that each increase
of 20 mm Hg in systolic BP (SBP) or 10 mm Hg in diastolic
BP (DBP) doubles the risk of CV death in individuals aged 40
to 69 years.4
Hypertension treatment guidelines recommend lowering BP
to <140/90 mm Hg or <130/80 mm Hg for patients with diabetes mellitus, chronic kidney disease (CKD), or other high risk
conditions.5 In the United States, only ≈50% of patients with
hypertension achieve BP <140/90 mm Hg.6 Among patients
requiring BP reduction of ≥20/10 mm Hg, initial combination therapy is recommended.5 Individual physician practice
Received July 6, 2012; first decision August 2, 2012; revision accepted October 27, 2012.
From the Temple University School of Medicine (Clinical Campus), Pittsburgh, PA (A.H.G.); Groupe d’analyse, Ltée, Montreal, Quebec, Canada (H.P.,
P.L., M.-H.L.); Novartis Pharma AG, Basel, Switzerland (H.F.); Analysis Group, Inc, Boston, MA (M.S.D.).
Parts of the work were presented as posters at the American Society of Hypertension 26th Annual Scientific Meeting and Exposition, New York, NY,
May 21–24, 2011.
Correspondence to Alan H. Gradman, Temple University School of Medicine (Clinical Campus), 1239 Shady Ave, Pittsburgh, PA 15232. E-mail
[email protected]
© 2012 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org
DOI:10.1161/HYPERTENSIONAHA.112.201566
309
310 Hypertension February 2013
BP reduction and goal attainment, as well as the impact on
healthcare resource use in a real-world, practice-based setting.
Methods
Data Source
Electronic medical chart data between January 2005 and November
2009 from a large integrated delivery network of physicians and
hospitals, all sharing a single laboratory, were used to conduct
the analysis. The database is de-identified and is in compliance
with the Health Insurance Portability and Accountability Act of
1996 to preserve patient anonymity and confidentiality. Data elements used in the present analysis included patient demographics,
inpatient and outpatient medical services, prescriptions, laboratory results, and clinical measures such as BP, height and weight,
and smoking status.
Study Design
Downloaded from http://hyper.ahajournals.org/ by guest on July 28, 2017
Adult patients with uncontrolled BP, newly initiated on antihypertensive therapy including angiotensin-converting enzyme inhibitors, calcium channel blockers, angiotensin II receptor blockers, or diuretics,
given as a single agent (monotherapy) or a drug combination, were
identified. The study population was stratified into the following mutually exclusive exposure groups: patients initiating combination therapy
for ≥60 days (combination therapy cohort) and patients initiating monotherapy for ≥60 days with the subsequent addition of a second agent
(add-on cohort). Combination therapy included a single-pill (fixeddose) combination or dual free combination of angiotensin-converting
enzyme inhibitor and calcium channel blocker, angiotensin-converting
enzyme inhibitor and diuretic, angiotensin II receptor blocker and calcium channel blocker, or angiotensin II receptor blocker and diuretic.
A baseline period of 90 days before treatment initiation was imposed
to evaluate baseline characteristics and to ascertain that patients had
uncontrolled BP, defined as ≥1 BP reading ≥140/90 mm Hg or ≥130/80
mm Hg for patients with diabetes mellitus or CKD.
We excluded from the analysis patients with history of CV event
at baseline (International Classification of Diseases, Ninth Revision,
Clinical Modification [ICD-9-CM] codes: 402.9x, 410.xx, 411.0x,
411.1x, 411.81, 411.89, 413.xx, 414.0x, 414.1x, 414.8x, 414.9x,
427.0x, 427.1x, 427.3x, 427.4x, 427.5x, 427.8x, 428.xx, 429.3x, and
430.xx-437.xx) to focus results on incident cases of CV events. Each
patient’s follow-up period spanned from their first antihypertensive
medication through the earliest of either treatment discontinuation or
end of data availability.
Study End Points
The study end points were risk of CV events or all-cause death, time
to BP goal attainment, and rates of healthcare resource use. Time to
BP goal attainment was defined as the time from treatment initiation
to the first of 2 consecutive target BP readings <140/90 mm Hg or
<130/80 mm Hg for patients with diabetes mellitus or CKD. The risk
of CV events or death was evaluated using the composite end point of
acute myocardial infarction (ICD-9-CM code: 410.xx), stroke/transient ischemic attack (TIA) (ICD-9-CM codes: 430.xx-435.xx), hospitalization for heart failure (ICD-9-CM code: 428.xx), and all-cause
death. Results were also reported for each CV end point separately.
Healthcare resource use was also calculated for both cohorts over the
follow-up period and stratified into 3 mutually exclusive components:
(1) urgent care services, which included hospitalizations and emergency room visits; (2) outpatient services; and (3) other services.
Statistical Analyses
To minimize the potential impact of confounding factors, we used
propensity score matching to assemble a population in which those
with initial and delayed treatment with a drug combination would
be demographically and clinically similar. The propensity score for
the receipt of combination therapy at treatment initiation is defined
as the conditional probability of initiating treatment with a drug
combination given a patient’s measured characteristics. Propensity
scores were calculated separately for each patient using a nonparsimonious multivariate logistic regression model, incorporating the
following baseline characteristics: age, sex, race, year of treatment
initiation, smoking status, concomitant medications (eg, antihyperlipidemics, antidiabetics, and nonsteroidal anti-inflammatory drugs),
comorbidities (eg, Charlson comorbidity index, anemia, CKD, diabetes, and obesity), clinical measures (ie, body mass index, BP, triglyceride, fasting plasma glucose, and cholesterol level), and healthcare
resource use. Patients initiating combination therapy were matched
1:1 with add-on patients based on their propensity score using a caliper of 5% and their BP stage.
Descriptive statistics were generated to summarize the baseline
characteristics of the studied population. Frequency counts and
percentages were used to summarize categorical variables, whereas means and SDs were used for continuous variables. Statistical
differences between matched cohorts were assessed using the
McNemar test (categorical variables) and paired 2-sided Student
t test (continuous variables). Kaplan-Meier analyses and log-rank
tests were performed to compare the time to BP goal attainment
among the 2 exposure groups and patients who developed a CV
event during the follow-up period versus those who did not, irrespective of exposure groups.
To assess the impact of initiating combination therapy on CV end
points and healthcare resource use, incidence rates of events were
calculated and compared between cohorts using incidence rate ratios
(IRRs). Incidence rate for each CV end point was calculated as the
number of patients with an event divided by the number of patientyears of observation, censored at the time of the first event, whereas
incidence rate for each resource use component was calculated as the
number of events divided by the number of patient-years of observation. Statistical differences between matched cohorts, as well as 95%
confidence intervals (CIs), were evaluated using conditional Poisson
regression models accounting for matched pairs. A sensitivity analysis excluding patients with diabetes mellitus or CKD at baseline was
also conducted.
In addition to univariate analyses, time-dependent multivariate
Cox proportional hazard models were estimated to assess the interrelationship between exposure groups, BP reduction and goal attainment, and the risk of developing a CV event. Three models were
fitted to assess the risk of CV events or all-cause death in which
a binary variable controlling for the exposure group was included
and patient BP status was inserted as a time-varying explanatory
variable. The time-dependent BP covariate was defined as follows:
(1; model 1) a binary variable indicating whether or not a patient
reached target BP during follow-up; (2; model 2) a categorical variable indicating the SBP and DBP stage at each BP reading; and
(3; model 3) a continuous variable indicating the value of the SBP
and DBP at each BP reading.
Statistical significance was assessed with a 2-sided test at α-level
≤0.05. All of the statistical analyses were conducted using SAS 9.2
(SAS Institute, Inc, Cary, NC).
Results
Baseline Characteristics of the Matched Cohorts
A total of 1808 patients initiating combination therapy and
3309 initiating monotherapy and subsequently switched to
combination therapy were identified. Among them, 1762
patients from the combination therapy cohort (97.5%) were
matched to an equal number of patients from the add-on cohort
to form the study population. Table 1 presents the baseline
characteristics of the matched cohorts. Overall, both exposure
groups were well matched in terms of age, sex, baseline BP
level and BP stage, concomitant medications, comorbidities,
and other health risk factors. Sixty-seven percent of patients
in each cohort had stage 1 and 33% stage 2 hypertension at
baseline. In the add-on cohort, the combination therapy was
prescribed at a median of 13.5 months after treatment initiation.
Gradman et al Combination Therapy, CV Events, and BP Control 311
Table 1. Baseline Characteristics of the Matched Cohorts
Characteristics
Combination Therapy (n=1762)
Add-On (n=1762)
P Value*
Treatment patterns
Follow-up, d, mean±SD
982±526
Time to switch, d, mean±SD [median]
1100±450
<0.0001
521±388 [412]
Year of treatment initiation, n (%)
2005
1010 (57.3%)
997 (56.6)
0.6500
2006
348 (19.8)
359 (20.4)
0.6272
2007
245 (13.9)
242 (13.7)
0.8840
2008
136 (7.7)
142 (8.1)
0.7043
2009
23 (1.3)
22 (1.2)
0.8527
Demographics†
Age, mean±SD
60.7±13.8
60.4±13.5
0.5587
Women, n (%)
975 (55.3)
1019 (57.8)
0.1239
1720 (97.6)
1707 (96.9)
0.1823
Analgesics, opioid
134 (7.6)
133 (7.5)
0.9466
β-Blockers
107 (6.1)
115 (6.5)
0.5575
Antihyperlipidemics
116 (6.6)
106 (6.0)
0.4658
89 (5.1)
111 (6.3)
0.0763
Antidiabetics
130 (7.4)
129 (7.3)
0.9423
Nonsteroidal anti-inflammatory drugs
118 (6.7)
121 (6.9)
0.8386
0.65±0.96
0.63±0.91
0.5366
90 (5.1)
91 (5.2)
0.9394
Chronic kidney disease, n (%)
161 (9.1)
177 (10.0)
0.3540
Diabetes mellitus, n (%)
564 (32.0)
544 (30.9)
0.4103
Gastroesophageal reflux disease, n (%)
224 (12.7)
220 (12.5)
0.8403
Hyperlipidemia (high cholesterol), n (%)
White, n (%)
Downloaded from http://hyper.ahajournals.org/ by guest on July 28, 2017
Baseline medication, n (%)‡
Antidepressants
Comorbidities‡
Deyo-Charlson comorbidity index, mean±SD
Anemia, n (%)
766 (43.5)
788 (44.7)
0.4326
Lupus, n (%)
5 (0.3)
4 (0.2)
0.7389
Obesity, n (%)
669 (38.0)
682 (38.7)
0.6585
14 (0.8)
12 (0.7)
0.6949
Systolic value, mean±SD
150.5±14.7
150.3±14.3
0.5591
Diastolic value, mean±SD
84.3±10.5
84.5±10.5
0.6592
Rheumatoid arthritis, n (%)
Blood pressure, mm Hg‡
Blood pressure stage, n (%)
At risk (130–139/80–89 mm Hg)
226 (12.8)
226 (12.8)
1.0000
Stage 1 (140–159/90–99 mm Hg)
952 (54.0)
952 (54.0)
1.0000
Stage 2 (≥160/100 mm Hg)
584 (33.1)
584 (33.1)
1.0000
Yes
145 (8.2)
159 (9.0)
0.4011
No
460 (26.1)
450 (25.5)
0.6935
1157 (65.7)
1153 (65.4)
0.8845
Obese: ≥30
613 (34.8)
613 (34.8)
1.0000
Overweight: 25-29
236 (13.4)
238 (13.5)
0.9213
77 (4.4)
82 (4.7)
0.6860
836 (47.4)
829 (47.0)
0.8154
Other health risk factors, n (%)‡
Smoking
Unknown
Body mass index, kg/m2
Normal: <25
Unknown
(Continued)
312 Hypertension February 2013
Table 1. (Continued)
Characteristics
Combination Therapy (n=1762)
Add-On (n=1762)
P Value*
Risky: <60
156 (8.9)
173 (9.8)
0.3190
Not risky: ≥60
617 (35.0)
652 (37.0)
0.2063
Unknown
989 (56.1)
937 (53.2)
0.0714
Yes: ≥110
372 (21.1)
357 (20.3)
0.5265
No: <110
410 (23.3)
458 (26.0)
0.0582
Unknown
980 (55.6)
947 (53.7)
0.2540
Elevated: ≥150
251 (14.2)
261 (14.8)
0.6264
Normal: <150
206 (11.7)
228 (12.9)
0.2566
1305 (74.1)
1273 (72.2)
0.2108
Yes
216 (12.3)
231 (13.1)
0.4398
No
253 (14.4)
277 (15.7)
0.2558
1293 (73.4)
1254 (71.2)
0.1316
eGFR, mL/min
Fasting glucose, mg/dL
Triglycerides, mg/dL
Unknown
Downloaded from http://hyper.ahajournals.org/ by guest on July 28, 2017
Elevated LDL (or total) cholesterol or low HDL
cholesterol§
Unknown
eGFR indicates estimated glomerular filtration rate; LDL, low-density lipoprotein. Data are n (%) unless otherwise specified.
*P value tested the null hypothesis that the distributions were the same between the 2 cohorts.
†Data were evaluated at treatment initiation.
‡Data were assessed during the 90-d baseline period.
§An elevated LDL (or total cholesterol) was defined as ≥160 mg/dL (or ≥240 mg/dL), whereas a low high-density lipoprotein was defined as <40 mg/dL in men
and <50 mg/dL in women.
Relationship Between Exposure Group and Risk of
CV Events
Incidence rates for CV events are presented in Figure 1.
Initiating combination therapy was associated with a significant risk reduction for CV events or all-cause death
compared with delayed treatment with a drug combination
All Patients
(1762 Patients in Each Cohort)
Incidence Rate*
(Combination Therapy
vs. Add-on)
(all patients: IRR, 0.66 [95% CI, 0.52–0.84], P=0.0008;
excluding patients with diabetes mellitus or CKD: IRR,
0.45 [95% CI, 0.29–0.69], P=0.0002). Of note, when evaluating each CV end point separately, the risk of developing
myocardial infarction, stroke/TIA, or hospitalization for
heart failure was consistently lower for the combination
P-Value†
IRR (95% CI)†
Acute Myocardial Infarction
0.45 vs. 0.99
0.19 (0.10 - 0.34)
Stroke/TIA
2.57 vs. 2.84
0.79 (0.59 - 1.06)
<.0001
0.1172
Hospitalization for Heart Failure
0.55 vs. 0.78
0.54 (0.31 - 0.95)
0.0311
Overall
3.34 vs. 4.10
0.62 (0.48 - 0.80)
0.0002
Overall (With Death)
3.58 vs. 4.28
0.66 (0.52 - 0.84)
0.0008
0.0002
Excluding Patients with Diabetes or CKD
(803 Patients in Each Cohort)
Acute Myocardial Infarction
0.24 vs. 0.68
0.12 (0.04 - 0.37)
Stroke/TIA
1.89 vs. 2.58
0.55 (0.33 - 0.91)
0.0200
Hospitalization for Heart Failure
0.34 vs. 0.63
0.41 (0.15 - 1.14)
0.0875
Overall
2.39 vs. 3.55
0.44 (0.28 - 0.68)
0.0002
Overall (With Death)
2.49 vs. 3.68
0.45 (0.29 - 0.69)
0.0002
0
0.25
0.5
0.75
Combination Therapy
Better
1.00
1.25
Add-on
Better
IRR=incidence rate ratio; CI=confidence interval; TIA=transient ischemic attack; CKD=chronic kidney disease.
* Number of patients with an event per 100 person-year.
† Statistical differences between exposure groups, as well as CIs, were calculated using conditional Poisson regressions adjusting for matched pairs.
Figure 1. Incidence rates and incidence rate ratios of cardiovascular (CV) events
Gradman et al Combination Therapy, CV Events, and BP Control 313
therapy cohort compared with the add-on cohort (not reaching statistical significance for stroke/TIA when analyzing
all of the patients and hospitalization for heart failure when
analyzing the subset of patients without diabetes mellitus
or CKD.
60.3%). Half of the patients in the combination therapy group
reached BP goal attainment by 6.0 months, whereas patients
in the add-on group required 8.3 months to achieve the same
result (log-rank P=0.0047; Figure 2B).
Relationship Between BP Goal Attainment and Risk
of CV Events
Relationship Between Exposure Group and BP Goal
Attainment
% of Patients Reaching Target BP
A
100%
90%
80%
70%
60%
Log-Rank P = 0.0040
50%
40%
30%
20%
10%
0%
0
3
6
9
12
15
18
21
24
27
30
33
36
Figure 2. A, Kaplan-Meier estimates of achieving
target blood pressure (BP) for each exposure
group for all patients. B, Kaplan-Meier estimates
of achieving target BP for each exposure group,
excluding patients with diabetes mellitus or
chronic kidney disease (CKD).
Time in Months
Combination Therapy
B
% of Patients Reaching Target BP
Downloaded from http://hyper.ahajournals.org/ by guest on July 28, 2017
Figure 3 presents the Kaplan-Meier estimates of target BP
achievement for patients who developed a CV event during the study versus those who did not among all of the
patients and the subset of patients without diabetes mellitus or CKD at baseline. The results of this analysis demonstrated that BP goal attainment was associated with reduced
risk of CV events regardless of the diabetes mellitus/CKD
status at baseline. More specifically, a larger proportion of
patients achieving target BP was found among patients without a CV event relative to patients with a CV event during
the follow-up period (all patients: 3 months, 24.1% versus
20.8%; 6 months, 37.0% versus 30.7%; 12 months, 54.0%
versus 46.0%; excluding patients with diabetes mellitus or
CKD: 3 months, 31.5% versus 24.8%; 6 months, 45.1%
Kaplan-Meier estimates of target BP achievement for each
exposure group are shown in Figure 2. During follow-up, the
overall proportion of patients achieving target BP was consistently higher in the combination therapy cohort compared with
the add-on cohort (3 months, 27.9% versus 19.6%; 6 months,
40.3% versus 32.6%; 12 months, 56.1% versus 50.6%), resulting in significantly shorter median time to achievement of target
BP (9.7 versus 11.9 months; log-rank P=0.0040; Figure 2A).
Similarly, when excluding patients with diabetes mellitus
or CKD at baseline, initial versus delayed treatment with
combination therapy was associated with significantly higher
rates of BP goal achievement (3 months, 38.2% versus 23.7%;
6 months, 49.7% versus 39.6%; 12 months, 66.5% versus
Add-on
100%
90%
80%
70%
60%
Log-Rank P = 0.0047
50%
40%
30%
20%
10%
0%
0
3
6
9
12
15
18
21
24
27
Time in Months
Combination Therapy
Add-on
30
33
36
314 Hypertension February 2013
A 100%
% of Patients Reaching Target BP
90%
80%
70%
Log-Rank P = 0.0011
60%
50%
40%
30%
20%
10%
0%
0
3
6
9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60
Time in Months
Without CV Event
With CV Event
100%
90%
% of Patients Reaching Target BP
Downloaded from http://hyper.ahajournals.org/ by guest on July 28, 2017
B
Figure 3. A, Kaplan-Meier estimates of achieving
target blood pressure (BP) for patients with and
without a cardiovascular (CV) event during the
follow-up for all patients. B, Kaplan-Meier estimates
of achieving target BP for patients with and without
a CV event during the follow-up, excluding patients
with diabetes mellitus or CKD.
80%
70%
Log-Rank P = 0.0067
60%
50%
40%
30%
20%
10%
0%
0
3
6
9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60
Time in Months
Without CV Event
With CV Event
versus 39.1%; 12 months, 64.2% versus 52.2%). Median time
to target BP achievement was shorter in event-free patients
(all patients, 10.6 versus 15.8 months, log-rank P=0.0011;
excluding patients with diabetes mellitus or CKD, 7.0 versus
10.7 months, log-rank P=0.0067).
Interrelationship Among Exposure Group, BP Goal
Attainment, and CV Events
The results of the time-dependent multivariate Cox models are
presented in Table 2 on the overall study population. According
to model 1, achieving target BP after treatment initiation was
associated with a statistically significant risk reduction of
23% for CV events or all-cause death (hazard ratio [HR], 0.77
[95% CI, 0.61–0.96]; P=0.0223). In model 2, where each BP
assessment was used to update the SBP and DBP stage during
the follow-up, the results indicated that an SBP >160 mm Hg
at the last reading was associated with a 2.2-fold increased
risk of developing a CV event or death compared with an SBP
reading of 120 to 139 mm Hg (HR, 2.19 [95% CI, 1.55–3.09];
P<0.0001). Furthermore, in model 3, where each BP reading
was used to update the SBP and DBP levels during the followup, we estimated that each increase of 1 mm Hg in SBP was
associated with a 2% increased risk of having an event (HR,
1.02 [95% CI, 1.01–1.03]; P<0.0001). Of note, as illustrated
by model 2, a DBP <80 mm Hg was independently associated
with an ≈2-fold increased risk of CV event or death relative
to a DBP of 80 to 89 mm Hg (HR, 1.88 [95% CI, 1.48–2.40]
P<0.0001).
Finally, after controlling for the time-varying BP goal attainment, initial treatment with a drug combination was associated with a residual risk reduction of 16% which approached
but did not reach statistical significance at the 5% level (model
1: HR, 0.84 [95% CI, 0.68–1.03]; P=0.0935).
Relationship Between Exposure Group and
Healthcare Resource Use
The impact of initial relative to delayed treatment with combination therapy on the rates of healthcare resource use is
illustrated in Figure 4. Overall, patients of the combination
therapy cohort had a significant reduction of 9% in all services compared with patients in the add-on cohort (IRR, 0.91
[95% CI, 0.90–0.92]; P<0.001). Each individual component
reached statistical significance in favor of the combination
therapy group (urgent care services: IRR, 0.88 [95% CI,
Gradman et al Combination Therapy, CV Events, and BP Control 315
Table 2. Impact of Exposure Group and Blood Pressure on the Risk of CV Events or All-Cause Death
Model Specification*
Estimate
Hazard Ratio (95% CI)
P Value
Model 1
Achieving target BP
Exposure group: combination therapy relative to add-on
−0.2653
0.77 (0.61–0.96)
0.0223
−0.1781
0.84 (0.68–1.03)
0.0935
0.0467
1.05 (0.76–1.45)
0.7761
Model 2
Systolic BP stage, mm Hg†
Normal (<120)
Prehypertension (120–139)
Reference
Stage 1 (140–159)
0.3401
1.41 (1.09–1.80)
0.0076
Stage 2 (≥160)
0.7833
2.19 (1.55–3.09)
<0.0001
0.6322
1.88 (1.48–2.40)
<0.0001
Diastolic BP stage, mm Hg†
Normal (<80)
Prehypertension (80–89)
Reference
Stage 1 (90–99)
−0.1865
Downloaded from http://hyper.ahajournals.org/ by guest on July 28, 2017
Stage 2 (≥100)
0.83 (0.54–1.27)
0.3946
−0.5000
0.61 (0.24–1.53)
0.2903
−0.2011
0.82 (0.66–1.01)
0.0568
Systolic
0.0206
1.02 (1.01–1.03)
<0.0001
Diastolic
−0.0407
0.96 (0.95–0.97)
<0.0001
−0.1872
0.83 (0.67–1.02)
0.0760
Exposure group: combination therapy relative to add-on
Model 3
Blood pressure, mm Hg†
Exposure group: combination therapy relative to add-on
CI indicates confidence interval; BP, blood pressure; CV, cardiovascular.
*Data are shown using time-dependent multivariate Cox proportional hazard models adjusting for matched pairs.
†Patient BP status was updated at the time of each BP reading.
Discussion
0.81–0.96], P=0.0022; outpatient services: IRR, 0.93 [95%
CI, 0.91–0.94], P<0.001; other services: IRR, 0.91 [95% CI,
0.90–0.91], P<0.001). Similar findings were obtained when
excluding patients with diabetes mellitus or CKD at baseline
(all services: IRR, 0.90 [95% CI, 0.89–0.91]; P<0.001).
Incidence Rate*
(Combination Therapy
vs. Add-on)
Based on real-world data, this large, retrospective, matched
cohort study was specifically designed to assess the impact of
initial versus delayed combination therapy on the risk of developing a CV event and to evaluate the interrelationship among
IRR (95% CI)†
P-Value†
All Patients
(1762 Patients in Each Cohort)
Urgent Care‡
0.25 vs. 0.28
0.88 (0.81 - 0.96)
0.0022
Outpatient Services
8.26 vs. 9.03
0.93 (0.91 - 0.94)
<.0001
Other Services
18.11 vs. 20.19
0.91 (0.90 - 0.91)
<.0001
All Services
26.62 vs. 29.50
0.91 (0.90 - 0.92)
<.0001
Excluding Patients with Diabetes or CKD
(803 Patients in Each Cohort)
Urgent Care‡
0.21 vs. 0.24
0.93 (0.81 - 1.06)
0.2777
Outpatient Services
7.60 vs. 8.34
0.93 (0.91 - 0.95)
<.0001
Other Services
15.43 vs. 18.02
0.89 (0.87 - 0.90)
<.0001
All Services
23.24 vs. 26.60
0.90 (0.89 - 0.91)
<.0001
0.75
IRR=incidence rate ratio; CI=confidence interval.
0.85
0.95
Combination Therapy
Better
* Number of events per person-year.
1.05
1.15
Add-on
Better
† Statistical differences between exposure groups, as well as CIs, were calculated using conditional Poisson regressions adjusting for matched pairs.
‡ Urgent care included hospitalizations and emergency-room visits.
Figure 4. Incidence rates and incidence rate ratios of healthcare resource use.
1.25
316 Hypertension February 2013
Downloaded from http://hyper.ahajournals.org/ by guest on July 28, 2017
BP reduction, goal attainment, and CV risk. The underlying
questions are critical for physicians treating patients with
hypertension. Although initial combination therapy accelerates the time course over which BP control is achieved, the
clinical value of this approach in terms of CV outcomes has
not been established. Although the VALUE data suggest that
BP control within 6 months of treatment initiation improves
long-term outcomes, the use of initial combination treatment
was not addressed in this study in which all of the patients
were initially treated with a single agent.13
Our results indicate that initial treatment with a drug combination was associated with a 34% risk reduction for CV
events or death relative to patients initiated on monotherapy
and subsequently switched to combination treatment by their
treating physician. Significant risk reductions were found for
2 individual components of the primary end point, myocardial
infarction and hospitalization for heart failure. The estimated
risk reduction of 21% for stroke/TIA did not reach statistical significance as an individual end point. This result might
be considered surprising given the evidence that stroke/TIA
is more BP sensitive than are coronary events. It could perhaps be explained by our strict definition of stroke/TIA (ICD9-CM codes: 430.xx-435.xx), which excluded individuals
with poorly characterized neurologic events and, hence, may
not have captured all of the events.
As anticipated, initial combination therapy was associated with more rapid and more effective BP control. During
follow-up, the proportion of patients achieving target BP was
consistently higher in the combination therapy cohort, and the
median time to achievement of target BP was significantly
reduced (9.7 versus 11.9 months; log-rank P =0.0040). These
findings are consistent with previous studies that document a
lag time in BP goal attainment in patients who are initiated
on monotherapy and later up-titrated to combination treatment.9,12,14–16 The length of this lag time is variable and is highly
dependent on the time course of drug titration. In this study,
in which treatment decisions were made by individual physicians rather than a research protocol, up-titration occurred
at an average of 13.5 months after treatment initiation. In
part, this lag time may reflect therapeutic inertia, although
our results also suggest that the use of a sequential monotherapy strategy was common among treating physicians. In
the add-on cohort, ≈40% of patients received ≥2 classes of
antihypertensive monotherapy before being switched to a drug
combination.
To assess the extent to which the observed difference in BP
goal attainment explained the CV risk reduction associated
with initial combination therapy, we fitted 3 time-dependent
Cox models to control for both the treatment exposure and
time-varying BP level. The results of this analysis indicate
that BP goal achievement after treatment initiation was associated with a statistically significant risk reduction of 23% for
CV events or all-cause death. After controlling for the timevarying target BP achievement status, initial treatment with a
combination was associated with a residual risk reduction of
16%, a finding that approached but did not reach statistical
significance (P=0.0935).
The explanation for the residual risk reduction, apparently
unrelated to BP control, is, to a large extent, speculative.
Indeed, it is possible that the entire benefit of initial combination therapy is, in fact, related to its effects on BP. The BP data
used in this study consisted only of recorded clinic BP measurements obtained at variable times, including days of office
visits scheduled after an adjustment of treatment regimens.
More sophisticated analyses of BP treatment effects including
rigorous ascertainment of trough BP, 24-hour ambulatory BP
monitoring, or home BP measurement might have provided
a more comprehensive and hence more accurate depiction
of on-treatment differences in BP parameters. Alternatively,
simultaneous administration of 2 agents with complimentary
pharmacological mechanisms could, theoretically, result in
synergistic effects through unknown mechanisms. Because
this study did not look independently at the different antihypertensive classes, it was not possible to determine whether
any drug class or combination of drug classes conferred benefits above and beyond BP reduction. Such potential drugspecific effects could serve as an explanation regarding the
reduced risk of hospitalization for heart failure observed in
the cohort receiving initial combination treatment. Additional
research is warranted to address these questions.
This study fills an important gap in the literature by examining the interrelationship among initial treatment with combination therapy, BP control, and CV events. A study assessing
whether, compared with antihypertensive monotherapy, a
combination of antihypertensive drugs provides greater CV
protection in a community practice setting has been published
recently by Corrao et al.7 In their case–control study, hypertensive patients who did and did not experience CV end points
were compared. Patients initiated on combination therapy had
an 11% CV risk reduction compared with those begun on a
single agent. In patients maintained on either monotherapy or
combination treatment for the entire follow-up period, combination therapy was associated with a 26% reduction of CV
risk. Patients who were initiated on monotherapy and subsequently switched to a combination were statistically indistinguishable from those who received long-term monotherapy
with regard to CV event rates.
Our study confirms these findings while addressing several important limitations. Although the authors performed
some statistical adjustments, their results were based on data
obtained from 2 very distinct patient populations, those who
did and did not experience CV events. In the present study,
we were able to directly control for potential confounding
factors affecting these 2 cohorts through propensity score
matching. Also, in the study by Corrao et al,7 no BP data were
reported, making it impossible for the authors to explore the
factors, including differences in on-treatment BP, which may
have accounted for the observed CV risk reduction in patients
receiving combination therapy. In the present study, 3 statistical models were used to assess the interrelationship among
exposure groups, BP goal attainment, and the risk of developing a CV event. As noted above, the results indicate that most,
but not all, of the beneficial effects of combination therapy are
related to more rapid BP control.
Another important finding of our study is the independent
increased CV risk associated with a low DBP. Thus, a DBP <80
mm Hg was associated with an ≈2-fold increased risk of a CV
event or death relative to a DBP between 80 and 89 mm Hg
Gradman et al Combination Therapy, CV Events, and BP Control 317
Downloaded from http://hyper.ahajournals.org/ by guest on July 28, 2017
(P<0.0001) after controlling for the SBP level. This finding
supports previous studies that have reported a J-shaped relationship between DBP and CV disease risk, with DBP <70 mm Hg
being acknowledged as a contributor to an increased CV disease risk.17–19 However, it is important to note that the current
study did not assess the numerical value below which a J-curve
is evident and, therefore, cannot determine whether values substantially below a DBP of 80 mm Hg are primarily responsible
for the observed increase in CV risk.
In addition, in this study, initiating combination therapy
also appeared to be effective in reducing healthcare resource
use. Patients whose physicians delayed the use of combination
treatment required more healthcare resource use per year in all
of the individual service components (emergency room visits
and hospitalizations, outpatient visits, and other services).
Although recent studies have questioned the use of lower BP
targets in patients with diabetes mellitus or CKD, the current
study used 130/80 mm Hg as the target BP for these patients.
A sensitivity analysis excluding patients with diabetes mellitus or CKD demonstrated that initial relative to delayed combination therapy resulted in a greater reduction in overall CV
events compared with the entire cohort. These results suggest
that the use of a lower BP target for patients with CKD or diabetes mellitus may have underestimated the impact of initial
combination treatment and expedited BP lowering.
Lastly, this study compared patients who initiated combination therapy versus those who initiated monotherapy but
later required combination treatment. As a group, the monotherapy cohort exhibited the same clinical characteristics that
had prompted other physicians to initiate combination treatment. In these patients, initial combination treatment was
associated with more rapid BP goal achievement and fewer
CV end points. Patients who initiated monotherapy but never
required combination therapy were not studied (n=4696).
Our results, therefore, do not provide evidence that initial
combination therapy is preferable for all of the patients.
Rather, the data indicate that combination therapy should
be initiated in all of the patients likely to require multiple
agents to reach goal BP. Although physicians cannot know
for certain which patients will require combination therapy,
it can be predicted with reasonable certainty. Overall, ≈75%
of patients require multiple drugs using current treatment
guidelines. Patients with stage 2 hypertension and those with
hypertension in the clinical setting of diabetes mellitus, obesity, or chronic renal disease, who constituted the bulk of our
study population, have a very high likelihood of requiring
multiple agents. The results of the current study support the
routine use of initial combination treatment in patients with
these characteristics. It is noteworthy that the mean baseline BP in the study population was ≈150/85 mm Hg and two
thirds had stage 1 hypertension.
Limitations
Limitations of this study include the use of electronic medical
charts that may contain inaccuracies in coding or omissions,
and patient visits that might have occurred outside of the data
vendor delivery network are not captured. Also, physician prescriptions may not reflect a patient’s actual compliance. To
assess BP control, the study required that patients had ≥ 1 visit
before and after treatment initiation. This requirement may
have resulted in the inclusion of patients who sought health
services more intensively and were potentially more closely
managed for their hypertension.
In addition, the identification of hypertensive patients relied
on a single elevated BP reading measured during the 3-month
baseline period, which is not a definitive standard for diagnosing hypertension. However, patients were also required to
initiate antihypertensive therapy, reducing the likelihood of
including nonhypertensive patients in the study population.
Another limitation of this study is the fact that patients who
remained on monotherapy throughout the follow-up period
were not analyzed. Therefore, as stated above, it is not possible to determine from this study whether initial combination
therapy is beneficial for all patients.
Finally, despite efforts made to control for a comprehensive
selection of baseline demographics and clinical characteristics in the matching algorithm, there may have been residual
confounding effects from factors that could not be observed in
the database and may have explained the physician’s choice
of initial treatment. Nevertheless, large observational studies, well designed and with appropriate statistical techniques
adjusting for potential confounding factors through matching
techniques, can provide valuable information with real-life
scenarios and high generalizability.
Perspectives
Results of the current real-world study suggest that early
versus delayed combination treatment is advantageous in
decreasing the risk of CV events in most patients with hypertension and that this effect occurs primarily through greater
BP reduction and more rapid achievement of goal BP. Initial
relative to subsequent treatment with combination therapy
was also associated with a significant reduction in healthcare
resource use. It is noteworthy that these results were obtained
in a patient population consisting largely of patients with
stage 1 hypertension in whom initial combination therapy is
not routinely recommended. Although these retrospective data
cannot be a sufficient basis for changing treatment guidelines,
they strongly suggest that the routine use of initial combination therapy is a superior treatment strategy for a large segment of the hypertensive population, including many patients
with relatively mild hypertension. The only apparent downside relates to patients with low diastolic BP in whom overly
aggressive BP reduction may be deleterious.
Source of Funding
This research was funded by Novartis Pharma AG, Basel, Switzerland.
Disclosures
Four of the authors (Ms Parise, Ms Lafeuille, Mr Lefebvre, and
Dr Duh) are employees of Analysis Group, Inc, a consulting company that has received research grants from Novartis Pharma AG.
Ms Falvey is an employee of Novartis Pharma AG. Dr Gradman has received research grants from Novartis Pharma AG, Basel, Switzerland.
References
1.Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke
statistics–2011 update: a report from the American Heart Association.
Circulation. 2011;123:e18–e209.
318 Hypertension February 2013
Downloaded from http://hyper.ahajournals.org/ by guest on July 28, 2017
2. Hobbs, Richard FD. Can combining different risk interventions into a single formulation contribute to improved cardiovascular disease risk reduction? The single pill of amlodipine/atorvastatin. Vasc Health Risk Manag.
2007;3:711–719.
3. Hoorn SV, Rodgers A. Global burden of blood-pressure-related disease,
2001. Lancet. 2008; 371:1513–1518.
4.Lewington S, Clarke R, Qizilbash N, Peto R, Collins R; Prospective
Studies Collaboration. Age-specific relevance of usual blood pressure
to vascular mortality: a meta-analysis of individual data for one million
adults in 61 prospective studies. Lancet. 2002;360:1903–1913.
5. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr,
Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ; Joint National
Committee on Prevention, Detection, Evaluation, and Treatment of High
Blood Pressure. National Heart, Lung, and Blood Institute; National High
Blood Pressure Education Program Coordinating Committee. Seventh report
of the Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure. Hypertension. 2003;42:1206–1252.
6. Egan BM, Zhao Y, Axon RN. US trends in prevalence, awareness, treatment,
and control of hypertension, 1988-2008. JAMA. 2010;303:2043–2050.
7. Corrao G, Nicotra F, Parodi A, Zambon A, Heiman F, Merlino L, Fortino
I, Cesana G, Mancia G. Cardiovascular protection by initial and subsequent combination of antihypertensive drugs in daily life practice.
Hypertension. 2011;58:566–572.
8. Weycker D, Edelsberg J, Vincze G, Levy DG, Kartashov A, Oster G.
Blood pressure control in patients initiating antihypertensive therapy. Ann
Pharmacother. 2008;42:169–176.
9. Brown MJ, McInnes GT, Papst CC, Zhang J, MacDonald TM. Aliskiren
and the calcium channel blocker amlodipine combination as an initial
treatment strategy for hypertension control (ACCELERATE): a randomised, parallel-group trial. Lancet. 2011;377:312–320.
10. Gradman AH, Basile JN, Carter BL, Bakris GL; American Society of
Hypertension Writing Group. Combination therapy in hypertension. J Am
Soc Hypertens. 2010;4:42–50.
11. Weir MR, Levy D, Crikelair N, Rocha R, Meng X, Glazer R. Time to
achieve blood-pressure goal: influence of dose of valsartan monotherapy and valsartan and hydrochlorothiazide combination therapy. Am J
Hypertens. 2007;20:807–815.
12.Zannad F. Managing hypertension: a question of STRATHE. J Hum
Hypertens. 2005;19(suppl 1):S3–S7.
13. Weber MA, Julius S, Kjeldsen SE, Brunner HR, Ekman S, Hansson L,
Hua T, Laragh JH, McInnes GT, Mitchell L, Plat F, Schork MA, Smith
B, Zanchetti A. Blood pressure dependent and independent effects of
antihypertensive treatment on clinical events in the VALUE Trial. Lancet.
2004;363:2049–2051.
14. Mancia G, Parati G, Bilo G, Choi J, Kilama MO, Ruilope LM; TALENT
Investigators. Blood pressure control by the nifedipine GITS-telmisartan
combination in patients at high cardiovascular risk: the TALENT study.
J Hypertens. 2011;29:600–609.
15.Feldman RD, Zou GY, Vandervoort MK, Wong CJ, Nelson SA,
Feagan BG. A simplified approach to the treatment of uncomplicated
hypertension: a cluster randomized, controlled trial. Hypertension.
2009;53:646–653.
16. Byrd JB, Zeng C, Tavel HM, Magid DJ, O’Connor PJ, Margolis KL,
Selby JV, Ho PM. Combination therapy as initial treatment for newly
diagnosed hypertension. Am Heart J. 2011;162:340–346.
17. Franklin SS, Lopez VA, Wong ND, Mitchell GF, Larson MG, Vasan RS,
Levy D. Single versus combined blood pressure components and risk
for cardiovascular disease: the Framingham Heart Study. Circulation.
2009;119:243–250.
18. Anderson RJ, Bahn GD, Moritz TE, Kaufman D, Abraira C, Duckworth
W; VADT Study Group. Blood pressure and cardiovascular disease
risk in the Veterans Affairs Diabetes Trial. Diabetes Care. 2011;34:
34–38.
19. Somes GW, Pahor M, Shorr RI, Cushman WC, Applegate WB. The role of
diastolic blood pressure when treating isolated systolic hypertension. Arch
Intern Med. 1999;159:2004–2009.
Novelty and Significance
What Is New?
This was the first study evaluating the comparative effectiveness of initial
versus delayed combination therapy on (1) CV event rates and its relationship to BP reduction and goal attainment and (2) healthcare resource use
using real-world data.
● Matched design ensured balanced characteristics between study cohorts.
●
What Is Relevant?
Initial combination therapy significantly increased the magnitude of BP reduction
and reduced the median time required to achieve BP targets.
●
Initial combination therapy significantly decreased the risk of CV events and
the rates of healthcare resource use.
●
Summary
Initial versus delayed treatment with combination therapy was associated with a decreased risk of CV events, and this effect occurs
primarily through better and more rapid BP control.
Initial relative to subsequent treatment with combination therapy was
also associated with a significant reduction in healthcare resource use.
Initial Combination Therapy Reduces the Risk of Cardiovascular Events in Hypertensive
Patients: A Matched Cohort Study
Alan H. Gradman, Hélène Parisé, Patrick Lefebvre, Heather Falvey, Marie-Hélène Lafeuille and
Mei Sheng Duh
Downloaded from http://hyper.ahajournals.org/ by guest on July 28, 2017
Hypertension. 2013;61:309-318; originally published online November 26, 2012;
doi: 10.1161/HYPERTENSIONAHA.112.201566
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2012 American Heart Association, Inc. All rights reserved.
Print ISSN: 0194-911X. Online ISSN: 1524-4563
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://hyper.ahajournals.org/content/61/2/309
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Hypertension can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about
this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Hypertension is online at:
http://hyper.ahajournals.org//subscriptions/