Clinical Trial
A Simplified Approach to the Treatment of
Uncomplicated Hypertension
A Cluster Randomized, Controlled Trial
Ross D. Feldman, Guang Y. Zou, Margaret K. Vandervoort, Cindy J. Wong,
Sigrid A.E. Nelson, Brian G. Feagan
Abstract
—Notwithstanding the availability of antihypertensive drugs and practice guidelines, blood pressure control
remains suboptimal. The complexity of current treatment guidelines may contribute to this problem. To determine
whether a simplified treatment algorithm is more effective than guideline-based management, we studied 45 family
practices in southwestern Ontario, Canada, using a cluster randomization trial comparing the simplified treatment
algorithm with the Canadian Hypertension Education Program guidelines. The simplified treatment algorithm consisted
of the following: (1) initial therapy with a low-dose angiotensin-converting enzyme inhibitor/diuretic or angiotensin
receptor blocker/diuretic combination; (2) up-titration of combination therapy to the highest dose; (3) addition of a
calcium channel blocker and up-titration; and (4) addition of a non—first-line antihypertensive agent. The proportion
of patients treated to target blood pressure (systolic blood pressure
140 mm Hg and diastolic blood pressure
90 mm Hg for patients without diabetes mellitus or systolic blood pressure
130 mm Hg and diastolic blood pressure
80 mm Hg for diabetic patients) at 6 months was analyzed at the practice level. The proportion of patients achieving
target was significantly higher in the intervention group (64.7% versus 52.7%; absolute difference: 12.0%; 95% CI:
1.5% to 22.4%;
P
0.026). Multivariate analysis of patient-level data showed that assignment to the intervention arm
increased the chance of reaching the target by 20% (
P
0.028), when adjusted for other covariates. In conclusion, the
Simplified Treatment Intervention to Control Hypertension Study indicates that a simplified antihypertensive algorithm
using initial low-dose fixed-dose combination therapy is superior to guideline-based practice for the management of
hypertension.
(
Hypertension
. 2009;53:646-653.)
Key Words:
hypertension management
randomized, controlled trial
fixed-dose combination therapy
cluster randomization
hypertension
T
reatment of hypertension remains suboptimal despite the
development of novel therapies and the widespread imple-
mentation of education programs. Although multiple barriers
exist to achieving better control of blood pressure, these mainly
consist of patient- and practitioner-centered factors.
From the patient perspective, poor adherence to antihyper-
tensive regimens is a significant component of the “treatment
gap.”
1–3
An important part of this problem is current prescrib-
ing practices. Unfortunately, most patients require
2 med-
ications to achieve optimal control,
4
and these multidrug
regimens are associated with lower adherence.
5,6
This has
been suggested to be the most important contribution to
inadequate blood pressure control.
7
Furthermore, switching
medications, a strategy featured prominently in most national
treatment guidelines, has also been linked to poor adherence.
8
Thus, the use of simpler, more effective drug regimens might
improve blood pressure control.
From a practitioner perspective, a number of behavioral
factors have been associated with poor blood pressure con-
trol. One of the most important factors is “therapeutic
inertia,” whereby practitioners fail to appropriately escalate
the intensity of therapy despite the presence of poorly
controlled hypertension.
9
We speculate that the increasingly
complex treatment regimens currently advocated by experts,
national guidelines, and the pharmaceutical industry might
contribute to this undesirable behavior.
Given these issues, a simple, step-care–based algorithm for
the pharmacological management of hypertension (Simpli-
fied Treatment Intervention to Control Hypertension
[STITCH]) was developed. This algorithm features the initial
Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.
Received September 22, 2008; first decision October 8, 2008; revision accepted January 28, 2009.
From the Robarts Clinical Trials (R.D.F., G.Y.Z., M.K.V., C.J.W., S.A.E.N., B.G.F.), Robarts Research Institute, London, Ontario, Canada; Schulich
School of Medicine and Dentistry, Department of Medicine (R.D.F., B.G.F.), Department of Physiology and Pharmacology (R.D.F.), and Department of
Epidemiology and Biostatistics (G.Y.Z., B.G.F.), University of Western Ontario, London, Ontario, Canada.
This trial has been registered at www.clinicaltrials.gov (identifier NCT00129909).
Correspondence to Ross D. Feldman, Robarts Research Institute, 100 Perth Dr, London, Ontario N6A 5K8, Canada. E-mail Ross.Feldman@lhsc.on.ca
© 2009 American Heart Association, Inc.
Hypertension
is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.108.123455
646
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use of a low dose of diuretic/angiotensin-converting enzyme
inhibitor or diuretic/angiotensin receptor blocker fixed-dose
combination. The rationale for this approach is that low-dose
combinations of antihypertensive drugs are more effective
than low-dose monotherapy and that the incidence of adverse
effects with low-dose combination therapy is similar to that
of placebo.
10,11
Moreover, half-standard doses of diuretic/an-
giotensin converting enzyme inhibitor, diuretic/angiotensin
receptor blocker combinations are less likely to disturb
glucose or potassium homeostasis.
10
From the patient per-
spective, use of fixed-dose combinations may improve adher-
ence.
12
From the physician perspective, this approach reduces
the need for switching drugs, and treatment can be easily
escalated. These properties may reduce therapeutic inertia
and increase blood pressure control rates. However, the use of
polytherapy with regard to antihypertensive efficiency has
been questioned.
13
Based on these considerations, we conducted a cluster-
randomized, controlled trial that compared a simplified algo-
rithm for the treatment of hypertension with conventional
guideline-based care.
Methods
Study Practices and Randomization Procedure
Our hypothesis was that use of a simplified algorithm for the
treatment of hypertension would result in better practice-level blood
pressure control than conventional guideline-based care. The goal
was to determine the effectiveness of the treatment algorithm within
the family practice setting. Because this intervention was directed at
the family practitioner and it would not be implementable at an
individual patient level, cluster design was necessarily adopted. In
addition, this cluster approach minimizes the risk of treatment
contamination at the patient level. Therefore practitioners, rather
than patients, were randomly assigned in a 1:1 ratio to the STITCH-
care treatment algorithm or to continue with usual management
according to Canadian Hypertension Education Program (CHEP)
guidelines. The randomization schedule was computer generated and
stratified by the year of graduation of the family physician (before
1984 or 1984 and later). Because of the nature of the intervention,
participants were aware of their treatment assignment.
The study was conducted at 45 (single-physician) family practices
in southwestern Ontario, Canada, between February 2005 and
January 2007. Initially 950 practices were approached, and 93
physicians who expressed an interest in participation were randomly
assigned to either STITCH care or to care based on the CHEP
recommendations (guideline care). To avoid contamination, separate
protocols were sent to practitioners assigned to STITCH care and
guideline care. From these practices, eligibility to continue was
based on practitioner ability to identify
50 patients with uncon-
trolled hypertension through chart review. Thirty five of the original
93 practices did not identify a sufficient number of patients and were
not further evaluated. The 58 practices able to identify 50 potential
subjects (and willing to continue) received their assigned interven-
tion. Those practices that were able to identify and enroll
30
patients with confirmed, uncontrolled hypertension were analyzed.
Because the study was analyzed at the cluster level, this was
predetermined as the minimum number of subjects required to give
a precise estimate of practice-level hypertension control. Participant
flow is depicted in Figure 1.
Patients
At each practice, data were collected from all of the eligible patients
who were willing to participate and give written informed consent to
a maximum of 50 patients. Patients were enrolled consecutively as
they arrived to their physician’s practice. Eligible patients were men
3 Practices Declined Participation
93 Randomized
47 Assigned to Receive STITCH-care
25 Completed Screening
10 Declined participation
2 Withdrew
10 Ineligible (unable to identify 50 patients)
46 Assigned to Receive GUIDELINE-care
33 Completed Screening
2 Declined participation
1 Withdrew
10 Ineligible (unable to identify 50 patients)
1 Withdrew after enrollment
96 Practices Assessed for Eligibility
30 Practices enrolled patients
3 Practices ineligible (unable to enrol 30 patients)
27 Practices analyzed
24 Practices enrolled patients
6 Practices ineligible
(unable to enrol 30 patients)
18 Practices analyzed
3 Withdrew after enrollment
SCREENING
INTERVENTION
ANALYSIS
Figure 1.
Consort diagram of STITCH study.
Feldman et al Fixed-Dose Combination Therapy for Hypertension
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and women with uncontrolled hypertension who were
18 years of
age. Both untreated and partially treated patients were eligible.
Uncontrolled hypertension was defined as systolic blood pressure
140 mm Hg or diastolic blood pressure
90 mm Hg for patients
without diabetes mellitus or systolic blood pressure
130 mm Hg or
diastolic blood pressure
80 mm Hg for patients with diabetes
mellitus. Patients with ischemic heart disease, atrial fibrillation,
peripheral vascular disease, stroke, stage 4 or 5 chronic kidney
disease (ie, those with an estimated glomerular filtration rate of
30
mL/min per 1.73 m
2
) or those participating in other hypertension
studies were not eligible.
For those partially treated patients enrolled in STITCH-care
practices, physicians were not encouraged to discontinue the pa-
tient’s baseline medications but were encouraged to make subse-
quent drug additions using the STITCH algorithm, focusing on the
use of fixed-dose combinations. Patients were not excluded for
reported intolerance to any individual drug recommended in the
STITCH algorithm.
Interventions
The STITCH algorithm consisted of 4 steps: (1) initial therapy with
a half tablet of a low-dose angiotensin-converting enzyme inhibitor/
diuretic or angiotensin receptor blocker/diuretic combination; (2)
up-titration of combination therapy successively to the highest dose
supplied; (3) addition of a calcium channel blocker and up-titration;
and (4) addition of one of the non–first-line antihypertensive agents.
Practitioners assigned to the STITCH-care group were educated on
Initial therapy with a low
dose ACE/diuretic or
ARB/diuretic combination
Continue with
current therapy
Continue with
current therapy
Up-titration of
combination therapy
successively to the
highest dose
IS BLOOD PRESSURE CONTROLLED?
Yes
Yes
No
Continue with
current therapy
Add calcium
channel blocker and
up-titrate
No
Add an
α
-blocker,
ß-blocker or
spironolactone
o
N
s
e
Y
Figure 2.
STITCH-care algorithm.
Table 1. Recommended STITCH-Care Fixed-Dose Combinations
Variable
Starting Dose Tablet*
Initial Dose Equivalent† Maximum Dose Tablet‡
Angiotensin-converting enzyme inhibitor/diuretic
Accuretic, Pfizer
10/12.5 mg quinapril HCT
0.50
20/25 mg
Coversyl Plus, Servier
4/1.25 mg perindopril erbumine-indapamide
0.75
4/1.25 mg
Inhibace Plus, Roche
5/12.5 mg cilazapril HCT
0.75
5/12.5 mg
Zestoretic, AstraZeneca
10/12.5 mg lisinopril-HCT
0.50
20/25 mg
Prinzide, Merck Frosst
10/12.5 mg lisinopril-HCT
0.50
20/25 mg
Vaseretic, Merck Frosst
5/12.5 mg enalapril HCT
0.50
10/25 mg
Angiotensin II receptor blocker/diuretic
Atacand Plus, AstraZeneca
16/12.5 mg candesartan HCT
0.75
16/12.5 mg
Avalide, Sanofi-Aventis
150/12.5 mg irbesartan-HCT
0.75
300/25 mg
Diovan-HCT, Novartis
80/12.5 mg valsartan-HCT
0.50
160/25 mg
Hyzaar, Merck Frosst
50/12.5 mg losartan HCT
0.75
100/25 mg
Micardis Plus, Boehringer Ingelheim
80/12.5 mg telmisartan-HCT
0.75
80/12.5 mg
HCT indicates hydrochlorothiazide.
*STITCH-care initial dose is half of the supplied starting dose tablet.
†This was a dose equivalent of a half tablet of the starting dose tablet relative to a defined “standard daily dose,” as published previously.
15
‡The maximum dose was supplied as a single tablet.
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the use of the treatment algorithm by an implementation team
consisting of the principal investigator and study personnel from the
coordinating center. Simplified aids to facilitate implementation
were supplied (including treatment algorithm cards and a listing of
applicable low-dose, fixed-dose combinations (Figure 2 and Table
1). The principal investigator (R.D.F.) followed up with each
physician by telephone on 1 occasion, 4 to 6 weeks after the
initiation visit. Practitioners assigned to the guideline care group
were not exposed to the STITCH algorithm. At these practices, the
CHEP guidelines (that were current at the time of the study) were
reviewed with the physician, and they were provided educational
materials for the management of hypertension.
The CHEP guidelines are similar in breadth and content to the
Seventh Joint National Committee on Prevention, Detection, Evalu-
ation, and Treatment of High Blood Pressure recommendations.
14
However, in the CHEP guidelines current at the time of the study,
fixed-dose combination drugs were not recommended as first-line
treatment even for those with stage 2 hypertension (as they are in the
Seventh Joint National Committee on Prevention, Detection, Evalu-
ation, and Treatment of High Blood Pressure and in the 2008 CHEP
recommendations).
For both treatment arms, the principal investigator was available
to the family practitioners for consultation. Our intent was to provide
equal access to expert advice and educational material to both
treatment groups.
Outcome Measures
The primary outcome measure was the proportion of patients
achieving target blood pressure at the practice level, as determined at
a 6-month follow-up assessment. A successful treatment was defined
as achieving a systolic blood pressure
140 mm Hg and diastolic
blood pressure
90 mm Hg for patients without diabetes mellitus or
systolic blood pressure
130 mm Hg and diastolic blood pressure
80 mm Hg for patients with diabetes mellitus. Secondary efficacy
outcomes were the change in systolic blood pressure and diastolic
blood pressure. Blood pressure was measured based on the average
of 5 readings, determined using a standardized and precalibrated
automated blood pressure device (BpTRU, VSM Med Tech). Practices
were educated in the use of the machine before initiation of the study,
and detailed instructions for taking the average blood pressure measure-
ment were attached to each machine to ensure consistent measurement
across practices. All of the antihypertensive medications received by the
patient during the study period were recorded on drug logs.
Assessment of total daily antihypertensive doses at the 6 month
visit was based on review of drug logs. Standard dose units for
hypertension treatment were assessed using our previously published
approach and were generally defined as twice the recommended
starting dose.
15
For example, a 12.5-mg dose of hydrochlorothiazide
was assessed as 0.5 standard units and a 25-mg dose assessed as 1.0
standard unit.
Table 2. Baseline Characteristics of the Practices and
Patients
Practice/Patient Characteristics Guideline Care STITCH Care
Practices 27 18
Median cluster size (range) 46 (25 to 50) 46 (26 to 50)
Proportion of physicians
graduated before 1984, n (%)
11 (40.7) 8 (44.4)
Mean recruitment duration by
cluster, d
140 169
Urban location, n (%) 25 (92.6) 17 (94.4)
Men, n (%) 20 (74.1) 15 (83.3)
Patients
No. of patients 1246 802
Recruitment duration, d 503 531
Age, mean (range), y 60.9 (18.6 to 93.0) 61.9 (20.4 to 92.8)
Women, % 53 56
Diabetic, % 15.9 15.1
Baseline SBP, mean
(SD), mm Hg
153.4 (14.9) 155.1 (13.7)
Baseline DBP, mean
(SD), mm Hg
87.7 (10.9) 88.1 (10.9)
SBP indicates systolic blood pressure; DBP, diastolic blood pressure.
Table 3. Outcomes by Treatment Group
Variable
Practice ID
12345678910111213
Guideline care
Cluster size 25 46 50 26 48 50 48 48 33 50 48 50 49
At target BP, % 0.04 0.57 0.62 0.46 0.65 0.80 0.42 0.10 0.64 0.66 0.65 0.56 0.37
Baseline SBP, mean 164.08 153.43 154.78 161.96 149.48 150.48 153.65 157.42 155.94 152.98 148.02 149.70 157.59
SBP mean 148.12 134.39 134.90 144.00 132.23 128.04 140.46 150.52 129.21 134.28 133.88 135.58 139.88
SBP difference
15.96
19.04
19.88
17.96
17.25
22.44
13.19
6.90
26.73
18.70
14.15
14.12
17.71
Baseline DBP, mean 93.84 85.39 89.38 88.31 85.38 87.18 84.48 98.54 87.24 87.12 83.15 83.88 87.33
DBP mean
84.92 77.07 79.22 79.38 85.69 75.30 78.04 92.83 75.30 79.66 80.38 77.28 78.35
DBP difference
8.92
8.33
10.16
8.92 0.31
11.88
6.44
5.71
11.94
7.46
2.77
6.60
8.98
STITCH care
Cluster size
45 50 50 33 48 50 49 38 49 42 49 46 50
At target BP, % 0.78 0.44 0.56 0.52 0.42 0.88 0.57 0.66 0.92 0.67 0.63 0.65 0.68
Baseline SBP, mean 152.16 158.64 157.60 159.42 155.40 153.16 151.53 155.26 158.69 160.88 157.73 150.17 155.12
SBP mean
129.00 141.62 133.98 138.79 141.71 126.76 133.73 129.13 127.31 133.48 134.76 132.20 128.82
SBP difference
23.16
17.02
23.62
20.64
13.69
26.40
17.80
26.13
31.39
27.40
22.98
17.98
26.30
Baseline DBP, mean 82.09 88.80 91.76 92.39 89.06 92.38 88.00 84.95 92.57 89.07 88.02 83.15 89.22
DBP mean
73.82 88.02 80.06 81.48 82.48 80.00 80.76 72.37 71.49 81.05 79.31 74.37 76.64
DBP difference
8.27
8.78
11.70
10.91
6.58
12.38
7.24
12.58
21.08
8.02
8.71
8.78
12.58
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Practitioner Satisfaction Survey
On the completion of the study, participating physicians were sent a
questionnaire assessing their satisfaction with their approach to the
management of hypertension. The questionnaire was composed of
the following 4 questions: (1) how effective is your treatment
approach in managing your patients with hypertension?; (2) how
feasible do you think it is to sustain the treatment approach in your
practice setting?; (3) how likely would you be to recommend your
treatment approach to a colleague?; and (4) overall, how satisfied are
you with your approach to hypertension management? The questions
were scored on a Likert scale, where 0 indicated the most negative
response and 10 indicated the most positive response.
Statistical Methods
Descriptive statistics were used to assess the demographic charac-
teristics of the patients and physicians. Because treatment strategies
to improve the management of hypertension were perceived and
implemented at the level of the practice, statistical inferences for the
primary outcome were based on the proportion of patients achieving
target blood pressure at the level of the practice rather than at the
patient level. The primary analysis compared the proportion of
patients achieving target blood pressure between the 2 treatment
groups using a 2-sample
t
test.
16
A similar approach was used to
compare the other secondary outcomes. The primary outcome was
also analyzed using a weighted
t
test.
17
We also evaluated patient-level data. Factors associated with
successful treatment to target blood pressure were evaluated using a
modified Poisson regression approach that yields risk ratios adjusted
for clustering.
18,19
Provider satisfaction data were analyzed using a
2-sample
t
test. All of the analyses were based on the intention-to-
treat principle. Statistical tests were 2 sided and were performed at
the 0.05 level of significance.
Sample Size
Based on data obtained from a preliminary study of the effects of
home blood pressure monitoring on blood pressure control,
15
the
interpractice SD of the proportion of patients achieving target blood
pressure was estimated to be 17%. Therefore, randomization of 23
practices per group provided 80% power to detect a difference of
15% in the proportion of patients achieving target blood pressure
between the treatment groups.
Ethics Approval and Informed Consent
The institutional review board at the University of Western Ontario
approved the protocol. All of the patients gave written informed consent.
Results
A total of 45 practices were successful in identifying
50
patients with uncontrolled hypertension and enrolling
30
patients with confirmed uncontrolled hypertension. Of these,
18 practices had been assigned to STITCH care and 27 had
been assigned to guideline care. The physician and patient
demographics were similar in the 2 treatment groups (Table 2).
A total of 2111 patients from these 45 practices were
evaluated. One patient recruited to STITCH care and 6 patients
from the guideline-care arm were ineligible because their base-
line blood pressure was already at target. The analyses were,
thus, based on data collected from 2104 patients with uncon-
trolled hypertension, of whom 49% were already being treated at
the time of their baseline assessment. Through the duration of
the study, 23 patients in the STITCH-care arm and 33 patients in
the guideline-care arm withdrew from the study.
Proportion of Patients Achieving Target
Blood Pressure
Patients treated at practices that were randomized to STITCH
care were more likely to reach target blood pressure (Table
3). At practices assigned to STITCH care, the mean success
rate of achieving target blood pressure at 6 months was 64.7%
compared with 52.7% for those assigned to guideline care
(between-group difference: 12.1%; 95% CI: 1.5% to 22.4%;
P
0.026). An analysis that weighted the
t
statistic for the
Table 3. Outcomes by Treatment Group (Continued)
Practice ID
14 15 16 17 18 19 20 21 22 23 24 25 26 27
50 50 47 50 50 47 50 44 50 50 50 44 44 49
0.60 0.44 0.66 0.72 0.80 0.45 0.38 0.55 0.52 0.76 0.46 0.57 0.57 0.24
148.96 158.27 159.34 160.48 152.52 158.21 153.70 149.98 152.24 140.58 152.12 156.98 146.52 151.37
134.72 136.78 131.96 131.98 128.12 140.77 136.90 136.86 136.00 125.98 137.38 134.39 135.64 142.04
14.24
21.14
27.38
28.50
24.40
17.45
16.80
13.11
16.24
14.60
14.74
22.59
10.89
9.33
82.22 88.60 92.85 91.14 83.54 85.02 91.66 87.41 84.74 86.76 89.64 81.82 95.75 89.24
74.00 80.42 83.64 79.12 72.90 76.98 84.12 81.00 76.96 73.98 81.58 74.61 81.09 85.24
8.22
8.18
9.21
12.02
10.64
8.04
7.54
6.41
7.78
12.78
8.06
7.20
14.66
4.00
50 43 26 49 35
0.50 0.63 0.85 0.61 0.69
151.24 147.79 156.19 153.63 160.63
130.92 130.05 124.81 134.14 131.60
20.51
17.74
31.38
19.49
29.03
88.53 89.53 81.12 86.14 84.14
78.62 80.37 68.46 78.10 73.63
9.81
9.16
12.65
8.04
10.51
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number of patients in a practice also showed significant and
similar results to the unweighted analysis.
Changes in Systolic and Diastolic Blood Pressures
After 6 months of treatment, practices assigned to STITCH
care had a mean (
SD) reduction of systolic blood pressure
of 22.6
4.9 mm Hg compared with 17.5
5.2 mm Hg for
practices assigned to guideline care (absolute difference:
5.2 mm Hg; 95% CI: 2.0 to 8.5 mm Hg;
P
0.002; Table 3).
The STITCH-care practices also demonstrated a greater
reduction in mean diastolic blood pressure than those as-
signed to guideline care (10.4
3.3 versus 8.2
3.1 mm Hg;
absolute difference: 2.2 mm Hg; 95% CI: 0.2 to 4.2 mm Hg;
P
0.03). Seven serious adverse events were reported (3 in
guideline care and 4 in STITCH care), including 3 deaths (all
in the guideline-care group) and 3 episodes of drug intoler-
ance (all in the STITCH-care group).
Exposure to Antihypertensive Drugs
Drug logs were used to assess adherence with the treatment
algorithms. In the guideline-care group, 15% of patients were
exposed to fixed-dose combination drugs. In contrast, in the
STITCH-care group, exposure to fixed-dose combination
drugs was significantly higher (85% versus 15%;
P
0.001).
Paralleling these findings, the number of individual drugs
prescribed (with a fixed-dose combination counting as 2
individual drugs) was significantly higher in the STITCH-
care practices compared with those assigned to guideline care
(2.3 versus 1.9 drugs; absolute difference: 0.4 drugs; 95% CI:
0.2 to 0.6;
P
0.001). These findings are consistent with the
greater use of fixed-dose combinations in patients assigned to
the STITCH-care arm (see Table 4).
Although more aggressive dosing might have been facili-
tated by the STITCH algorithm, the number of standard doses
prescribed was similar in the 2 groups. In fact, the number of
standard doses of antihypertensive drug prescribed tended to
be higher in the guideline care arm: (1.7 versus 2.0 standard
doses; absolute difference:
0.3; 95% CI:
0.5 to 0.01;
P
0.06). However, it should be noted that the proportion of
patients who were up-titrated during the study was higher in
the STITCH-care group (82.6% versus 69.6%; between-
group difference: 13.0%; 95% CI: 3.8% to 22.3%;
P
0.007).
Predictors of Achieving Blood Pressure Targets
As depicted in Table 5, patient gender, patient age group, and
physician graduation before 1984 were not predictors of
blood pressure control at 6 months. The multivariate model
identified 2 factors that were independently associated with
successful treatment to target blood pressure. Assignment to the
STITCH-care arm increased the probability of achieving this
Table 4. Antihypertensive Medication Use at Baseline and Month 6
Hypertensive Medications
Baseline, % 6 Mo, %
STITCH Care (n
802) Guideline Care (n
1246) STITCH Care (n
802) Guideline Care (n
1246)
-Adrenergic antagonists
0.1
1.2
0.6
1.5
– and
-Adrenergic antagonist
0.1
0.2
0.2
0.6
Angiotensin II receptor antagonists
6.4
8.3
2.0
18.3
Angiotensin-converting enzyme
inhibitors
13.8
20.8
5.0
32.6
-Adrenergic antagonists
9.6
11.2
12.2
19.9
Calcium channel blockers
13.8
16.9
29.6
30.3
Centrally acting antiadrenergic agents
0
0.1
0.2
0.3
Diuretics
18.7
21.7
9.1
36.9
Angiotensin II receptor
antagonist/diuretic combinations
7.5
7.6
43.5
14.4
Angiotensin-converting enzyme
inhibitor/diuretic combinations
3.7
1.5
39.3
2.0
-Adrenergic antagonist/diuretic
combination
0 0.2 0 0.4
Table 5. Predictors of Achieving Blood Pressure Target
Determinant
Univariate Analyses Multivariate Model
Risk Ratio 95% CI
P
*† Risk Ratio 95% CI
P
*†
STITCH-care
1.2 1.02 to 1.40 0.03 1.2 1.0 to 1.4 0.03
Age (per 10 year increase) 1.0 0.97 to 1.06 0.48
Female
1.0 0.86 to 1.03 0.22
Not diabetic
2.5 2.02 to 3.05
0.001 2.5 2.0 to 3.1
0.001
Physician before 1984
1.1 0.88 to 1.26 0.63
*The analysis was conducted using a modified Poisson regression model that evaluated patient-level data.
†
P
values were derived by adjustment for clustering in the model.
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goal by 20% (risk ratio: 1.20; 95% CI: 1.02 to 1.40;
P
0.03).
Patients without diabetes mellitus had more than double the
probability of reaching their target blood pressure independent of
the treatment assignment. This is consistent with previous
evidence of lower rates of blood pressure control in patients with
diabetes mellitus (primarily ascribed to the lower targets for this
subgroup of hypertensive patients).
20
Provider Satisfaction
The physicians in the STITCH-care arm were somewhat
more satisfied with their approach to managing hypertension
than physicians in the guideline-care arm (8.9 versus 8.2;
absolute difference: 0.7; 95% CI: 0.4 to 1.4;
P
0.04). The
physicians in the STITCH-care arm also tended to feel that
they were more effective in managing patients with hyper-
tension (8.70 versus 8.00; absolute difference: 0.70; 95% CI:
0.02 to 1.40;
P
0.06) and were more willing to recommend
their approach to other physicians (8.70 versus 7.70; absolute
difference: 1.00; 95% CI: 0.02 to 2.10;
P
0.05). There was
no difference between the treatment group arms in their
perspective of the feasibility of sustaining their current
treatment approach (8.20 versus 7.90; absolute difference:
0.30; 95% CI: 0.20 to 1.10;
P
0.14).
Discussion
Identification of new strategies for improving blood pressure
control in a family practice setting is a healthcare priority.
Our study demonstrates that a simplified algorithm for the
management of hypertension is implementable, changes
physician-prescribing patterns, and results in better blood
pressure control than conventional guideline-based care.
Notwithstanding the competing influences of both pharma-
ceutical company marketing and the educational initiatives of
the CHEP, our simple implementation process, consisting of
an initial meeting and single follow-up telephone call by a
clinical pharmacologist, changed physician behavior. This
behavioral change is probably best demonstrated by the
6-fold increase in the use of fixed-dose antihypertensive
combination drugs by STITCH-care physicians in compari-
son with the guideline-based practices. However, most im-
portantly, blood pressure was improved in practices assigned
to the STITCH-care arm. Furthermore, STITCH-care physi-
cians reported greater satisfaction with their management of
hypertension, suggesting that STITCH care is a practicable
strategy for use by community physicians.
The STITCH algorithm featured the initial use of combi-
nation therapy. It is notable that several previous studies have
suggested that initial therapy with specific fixed-dose combina-
tions results in superior blood pressure reduction in comparison
with monotherapy-based approaches. However, these studies
used mandated regimens in rigidly conducted clinical trials and
relatively high initial drug doses.
21,22
In contrast, our trial used a
“critical pathway” approach to educating physicians regarding a
simplified treatment algorithm that was not dependent on the
prescription of specific drug combinations. Accordingly, we
believe that these findings are more widely generalizable for the
management of hypertension.
Which components of STITCH were responsible for the
effectiveness of the algorithm? Although this question was
not directly addressed in the study, 3 factors should be
considered. First, use of the algorithm might have facilitated
the use of more intensive dosing regimens by physicians (ie,
overcoming therapeutic inertia). Second, use of fixed-dose
combinations may have improved adherence by patients, as
has been suggested in observation studies. Finally, use of
combination therapy may be intrinsically more effective
because of synergy between agents. However, with respect to
the first possibility, our analysis of dose intensity showed that
practices assigned to STITCH care did not receive more
aggressive treatment, as assessed by the number of standard
doses prescribed. On the other hand, patients in the STITCH-
care arm were more likely to have had their antihypertensive
dose up-titrated. Therefore, whether the STITCH algorithm
attenuated therapeutic inertia cannot be resolved. Thus, we
speculate that the effectiveness of STITCH is more likely
related to better adherence by patients and/or the use of more
effective drug combinations (ie, minimizing the use of
less-than-additive 2- or 3-drug combinations, a phenomenon
suggested to occur with polytherapy in hypertension).
13
The 2008 CHEP guidelines included a new recommendation
supporting the use of initial therapy with a fixed-dose combina-
tion as a first-line choice. Notably, based on the 2008 CHEP
recommendations, 45% of STITCH-care and 39% of guideline-
care patients would have been candidates for initial fixed-dose
combination therapy at baseline. However, it is important to
emphasize that starting with a fixed-dose combination is only 1
of 6 first-line recommended choices for initiation of therapy in
this group. We would suggest that, based on our findings, a
fixed-dose combination might be the preferred initial treatment
in this subgroup (versus initiation with a single agent).
Limitations
Our study has some limitations. The STITCH algorithm was
implemented by a single clinical pharmacologist (R.D.F.).
Whether similar results could be obtained with widespread
implementation is unknown. Second, the imbalance between
numbers of practices initiated in STITCH-care versus
guideline-care arms requires consideration. This imbalance
raises the possibility that the physicians who participated in
the STITCH-care arm may have been different, in terms of
their behavior, from those assigned to the GUIDELINE-care
arm. However, the majority of the practice “dropouts” (35 of
48 practices) occurred before site initiation (ie, before the
point at which intervention sites were introduced to the
treatment algorithm). Among practices that actively started
screening, dropout rates were comparable. Second, we could
not identify any practice or patient level factor that would
support the existence of a difference between treatment arms.
Third, the treatment effect size was relatively large. We do
not believe it is plausible that confounding would result in a
difference of this magnitude. Moreover, the trial was de-
signed with a 1:1 ratio between STITCH care and guideline
care, which, in general, has higher power than an unbalanced
trial. The unbalanced ratio of intervention:control sites in
STITCH would have been expected to reduce the power of
the study to identify significant differences. This implies that
our results are likely conservative.
652 Hypertension
April 2009
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Perspectives
Use of a simplified algorithm for the treatment of hypertension
featuring the initial use of low-dose, fixed-drug combination
drugs is implementable, accepted by family physicians, and
results in improved blood pressure control. This return to step
care may be an important way forward for the treatment of
hypertension. We also speculate that such an approach may be
broadly applicable for the treatment of other chronic diseases.
Acknowledgments
Coordinating center personnel include the following individuals:
M. Abboud, B. Annunziello, T. Clayton, B. Feagan, R. Feldman, L.
Jensen, E. Karugu, H. Kaufman, C. Matthews, J. MacKay, K.
Greenwood, S. Nelson, N. Ng, W. Piper, L. Robinson, B. Sarazin, C.
Trinidad, M. Vandervoort, C. Wong, J. Xie, and G. Y. Zou.
The following family practitioners participated in the study: Ancaster:
B. B. Loewith; Brantford: W. S. Tsuchida, D. C. Vincent; Burlington:
R. R. Jhirad, A. Nayar; Chatham: J. Boekhoud, S. Munro; Exeter: D.
Hodder; Hamilton: R. D. Arora, T. Subramanian, L. S. Zavodni, Ilder-
ton: G. Nancekievill; Kitchener: K. Bedrosian, B. Huth, J. A. King, S.
MacGregor, R. Nicholson, T. Szozda; London: T. Alam, E. Arcia-
Bravo, E. Armogan, V. Chawla, G. Debosz-Szczerbowski, P. Dickie, P.
Dzongowski, J. Horne, S. Joshi, R. Komar, A. Mawji, S. Petrlich, A.
Richard, F. Wong; St Mary’s: S. Hiscock; St Thomas: B. Hertwig;
Stratford: D. Crowley; Strathroy: M. Mithoowani; Thedford: L. Gibbs;
Waterloo: F. Dawood, G. Pannozzo, J. Peet; Windsor: M. Bilibajkich,
D. Bridgeo, M. Zajner; and Woodstock: J. Brioux.
We acknowledge the contribution of Suzanne Vandervoort, the
study’s initial coordinator. We thank Beverley Jasevicius for expert
secretarial assistance.
Sources of Funding
The trial was supported by an independent grant from Pfizer Canada.
The sponsor had no role in the design and conduct of the study;
collection, management, analysis, and interpretation of the data;
preparation review; or approval of the article.
Disclosures
R.D.F. reports receiving research funding from Pfizer and has been
a paid consultant or on advisory boards for Bayer, Boehringer-
Ingleheim, Pfizer, Bristol Myers Squibb, Sanofi-Aventis, Schering-
Plough, Merck, and Servier. B.G.F. reports receiving research
funding unrelated to the topic of the article from Synta, Millennium,
Schering Canada, Celltech, Centocor, Elan/Biogen, Berlex, Ortho-
Biotech, Protein Design Labs, ISIS, Santarus, Schering Plough,
Celgene, UCB Pharma, Napo Pharma, BMS, Abbott, and Otsuka. He
also reports receiving consulting and lecture fees from UCB Pharma,
Schering Canada, Proctor and Gamble, Elan/Biogen, Millennium,
Protein Design Labs, Berlex, AstraZeneca, Celgene, Abbott, Santa-
rus, GeneLogic Inc, Cerimon Pharmaceuticals, Tioga Pharmaceuti-
cals, BMS, ISIS, Serono, Teva, Genentech, and CombinatoRx. No
other financial disclosures were reported.
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