Determinants of Achieving Early Blood Pressure Control with

Monotherapy in a Primary Care Setting

Simon Stewart, PhD;
1
Melinda J. Carrington, PhD;
1
Carla H. Swemmer, MBChB;
2
Nicol P. Kurstjens, PhD;
2
Alex Brown, PhD;
3
Louise M. Burrell, MD;
4
Mark Nelson, PhD;
5
Nigel P. Stocks, MD;
6
Garry L. Jennings, MD;
7
On behalf of the VIPER-BP Study
Investigators
From the Department of Preventative Health and NHMRC Centre of Research Excellence to Reduce Inequality in Heart Disease, Baker IDI Heart and
Diabetes Institute, Melbourne, Vic.,
1
Novartis Pharmaceuticals Australia Pty Ltd, Sydney, NSW,
2
Baker IDI Heart and Diabetes Institute, Alice Springs,
NT,
3
Departments of Medicine and Cardiology, Austin Health, University of Melbourne, Melbourne, Vic.,
4
Menzies Research Institute Tasmania,
University of Tasmania, Hobart, Tas.,
5
University of Adelaide, Adelaide, SA,
6
and Baker IDI Heart and Diabetes Institute, Melbourne, Vic., Australia
7
This study sought to identify the determinants of early blood
pressure (BP) control associated with monotherapy in
hypertensive individuals being managed in the primary care
setting. The Valsartan Intensied Primary Care Reduction of
Blood Pressure (VIPER-BP) study, was a multicenter, ran-
domized controlled trial of an intensive approach to BP
management. During a standardized run-in, 2185 partici-
pants commenced monotherapy (valsartan 80 mg/d) for 14
to 28 days. A total of 1978 participants aged 5912 years
(60% men) completed the run-in phase. Of these, 15.1%,
43.5%, and 41.4% participants had an initial BP target of
125/75, 130/80, and 140/90 mm Hg, respectively. A total
of 416 of 2185 participants (19.0%) subsequently achieved
their individual BP target during run-in with a mean BP
change of 22.612.1/12.98.2 mm Hg vs 4.216.2/
3.09.6 mm Hg for the rest (P<.001). These early
responders were more likely to be women (adjusted odds
ratio, 1.41; 95% condence interval, 1.101.80), had lower
BP at baseline, were less likely to have been treated
previously (or for less time), and had a less stringent BP
target. An initial period of monotherapy achieved BP control
in a high proportion of hypertensive individuals with key
groups (including women and de novo cases) more likely to
show an early BP response. J Clin Hypertens (Greenwich).
2013;15:674680. 2013 Wiley Periodicals, Inc.
Elevated blood pressure (BP), or hypertension, represents
one of the most preventable and yet seemingly intractable
contributors to cardiovascular disease (CVD). Overall,
hypertension is estimated to contribute to around 30%to
40% of all-cause or CVD-related case fatalities in high-
income countries such as the United States.
1
A critical
factor in this phenomenon is the high proportion of
identied individuals with hypertension who remain
above their BP target and therefore at sustained elevated
risk for a primary or secondary cardiovascular event.
2
Given the volume of cases, the majority of such individ-
uals are managed in the primary care environment using
ofce-based measurements of BP, although there is
increasing focus on 24-hour ambulatory monitoring
and home-based monitoring
3
to minimize potential
white-coat or masked hypertension and inappropriate
or foregone treatment.
4
In Australia, nearly 1 in 10
primary care encounters is related to hypertension
5

more than any other single contributor to health care

activity. As indicated, despite an array of effective
pharmacologic agents, particularly when applied in
combination (preferably a single pill to encourage treat-
ment adherence), BP control rates remain suboptimal.
Beyond the application of pharmacotherapy, there is
strong evidence, including a Cochrane review of the
literature, that more intensive and structured manage-
ment in the primary care setting will signicantly
improve BP control rates.
6
We therefore conducted the
multicenter, randomized Valsartan Intensied Primary
Care Reduction of Blood Pressure (VIPER-BP) study
7
to
test the clinical effectiveness and overall safety of a more
intensive and structured approach to optimizing BP
control in a group of individuals with persistently high
BP levels in primary care. During the randomized
component of comparing the VIPER-BP intervention
(n=1038) with an enhanced form of usual care (n=524),
the primary endpoint (individual risk-based BP target)
was achieved in 36.2% vs 27.4% of participants,
respectively (adjusted relative risk 1.28 in favor of the
intervention; P=.001) and the classical BP target of
140/90 mm Hg in 63.5% vs 54.0% of participants
(adjusted relative risk 1.18 in favor of the intervention;
P<.001).
8
However, prior to randomization, a total of
2185 participants were exposed to a standardized run-in
period comprising clinical proling and low-dose angio-
tensin receptor blockers (ARBs) for 28 days.
STUDY HYPOTHESIS
Prior to the commencement of the VIPER-BP interven-
tion we hypothesised that <10%of initially eligible study
participants would achieve their individualized BP target
during the study run-in period. We further hypothesized
that if they did achieve this target (and were therefore not
Address for correspondence: Simon Stewart, PhD, PO Box 6492, St
Kilda Road Central, Melbourne, Vic. 8008, Australia
E-mail: simon.stewart@bakeridi.edu.au
Manuscript received: March 21, 2013; revised: May 21, 2013;
accepted: June 3, 2013
DOI: 10.1111/jch.12164
674 The Journal of Clinical Hypertension Vol 15 | No 9 | September 2013 Ofcial Journal of the American Society of Hypertension, Inc.
ORI GI NAL PAPER
eligible for study randomization), the majority of partic-
ipants would be those who had only recently commenced
antihypertensive therapy. As part of a prospective
analysis plan, therefore, we report on the proportion
and characteristics of initially eligible participants in
the VIPER-BP study who responded to the standardized
run-in period, as compared with those in whom BP
remained elevated above their individualised target.
METHODS
As described in our previous reports describing the
rationale and design of the study
7
and the primary
results in favor of the study intervention of more
intensive primary care management overall,
8
the
VIPER-BP study was a pragmatic, multicenter random-
ized controlled trial involving a total of 119 general
practices Australia-wide. The study received ethics
approval from all relevant bodies including the Alfred
Hospital Ethics of Human Research Committee, Mel-
bourne, Australia, in accordance with the Declaration of
Helsinki (2008). After initial enrollment a total of 2185
of 2337 (93.5%) participants with elevated BP accord-
ing to national guidelines at the time of the study (>140/
90 mm Hg for those without CVD, >130/80 mm Hg
for those with established CVD, diabetes or other forms
of end-organ damage, and >125/75 mm Hg for those
with evidence of renal damage [proteinuria])
9
entered a
standardized run-in phase prior to randomization (see
below). Key exclusion criteria included participants
receiving triple antihypertensive therapy to control their
BP at the time of enrolment, those who had a systolic BP
>180 mm Hg, and anyone who was unable to provide
informed consent and/or was intolerant to or contrain-
dicated for the planned study therapy (including ARBs).
Initial Proling and Run-In Treatment
Following initial study enrollment, a standardized
process of clinical proling and study treatment was
initiated. Clinical proling (facilitated by a computer
program provided by Baker IDI, Melbourne, Vic.,
Australia) ensured that all participants entering the
run-in phase had their BP levels veried and their initial
BP targets established according to their absolute risk
for a 5-year cardiovascular event (based on the Fra-
mingham Risk Score)
10
and evidence of pre-existing
CVD, diabetes, or potential end-organ damage caused
by elevated BP. The latter two comprised further
delineation of initial BP targets based on more denitive
investigation of potentially undiagnosed diabetes and/or
renal damage (based on initial urine dip-stick testing for
proteinuria). As described in more detail previously, BP
was recorded according to a standardized protocol and
using validated automated devices. It should be empha-
sized, therefore, that the initial BP target (at study run-
in) could be lowered by randomization following
further clinical investigation.
At the commencement of study run-in, all previously
prescribed antihypertensive therapy was ceased and a
starting dose of valsartan 80 mg/d was initiated.
Participants were then scheduled to return at 14 and
28 days post-commencement of run-in for BP assess-
ment by their general practitioner (GP) and study team
at the participating clinic. Rescue randomization was
initiated if, at 14 days (or any time during the run-in
stage), the patient recorded a systolic BP >180 mm Hg
or the GP believed it was clinically indicated to
immediately commence higher doses of antihypertensive
therapy for that individual. There were 3 possible
outcomes for the 2185 participants who commenced the
VIPER-BP study run-in phase: (1) randomization into
the comparison phase of the VIPER-BP study due to the
lack of achievement of individualized BP control within
28 days (with potential rescue randomization at day
14), (2) early response to the run-in phase of
treatment with attainment of individualized BP target
(nalized prior to potential randomization), and (3)
early withdrawal (a total of 207 participants in this
latter group were withdrawn from the study prior to
randomization). This group comprised 108 men (aged
5512 years) and 99 women (aged 6112 years) of
whom 74 of 2185 (3.4%) were lost to follow-up, 56
(2.6%) experienced an adverse event, 40 (1.8%) with-
drew their consent to participate, 20 (0.9%) were
withdrawn according to investigators discretion, and
the remainder (n=17, 0.8%) due to other reasons. This
report focuses on the 1978 participants who were either
randomized (n=1562) or who achieved their individu-
alized BP goal during the run-in phase (n=416); the
latter group representing 19.0% (95% condence
interval [CI], 17.4%20.8%) of those who commenced
the run-in phase. Participants in groups 2 and 3 (ie,
nonrandomized) were not subject to any further follow-
up postrun-in.
Statistical Analyses
Study data were analyzed using SPSS for Windows
version 17.0 (SPSS Inc, Chicago, IL). Continuous data
are presented as meanstandard deviation and categor-
ical data as a percentage. Between-group (univariate)
comparisons were assessed by Student t tests and chi-
square test (with calculation of odds ratios [ORs] and
95% CIs) where appropriate. Independent correlates of
achieving individual BP target were determined by
multiple logistic regression using the variables listed in
Table I (a step-wise model [backward elimination]
excluded variables at the level of P>.1 for each step).
Separate models were constructed for men and women
to identify potential differences.
RESULTS
Baseline Characteristics
Table I summarizes the demographic and clinical prole
of 1978 participants who completed the standardized
run-in period according to their BP response at study
enrollment.
Overall, the mean age was 59 years, 60% were men,
and 61% were prescribed antihypertensive therapy (for
Ofcial Journal of the American Society of Hypertension, Inc. The Journal of Clinical Hypertension Vol 15 | No 9 | September 2013 675
Early BP Control in Primary Care | Stewart et al.
a mean of 5.6 years) prior to study enrollment. A
similar proportion of participants had an initial BP
target of 130/80 mm Hg (44%) or 140/90 mm Hg
(41%). The demographic prole of male and female
participants varied including age (women were slightly
older), living, and employment status. Similarly, from a
clinical perspective although there were more women
with a history of hypertension, overall, the risk prole of
male participants was elevated in comparison to their
female counterparts.
BP Change During the Standardized Run-In Period
A total of 590 (29.8%) and 638 (32.3%) participants
recorded a lower systolic and diastolic BP, respectively,
from enrollment to the end of the 28-day study run-in
period of valsartan 80 mg/d, respectively. The majority
of patients (around 70%) recorded a stable and even
increased systolic (up to 60 mm Hg) and diastolic (up
to 40 mm Hg) BP during the run-in period. There was
a strong but not complete linear relationship in the
magnitude of change in systolic and diastolic BP among
TABLE I. Clinical and Demographic Prole of Study Cohort According to Sex and Initial BP Response
All (N=1978) Men (n=1189) Women (n=789)
Achieved BP Target
During Run-In (n=416)
Persistently Elevated
BP (n=1562)
Sociodemographic prole
Age, y 59.012.1 58.412.2 59.911.9 58.312.3 59.312.0
Male, % 1189 (60.0) 1189 (100) 226 (54.3) 963 (61.7)
>12 years education, % 882 (44.6) 617 (70.0) 265 (30.0) 202 (50.5) 680 (44.9)
Live alone, % 684 (34.6) 390 (32.8) 294 (37.2) 157 (38.0) 527 (34.6)
Employed, % 974 (49.2) 641 (53.9) 333 (42.2) 221 (55.4) 753 (49.7)
Metropolitan area, % 1837 (92.9) 1104 (92.9) 733 (92.9) 384 (92.3) 1453 (93.0)
Cardiovascular prole
Current smoker, % 293 (14.8) 197 (16.6) 96 (12.2) 50 (12.1) 243 (15.7)
Obese (BMI >30 kg/m
2
), % 1009 (51.0) 598 (50.3) 411 (52.1) 171 (41.5) 838 (53.7)
Prior hypertension, % 1211 (61.2) 709 (59.6) 502 (63.6) 166 (39.9) 1045 (66.9)
Diabetes (type 1 or 2), % 375 (19.0) 238 (20.0) 137 (17.4) 47 (11.3) 328 (21.0)
Cerebrovascular disease, % 75 (3.8) 41 (3.5) 34 (4.3) 8 (4.3) 67 (4.3)
Coronary artery disease, % 152 (7.7) 106 (8.9) 46 (5.8) 21 (5.1) 131 (8.4)
Absolute risk score, % 14.09.4 16.79.9 9.86.7 11.88.4 14.69.6
AUSDRISK score, % 16.75.6 17.65.6 15.35.2 14.65.4 17.25.5
Clinical prole
Systolic/diastolic BP, mm Hg 15213/90 11 15313/9111 15214/8911 14812/8810 15314/9111
Total cholesterol, mmol/L 5.31.1 5.21.1 5.41.1 5.21.1 5.41.0
Low-density lipoprotein, mmol/L 3.11.0 3.11.0 3.11.0 3.01.0 3.30.9
High-density lipoprotein, mmol/L 1.40.5 1.30.5 1.60.5 1.40.5 1.50.5
Hemoglobin A
1c
in diabetics, % 7.11.7 7.31.7 6.81.5 7.01.7 7.21.6
Body mass index, kg/m
2
30.66.3 30.66.0 30.86.8 29.76.5 30.96.3
Proteinuria, % 297 (15.0) 189 (15.9) 108 (13.7) 21 (5.1) 276 (17.7)
NYHA class II, III, or IV, % 528 (26.7) 296 (24.9) 232 (29.4) 90 (21.6) 438 (28.0)
ECG evidence of LVH, % 131 (6.6) 104 (8.8) 27 (3.4) 20 (5.5) 111 (7.4)
Depressive symptoms, % 681 (34.4) 372 (31.3) 309 (39.2) 147 (35.4) 534 (34.3)
Estimated GFR, mL/min/172 m
2
88.219.7 88.619.7 87.619.6 88.019.7 89.019.7
BP management at enrollment
Current drug therapy, % 1201 (60.7) 703 (59.1) 498 (63.1) 164 (39.4) 1037 (66.4)
Two antihypertensive agents, % 230 (11.6) 146 (12.3) 84 (10.7) 3.36.4 6.28.4
Years of drug therapy 5.68.1 5.37.6 6.18.7 16 (3.5) 214 (13.7)
Angiotensin receptor blocker, % 486 (24.6) 250 (21.0) 236 (29.9) 76 (18.3) 410 (26.3)
ACE inhibitor, % 344 (17.4) 231 (19.4) 113 (14.3) 57 (13.7) 287 (18.4)
Calcium antagonist, % 215 (10.9) 139 (11.7) 76 (9.6) 16 (3.9) 199 (12.7)
b-Blockers, % 75 (3.8) 35 (2.9) 40 (5.1) 8 (1.9) 67 (4.3)
Diuretic, % 62 (3.1) 26 (2.2) 36 (4.6) 7 (1.7) 55 (3.5)
Initial BP target at commencement of run-in
BP 125/75 mm Hg, % 299 (15.1) 194 (16.3) 105 (13.3) 22 (5.3) 277 (17.7)
BP 130/80 mm Hg, % 861 (43.5) 502 (42.2) 359 (45.5) 116 (27.9) 745 (47.7)
BP 140/90 mm Hg, % 818 (41.4) 493 (41.5) 325 (41.2) 278 (66.8) 540 (34.6)
Abbreviations: ACE, angiotensin-converting enzyme; AUSDRISK, Australian Type 2 Diabetes Risk Assessment tool; BMI, body mass index; BP, blood
pressure; ECG, electrocardiographic; GFR, glomerular ltration rate; LVH, left ventricular hypertrophy; NYHA, New York Heart Association. Obesity was
dened as a body mass index >30 kg/m
2
. Depressive symptoms were determined by a positive response to the 2-item Arrol questionnaire. Complete
sociodemographic and clinical data were available in 1913 participants. Coded 12-lead electrocardiographic data were available in 1865 participants.
676 The Journal of Clinical Hypertension Vol 15 | No 9 | September 2013 Ofcial Journal of the American Society of Hypertension, Inc.
Early BP Control in Primary Care | Stewart et al.
participants. For every unit (mm Hg) of change in
diastolic BP there was a 1.2 mm Hg change in systolic
BP (r
2
=.50, P<.001). Overall, there was a gradient in BP
response according to prior treatment but with inherent
variability (as demonstrated by non-Gaussian
distributions) within each treatment category: change
in systolic and diastolic BP being 11.416.7/
7.310.2 mm Hg, 5.515.7/3.29.0 mm Hg,
and +1.719.4/+0.610.7 mm Hg for those prescribed
no, 1, or 2 antihypertensive agents, respectively.
Responders Vs Nonresponders
A larger than hypothesized group achieved their indi-
vidualized BP target during the run-in period416
participants (19.0%; 95% CI, 17.4%20.8%). Consis-
tent with the distribution of BP responses, 1562 partic-
ipants (71.5% of those who commenced run-in) were
subsequently randomized, including 84 participants
who were rescue randomized with markedly elevated
BP (18414/9813 mm Hg). Overall, the mean change
in BP in those who achieved their target BP was
22.612.1/12.98.2 mm Hg (early BP responders)
compared with 4.216.2/3.09.6 mm Hg in those
who were randomized on the basis of not reaching their
individual BP target.
Table I also compares the demographic and clinical
proles of the two groups of responders and
nonresponders. For example, there were proportion-
ately fewer men, obese individuals, and participants
previously treated for hypertension (with almost half the
number of years of antihypertensive treatment among
such individuals) among those who subsequently
achieved their individual BP target during the 28-day
run-in period. Alternatively, participants with persis-
tently elevated BP following the run-in period and
therefore randomized into the VIPER-BP study had
higher baseline BP values and, in turn, higher absolute
cardiovascular risk scores and potential to develop type
2 diabetes (with almost double the number of pre-
existing cases).
The Figure shows the overall pattern of BP response
for the 3 different BP target groups (initial targets set by
the GP at the start of the run-in period) among early BP
responders compared with those who were randomized.
In the lowest BP target group (<125/75 mm Hg),
patients with the largest falls in BP required to reach
their individual target, a total of 22 of 299 participants
(7.4%) achieved their BP target. This compared with
116 of 861 (13.5%) in the <130/80 mm Hg BP target
group and 278 of 818 (34.0%) in the <140/90 mm Hg
group. There were similar changes in BP across all 3 BP
target groups in respect to systolic (range
21.8 mm Hg to 23.1 mm Hg) and diastolic BP
(range 12.8 mm Hg to 12.9 mm Hg) in those who
achieved their BP target. A similar (but less pronounced
in respect to BP change) trend in systolic (range
4.0 mm Hg to 4.6 mm Hg) and diastolic BP (range
2.5 mm Hg to 3.8 mm Hg) was observed across the
BP target groups among those randomized on the basis
of not achieving their individual BP target.
Table II shows the pattern of BP change from baseline
to 14 and 28 days for men and women separately
according to their BP status at the end of the study run-
in. Overall, women had lower systolic BP values than
men and the greatest differences were observed at
14 days. Among those who achieved their individual BP
target, women had the greatest decline in mean BP
values (>4 mm Hg in systolic BP [P<.001] and
1 mm Hg in diastolic BP [P<.05]) from baseline to
28 days.
FIGURE. Change in mean systolic and diastolic blood pressure (BP) according to initial BP target and nal BP status. Data values are mean
(upper standard deviation) for those who achieved their BP target (red lines) and those randomized (blue lines) due to persistently elevated BP.
Ofcial Journal of the American Society of Hypertension, Inc. The Journal of Clinical Hypertension Vol 15 | No 9 | September 2013 677
Early BP Control in Primary Care | Stewart et al.
Independent Correlates of Achieving Individual BP
Target
Adjusting for demographic and clinical prole, women
were almost 1.5-fold more likely than men to achieve
their individual BP target (24.1% vs 19.0% men:
adjusted OR, 1.41; 95% CI, 1.101.80; P=.007) while
obese participants were less likely (16.9% vs 25.0%
nonobese: OR, 0.63; 95% CI, 0.500.81; P<.001). For
every unit increase in systolic BP (OR, 0.96; 95% CI,
0.950.97/mm Hg; P<.001) and diastolic BP (OR, 0.97;
95% CI, 0.960.98/mm Hg; P<.001) participants were
less likely to achieve their BP target. As hypothesized,
patients already taking 1 more antihypertensive agent
prior to study enrollment (13.7% vs the rest 32.6%:
OR, 0.33; 95% CI, 0.250.42; P<.001) and/or pre-
scribed combination therapy (7.0% vs the rest 22.9%:
OR, 0.36; 95% CI, 0.200.62; P<.001) were also less
likely to achieve their target BP during this timeframe.
Overall, compared with those not taking prior antihy-
pertensive treatment, participants prescribed one agent
were around one half less likely to achieve their BP
target during run-in (OR, 0.51; 95% CI, 0.400.66;
P<.001) and around one quarter likely than those taking
2 agents (OR, 0.24; 95% CI, 0.140.42).
The duration of prescribed antihypertensive therapy
was also important, with those treated for longer being
less likely to achieve their BP target during this period
(OR, 0.97; 95% CI, 0.950.99 per year of treatment;
P=.006). Finally, the less stringent the BP target estab-
lished at baseline, the more likely a participant achieved
the BP goal (OR, 2.01, 95% CI, 1.233.29; P<.005 and
OR, 8.43; 95% CI, 5.2013.7; P<.001 for a BP target of
130/80 mm Hg and 140/90 mm Hg, respectively,
compared with the lowest BP target). The same corre-
lates of achieving individual BP target were found in
men and women, with one notable exception: married
women were around 2-fold less likely to achieve their
BP target (adjusted OR, 0.49; 95% CI, 0.260.93 vs
nonmarried women; P=.028).
DISCUSSION
When designing the VIPER-BP study, we hypothesized
that a maximum of 1 in 10 patients being managed for
hypertension in the primary care, when challenged with
a standardized period of clinical proling and low-dose
ARB therapy, would achieve their individualized BP
target. In reality, excluding those who withdrew from
the early stages of the study for other reasons (around
1 in 3 participants) had a positive BP response, with
almost 1 in 5 participants overall achieving their
individual BP target at the point of potential random-
ization to more intensive therapy. For these participants,
the BP response was quite dramatic. In men, there was a
mean fall of 22/14 mm Hg in systolic and diastolic BP
and in women an even greater mean fall of 26/
15 mm Hg. Alternatively, for a majority of those who
remained above their BP target and therefore random-
ized, there was an increase in BP (up to 60/40 mm Hg,
with 4% experiencing a systolic BP >180 mm Hg) with
a mean overall fall in systolic and diastolic BP of 4/
3 mm Hg. On an adjusted basis, early BP responders
were more likely to be women (1.5-fold more likely to
achieve their BP target compared with men), although
married women were less likely to have an early BP
response compared with nonmarried women. Early BP
responders had a lower presenting systolic and/or
diastolic BP, had fewer years of antihypertensive treat-
ment, were less likely to be prescribed 1 or 2 antihy-
pertensive agents, and were more likely to be assigned
an initial BP target of 140/90 mm Hg compared with
the more stringent targets. In both sexes, there was a
clear gradient in respect to BP control according to more
stringent targets. Ultimately, this meant that the run-in
period of the VIPER-BP study truly represented a
wheat from the chaff process that meant that partic-
ipants with both persistently elevated BP and more
stringent BP targets based on absolute risk were
randomized into the subsequent study. From a clinical
TABLE II. Change in Mean Systolic and Diastolic BP According to Final BP Status and Sex
Achieved BP Target (n=416) Randomized (n=1562)
Men (n=226) Women (n=190) Men (n=963) Women (n=599)
Baseline (n=1978)
Systolic BP mm Hg 149.310.4 148.912.5 154.113.0 152.713.5
Diastolic BP mm Hg 88.59.9 88.510.2 91.511.3 89.710.8
Achieved BP target
14 days (n=1794)
Systolic BP mm Hg 129.57.4 125.58.4 150.216.7 147.917.1
Diastolic BP mm Hg 76.88.4 76.87.4 88.711.3 86.910.3
Mean BP change mm Hg 19.3/11.4 20.8/10.0
28 days (n=1734)
Systolic BP mm Hg 127.97.1 126.39.6 150.216.4 148.817.1
Diastolic BP mm Hg 75.37.6 75.98.6 88.511.4 87.210.2
Mean BP change mm Hg 21.9/13.7 26.0/14.7
Change in blood pressure (BP) from baseline and achieved individualized BP target calculated only for individuals with data recorded at each time point.
678 The Journal of Clinical Hypertension Vol 15 | No 9 | September 2013 Ofcial Journal of the American Society of Hypertension, Inc.
Early BP Control in Primary Care | Stewart et al.
translation perspective, these data reinforce the poten-
tial to achieve early BP control, particularly among
women, nonobese individuals, and those with a recent
history of hypertension (as reected in both the duration
and intensity of prior treatment) via a fairly simple
process of structured care and treatment (in this case, a
low-dose ARB). Individuals previously prescribed 2
antihypertensive agents were least likely to respond
(<1 in 10) to this strategy, while positive BP responses
were broadly apparent within 14 days and sustained up
to 28 days.
It is important to emphasize that the study run-in
period with multiple BP measuring points undoubtedly
unmasked the phenomenon of regression to the
mean
11
with relatively small changes in BP values
enabling some individuals to achieve their BP target
(particularly the historical BP target of 140/
90 mm Hg). Moreover, introduction of new antihy-
pertensive therapy, even in the form of low-dose ARB
therapy, occurred in 40% of participants. However,
the almost immediate impact of standardized proling
and management with a low-dose ARB (valsartan
80 mg/d) in this large study cohort, among a predom-
inance of individuals with a long history of persistently
elevated BP, is of clinical importance. These data
reinforce the potential to reassess the need for higher
doses and combination antihypertensive therapy in a
signicant proportion of treated individuals who are
assumed to have persistently elevated BP. This is not
unprecedented given reports from the Second Austra-
lian National Blood Pressure Study (ANBP II), which
demonstrated a similar phenomenon of normalized BP
(often sustained) following withdrawal of antihyper-
tensive therapy for trial purposes.
12
In this instance,
the treatment challenge was a low-dose ARB that
resulted in only 4% of participants requiring a rescue
randomization for markedly elevated BP in addition to
a further 10% who withdrew from the study for other
reasons. Such an approach (ie, structured proling and
initial BP management) that has been shown to
improve outcomes when applying more intensive anti-
hypertensive management
6,13
has equivalent potential
to identify those who may respond to lower doses of
antihypertensive therapy or even cease active pharma-
cotherapy, with the need for only routine surveillance
thereafter to ensure a more intensive approach isnt
required in time. At the very least, the results of the
randomized component of the VIPER-BP study (where
individual BP targets proved difcult to achieve)
8
demonstrated that the standardized run-in period was
effective in selecting a higher-risk group of participants
who truly required a more intensive approach to BP
management. Given the enormous primary care burden
of hypertension and its associated costs,
14
such an
approach to sorting the wheat from the chaff has the
potential to not only save costs (pending a formal
health economic analysis of study data) but ensure
valuable time and services are reserved for those who
need it most.
STUDY LIMITATIONS
Beyond the issue of regression to the mean, there are a
number of study limitations that require comment.
Firstly, given that this was a clinical trial, with pressure
to recruit eligible patients, it is certainly possible that
initial recruitment of participants with only slightly
elevated BP (above their initial BP target) occurred. BP
targets also became more stringent during the run-in
period as more denitive proling of diabetes status and
renal function were undertaken with the proportion of
randomized participants with an initial vs nalized BP
target of <140/90 mm Hg changing from 34% to 29%.
Consistent with recently updated National Institute of
Clinical Excellence recommendations in the United
Kingdom,
15
it might be argued that the lower and more
stringent risk-based BP targets will soon be replaced
with historically higher BP targets. As in most clinical
settings, we relied on ofce BP measurements (with
strict protocols) but not 24-hour ambulatory BP mon-
itoring or home BP monitoring, which may well have
reduced the number of eligible participants by revealing
a greater component of underlying white-coat hyper-
tension.
4
We also relied on self-reported adherence to
prescribed therapy. Moreover, as a nonblinded study,
we cannot determine whether a placebo arm would
have had a similar impact, although everyone received
the standardized therapy and there appeared to be a
marked, dichotomous response. We also do not have
extended follow-up for nonrandomized participants,
nor did we examine potential changes in lifestyle during
this period (although these are unlikely to explain the
major changes in BP prole over 28 days). Finally, as
this was a clinical trial cohort being managed with the
Australian health care system and being treated with
the same ARB therapy, all interpretation of study data
and its implications for other clinical settings needs to
be applied cautiously, particularly as patient visits
and drug treatment are provided free or are heavily
subsidized.
CONCLUSIONS
Despite these limitations, however, these data derived
from one of the largest trials of BP management in
primary care demonstrate a clear potential to sort the
wheat from the chaff in respect to the need for less
rather than more intensive antihypertensive therapy in
some individuals. The relatively simple act of providing
more care and attention (particularly among women
and those with a BP close to their ideal target) appears
to provide a therapeutic response in up to one fth of
individuals with elevated BP.
AUTHOR CONTRIBUTIONS
All authors were involved in the original design,
conduct, and interpretation of the VIPER-BP study.
Data were generated from the original study dataset
under the supervision of MC and SS. SS wrote the rst
draft of the manuscript and all authors contributed
Ofcial Journal of the American Society of Hypertension, Inc. The Journal of Clinical Hypertension Vol 15 | No 9 | September 2013 679
Early BP Control in Primary Care | Stewart et al.
to data interpretation and nalizing the submitted
manuscript.
Acknowledgments: We gratefully acknowledge all GP investigators
8
and study
nurse coordinators for participating in the VIPER-BP study. VIPER-BP was
designed by Baker IDI Heart and Diabetes Institute (Simon Stewart, Melinda
Carrington, and Garry Jennings) in consultation with a scientic advisory board
(Craig Anderson, John Amerena, Alex Brown, Louise Burrell, Fred DeLooze,
Mark Harris,* Joseph Hung, Henry Krum, Mark Nelson, Markus Schlaich, Nigel
Stocks).
Sources of funding: SS and MC are supported by the National Health and
Medical Research Council of Australia. This research was sponsored by
Novartis Pharmaceuticals Australia Pty Ltd. It was also supported in part by
the Victorian Governments Operational Infrastructure Support Program.
Disclosures: This research was sponsored by Novartis Pharmaceuticals
Australia Ltd (*did not receive funding). The study was designed by the
VIPER-BP investigators in consultation with the sponsors.
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