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 Intensified Primary Care Reduction of Blood Pressure (VIPER-BP) study, was a multicenter, randomized controlled trial of an intensive approach to BP management. During a standardized run-in, 2185 participants commenced monotherapy (valsartan 80 mg/d) for 14 to 28 days. A total of 1978 participants aged 59±12 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 −22.6±12.1/−12.9±8.2 mm Hg vs −4.2±16.2/−3.0±9.6 mm Hg for the rest (P<.001). These early responders were more likely to be women (adjusted odds ratio, 1.41; 95% confidence interval, 1.10–1.80), 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.
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. A critical factor in this phenomenon is the high proportion of identified individuals with hypertension who remain above their BP target and therefore at sustained elevated risk for a primary or secondary cardiovascular event. Given the volume of cases, the majority of such individuals are managed in the primary care environment using office-based measurements of BP, although there is increasing focus on 24-hour ambulatory monitoring and home-based monitoring to minimize potential white-coat or masked hypertension and inappropriate or foregone treatment. In Australia, nearly 1 in 10 primary care encounters is related to hypertension5—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 treatment 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 management in the primary care setting will significantly improve BP control rates. We therefore conducted the multicenter, randomized Valsartan Intensified Primary Care Reduction of Blood Pressure (VIPER-BP) study 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). However, prior to randomization, a total of 2185 participants were exposed to a standardized run-in period comprising clinical profiling and low-dose angiotensin receptor blockers (ARBs) for 28 days.
Prior to the commencement of the VIPER-BP intervention 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 eligible for study randomization), the majority of participants 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.
As described in our previous reports describing the rationale and design of the study and the primary results in favor of the study intervention of more intensive primary care management overall, the VIPER-BP study was a pragmatic, multicenter randomized 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, Melbourne, Australia, in accordance with the Declaration of Helsinki (2008). After initial enrollment a total of 2185 of 2337 (93.5%) participants with elevated BP according 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]) 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 contraindicated for the planned study therapy (including ARBs).
Initial Profiling and Run-In Treatment
Following initial study enrollment, a standardized process of clinical profiling and study treatment was initiated. Clinical profiling (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 verified and their initial BP targets established according to their absolute risk for a 5-year cardiovascular event (based on the Framingham Risk Score) 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 definitive 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 emphasized, 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 assessment 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 (finalized 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 55±12 years) and 99 women (aged 61±12 years) of whom 74 of 2185 (3.4%) were lost to follow-up, 56 (2.6%) experienced an adverse event, 40 (1.8%) withdrew their consent to participate, 20 (0.9%) were withdrawn according to investigator's 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 individualized BP goal during the run-in phase (n=416); the latter group representing 19.0% (95% confidence 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 post–run-in.
Study data were analyzed using SPSS for Windows version 17.0 (SPSS Inc, Chicago, IL). Continuous data are presented as mean±standard deviation and categorical 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 1 (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.
Table 1. Clinical and Demographic Profile of Study Cohort According to Sex and Initial BP Response
Achieved BP Target During “Run-In” (n=416)
Persistently Elevated BP (n=1562)
Abbreviations: ACE, angiotensin-converting enzyme; AUSDRISK, Australian Type 2 Diabetes Risk Assessment tool; BMI, body mass index; BP, blood pressure; ECG, electrocardiographic; GFR, glomerular filtration rate; LVH, left ventricular hypertrophy; NYHA, New York Heart Association. Obesity was defined as a body mass index >30 kg/m2. 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.
>12 years education, %
Live alone, %
Metropolitan area, %
Current smoker, %
Obese (BMI >30 kg/m2), %
Prior hypertension, %
Diabetes (type 1 or 2), %
Cerebrovascular disease, %
Coronary artery disease, %
Absolute risk score, %
AUSDRISK score, %
Systolic/diastolic BP, mm Hg
Total cholesterol, mmol/L
Low-density lipoprotein, mmol/L
High-density lipoprotein, mmol/L
Hemoglobin A1c in diabetics, %
Body mass index, kg/m2
NYHA class II, III, or IV, %
ECG evidence of LVH, %
Depressive symptoms, %
Estimated GFR, mL/min/172 m2
BP management at enrollment
Current drug therapy, %
Two antihypertensive agents, %
Years of drug therapy
Angiotensin receptor blocker, %
ACE inhibitor, %
Calcium antagonist, %
Initial BP target at commencement of run-in
BP ≤125/75 mm Hg, %
BP ≤130/80 mm Hg, %
BP ≤140/90 mm Hg, %
Table 1 summarizes the demographic and clinical profile 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 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 profile 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 profile 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 participants. For every unit (mm Hg) of change in diastolic BP there was a 1.2 mm Hg change in systolic BP (r2=.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 −11.4±16.7/−7.3±10.2 mm Hg, −5.5±15.7/−3.2±9.0 mm Hg, and +1.7±19.4/+0.6±10.7 mm Hg for those prescribed no, 1, or 2 antihypertensive agents, respectively.
Responders Vs Nonresponders
A larger than hypothesized group achieved their individualized BP target during the run-in period—416 participants (19.0%; 95% CI, 17.4%–20.8%). Consistent with the distribution of BP responses, 1562 participants (71.5% of those who commenced run-in) were subsequently randomized, including 84 participants who were rescue randomized with markedly elevated BP (184±14/98±13 mm Hg). Overall, the mean change in BP in those who achieved their target BP was −22.6±12.1/−12.9±8.2 mm Hg (early BP responders) compared with −4.2±16.2/−3.0±9.6 mm Hg in those who were randomized on the basis of not reaching their individual BP target.
Table 1 also compares the demographic and clinical profiles of the two groups of responders and nonresponders. For example, there were proportionately 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 persistently 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 2 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.
Table 2. Change in Mean Systolic and Diastolic BP According to Final BP Status and Sex
Achieved BP Target (n=416)
Change in blood pressure (BP) from baseline and achieved individualized BP target calculated only for individuals with data recorded at each time point.
Systolic BP mm Hg
Diastolic BP mm Hg
Achieved BP target
14 days (n=1794)
Systolic BP mm Hg
Diastolic BP mm Hg
Mean BP change mm Hg
28 days (n=1734)
Systolic BP mm Hg
Diastolic BP mm Hg
Mean BP change mm Hg
Independent Correlates of Achieving Individual BP Target
Adjusting for demographic and clinical profile, 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, 1.10–1.80; P=.007) while obese participants were less likely (16.9% vs 25.0% nonobese: OR, 0.63; 95% CI, 0.50–0.81; P<.001). For every unit increase in systolic BP (OR, 0.96; 95% CI, 0.95–0.97/mm Hg; P<.001) and diastolic BP (OR, 0.97; 95% CI, 0.96–0.98/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, 0.25–0.42; P<.001) and/or prescribed combination therapy (7.0% vs the rest 22.9%: OR, 0.36; 95% CI, 0.20–0.62; P<.001) were also less likely to achieve their target BP during this timeframe. Overall, compared with those not taking prior antihypertensive treatment, participants prescribed one agent were around one half less likely to achieve their BP target during run-in (OR, 0.51; 95% CI, 0.40–0.66; P<.001) and around one quarter likely than those taking 2 agents (OR, 0.24; 95% CI, 0.14–0.42).
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, 0.95–0.99 per year of treatment; P=.006). Finally, the less stringent the BP target established at baseline, the more likely a participant achieved the BP goal (OR, 2.01, 95% CI, 1.23–3.29; P<.005 and OR, 8.43; 95% CI, 5.20–13.7; 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 correlates 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, 0.26–0.93 vs nonmarried women; P=.028).
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 profiling 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 randomization 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 randomized, 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 treatment, were less likely to be prescribed 1 or 2 antihypertensive 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 participants with both persistently elevated BP and more stringent BP targets based on absolute risk were randomized into the subsequent study. From a clinical translation perspective, these data reinforce the potential to achieve early BP control, particularly among women, nonobese individuals, and those with a recent history of hypertension (as reflected 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” 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 antihypertensive therapy, even in the form of low-dose ARB therapy, occurred in 40% of participants. However, the almost immediate impact of standardized profiling and management with a low-dose ARB (valsartan 80 mg/d) in this large study cohort, among a predominance 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 significant proportion of treated individuals who are assumed to have persistently elevated BP. This is not unprecedented given reports from the Second Australian National Blood Pressure Study (ANBP II), which demonstrated a similar phenomenon of normalized BP (often sustained) following withdrawal of antihypertensive therapy for trial purposes. 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 profiling and initial BP management) that has been shown to improve outcomes when applying more intensive antihypertensive management[6, 13] has equivalent potential to identify those who may respond to lower doses of antihypertensive therapy or even cease active pharmacotherapy, with the need for only routine surveillance thereafter to ensure a more intensive approach isn't required in time. At the very least, the results of the randomized component of the VIPER-BP study (where individual BP targets proved difficult to achieve) 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, 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.
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 definitive profiling of diabetes status and renal function were undertaken with the proportion of randomized participants with an initial vs finalized 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, 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 office BP measurements (with strict protocols) but not 24-hour ambulatory BP monitoring or home BP monitoring, which may well have reduced the number of eligible participants by revealing a greater component of underlying white-coat hypertension. 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 profile 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.
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 fifth of individuals with elevated BP.
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 first draft of the manuscript and all authors contributed to data interpretation and finalizing the submitted manuscript.
We gratefully acknowledge all GP investigators 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 scientific 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 Government's Operational Infrastructure Support Program.
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.