determinants of achieving early blood pressure control with monotherapy in a primary care setting

Determinants of Achieving Early Blood Pressure Control withMonotherapy 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 StudyInvestigators

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., Australia7

This study sought to identify the determinants of early bloodpressure (BP) control associated with monotherapy inhypertensive individuals being managed in the primary caresetting. The Valsartan Intensified Primary Care Reduction ofBlood Pressure (VIPER-BP) study, was a multicenter, ran-domized controlled trial of an intensive approach to BPmanagement. During a standardized run-in, 2185 partici-pants commenced monotherapy (valsartan 80 mg/d) for 14to 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 totalof 416 of 2185 participants (19.0%) subsequently achieved

their individual BP target during run-in with a mean BPchange 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 earlyresponders were more likely to be women (adjusted oddsratio, 1.41; 95% confidence interval, 1.10–1.80), had lowerBP at baseline, were less likely to have been treatedpreviously (or for less time), and had a less stringent BPtarget. An initial period of monotherapy achieved BP controlin a high proportion of hypertensive individuals with keygroups (including women and de novo cases) more likely toshow an early BP response. J Clin Hypertens (Greenwich).2013;15:674–680. ª2013 Wiley Periodicals, Inc.

Elevated blood pressure (BP), or hypertension, representsone of themost preventable and yet seemingly intractablecontributors to cardiovascular disease (CVD). Overall,hypertension is estimated to contribute to around 30% to40% of all-cause or CVD-related case fatalities in high-income countries such as the United States.1 A criticalfactor in this phenomenon is the high proportion ofidentified individuals with hypertension who remainabove their BP target and therefore at sustained elevatedrisk 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 usingoffice-based measurements of BP, although there isincreasing focus on 24-hour ambulatory monitoringand home-based monitoring3 to minimize potentialwhite-coat or masked hypertension and inappropriateor foregone treatment.4 In Australia, nearly 1 in 10primary care encounters is related to hypertension5—more than any other single contributor to health careactivity. As indicated, despite an array of effectivepharmacologic agents, particularly when applied incombination (preferably a single pill to encourage treat-ment adherence), BP control rates remain suboptimal.

Beyond the application of pharmacotherapy, there isstrong evidence, including a Cochrane review of theliterature, that more intensive and structured manage-ment in the primary care setting will significantlyimprove BP control rates.6 We therefore conducted themulticenter, randomized Valsartan Intensified PrimaryCare Reduction of Blood Pressure (VIPER-BP) study7 totest the clinical effectiveness and overall safety of a moreintensive and structured approach to optimizing BPcontrol in a group of individuals with persistently highBP levels in primary care. During the randomizedcomponent 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 theintervention; 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 of2185 participants were exposed to a standardized run-inperiod comprising clinical profiling and low-dose angio-tensin receptor blockers (ARBs) for 28 days.

STUDY HYPOTHESISPrior to the commencement of the VIPER-BP interven-tion we hypothesised that <10% of initially eligible studyparticipants would achieve their individualized BP targetduring the study run-in period. We further hypothesizedthat if they did achieve this target (and were therefore not

Address for correspondence: Simon Stewart, PhD, PO Box 6492, StKilda Road Central, Melbourne, Vic. 8008, AustraliaE-mail: [email protected]

Manuscript received: March 21, 2013; revised: May 21, 2013;accepted: June 3, 2013DOI: 10.1111/jch.12164

674 The Journal of Clinical Hypertension Vol 15 | No 9 | September 2013 Official Journal of the American Society of Hypertension, Inc.

ORIGINAL PAPER

eligible for study randomization), the majority of partic-ipants would be those who had only recently commencedantihypertensive therapy. As part of a prospectiveanalysis plan, therefore, we report on the proportionand characteristics of initially eligible participants inthe VIPER-BP study who responded to the standardizedrun-in period, as compared with those in whom BPremained elevated above their individualised target.

METHODSAs described in our previous reports describing therationale and design of the study7 and the primaryresults in favor of the study intervention of moreintensive primary care management overall,8 theVIPER-BP study was a pragmatic, multicenter random-ized controlled trial involving a total of 119 generalpractices Australia-wide. The study received ethicsapproval from all relevant bodies including the AlfredHospital Ethics of Human Research Committee, Mel-bourne, Australia, in accordance with the Declaration ofHelsinki (2008). After initial enrollment a total of 2185of 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 Hgfor those with established CVD, diabetes or other formsof end-organ damage, and >125/75 mm Hg for thosewith evidence of renal damage [proteinuria])9 entered astandardized run-in phase prior to randomization (seebelow). Key exclusion criteria included participantsreceiving triple antihypertensive therapy to control theirBP at the time of enrolment, those who had a systolic BP>180 mm Hg, and anyone who was unable to provideinformed consent and/or was intolerant to or contrain-dicated for the planned study therapy (including ARBs).

Initial Profiling and Run-In TreatmentFollowing initial study enrollment, a standardizedprocess of clinical profiling and study treatment wasinitiated. Clinical profiling (facilitated by a computerprogram provided by Baker IDI, Melbourne, Vic.,Australia) ensured that all participants entering therun-in phase had their BP levels verified and their initialBP targets established according to their absolute riskfor a 5-year cardiovascular event (based on the Fra-mingham Risk Score)10 and evidence of pre-existingCVD, diabetes, or potential end-organ damage causedby elevated BP. The latter two comprised furtherdelineation of initial BP targets based on more definitiveinvestigation of potentially undiagnosed diabetes and/orrenal damage (based on initial urine dip-stick testing forproteinuria). As described in more detail previously, BPwas recorded according to a standardized protocol andusing validated automated devices. It should be empha-sized, therefore, that the initial BP target (at study run-in) could be lowered by randomization followingfurther clinical investigation.

At the commencement of study run-in, all previouslyprescribed antihypertensive therapy was ceased and astarting dose of valsartan 80 mg/d was initiated.

Participants were then scheduled to return at 14 and28 days post-commencement of run-in for BP assess-ment by their general practitioner (GP) and study teamat the participating clinic. Rescue randomization wasinitiated if, at 14 days (or any time during the run-instage), the patient recorded a systolic BP >180 mm Hgor the GP believed it was clinically indicated toimmediately commence higher doses of antihypertensivetherapy for that individual. There were 3 possibleoutcomes for the 2185 participants who commenced theVIPER-BP study run-in phase: (1) randomization intothe comparison phase of the VIPER-BP study due to thelack of achievement of individualized BP control within28 days (with potential rescue randomization at day14), (2) “early response” to the run-in phase oftreatment with attainment of individualized BP target(finalized prior to potential randomization), and (3)early withdrawal (a total of 207 participants in thislatter group were withdrawn from the study prior torandomization). This group comprised 108 men (aged55�12 years) and 99 women (aged 61�12 years) ofwhom 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%) werewithdrawn according to investigator’s discretion, andthe remainder (n=17, 0.8%) due to other reasons. Thisreport focuses on the 1978 participants who were eitherrandomized (n=1562) or who achieved their individu-alized BP goal during the run-in phase (n=416); thelatter group representing 19.0% (95% confidenceinterval [CI], 17.4%–20.8%) of those who commencedthe run-in phase. Participants in groups 2 and 3 (ie,nonrandomized) were not subject to any further follow-up post–run-in.

Statistical AnalysesStudy data were analyzed using SPSS for Windowsversion 17.0 (SPSS Inc, Chicago, IL). Continuous dataare presented as mean�standard 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] and95% CIs) where appropriate. Independent correlates ofachieving individual BP target were determined bymultiple logistic regression using the variables listed inTable 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 womento identify potential differences.

RESULTS

Baseline CharacteristicsTable I summarizes the demographic and clinical profileof 1978 participants who completed the standardizedrun-in period according to their BP response at studyenrollment.

Overall, the mean age was 59 years, 60% were men,and 61% were prescribed antihypertensive therapy (for

Official 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. Asimilar proportion of participants had an initial BPtarget of ≤130/80 mm Hg (44%) or ≤140/90 mm Hg(41%). The demographic profile of male and femaleparticipants varied including age (women were slightlyolder), living, and employment status. Similarly, from aclinical perspective although there were more womenwith a history of hypertension, overall, the risk profile ofmale participants was elevated in comparison to theirfemale counterparts.

BP Change During the Standardized Run-In PeriodA total of 590 (29.8%) and 638 (32.3%) participantsrecorded a lower systolic and diastolic BP, respectively,from enrollment to the end of the 28-day study run-inperiod of valsartan 80 mg/d, respectively. The majorityof patients (around 70%) recorded a stable and evenincreased systolic (up to ≥60 mm Hg) and diastolic (upto ≥40 mm Hg) BP during the run-in period. There wasa strong but not complete linear relationship in themagnitude of change in systolic and diastolic BP among

TABLE I. Clinical and Demographic Profile 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 profile

Age, y 59.0�12.1 58.4�12.2 59.9�11.9 58.3�12.3 59.3�12.0

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 profile

Current smoker, % 293 (14.8) 197 (16.6) 96 (12.2) 50 (12.1) 243 (15.7)

Obese (BMI >30 kg/m2), % 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, % 14.0�9.4 16.7�9.9 9.8�6.7 11.8�8.4 14.6�9.6

AUSDRISK score, % 16.7�5.6 17.6�5.6 15.3�5.2 14.6�5.4 17.2�5.5

Clinical profile

Systolic/diastolic BP, mm Hg 152�13/90 �11 153�13/91�11 152�14/89�11 148�12/88�10 153�14/91�11

Total cholesterol, mmol/L 5.3�1.1 5.2�1.1 5.4�1.1 5.2�1.1 5.4�1.0

Low-density lipoprotein, mmol/L 3.1�1.0 3.1�1.0 3.1�1.0 3.0�1.0 3.3�0.9

High-density lipoprotein, mmol/L 1.4�0.5 1.3�0.5 1.6�0.5 1.4�0.5 1.5�0.5

Hemoglobin A1c in diabetics, % 7.1�1.7 7.3�1.7 6.8�1.5 7.0�1.7 7.2�1.6

Body mass index, kg/m2 30.6�6.3 30.6�6.0 30.8�6.8 29.7�6.5 30.9�6.3

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 m2 88.2�19.7 88.6�19.7 87.6�19.6 88.0�19.7 89.0�19.7

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) 3.3�6.4 6.2�8.4

Years of drug therapy 5.6�8.1 5.3�7.6 6.1�8.7 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 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.



participants. For every unit (mm Hg) of change indiastolic BP there was a 1.2 mm Hg change in systolicBP (r2=.50, P<.001). Overall, there was a gradient in BPresponse according to prior treatment but with inherentvariability (as demonstrated by non-Gaussiandistributions) within each treatment category: changein 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 prescribedno, 1, or 2 antihypertensive agents, respectively.

Responders Vs NonrespondersA larger than hypothesized group achieved their indi-vidualized BP target during the run-in period—416participants (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) weresubsequently randomized, including 84 participantswho were rescue randomized with markedly elevatedBP (184�14/98�13 mm Hg). Overall, the mean changein 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 thosewho were randomized on the basis of not reaching theirindividual BP target.

Table I also compares the demographic and clinicalprofiles of the two groups of responders andnonresponders. For example, there were proportion-ately fewer men, obese individuals, and participantspreviously treated for hypertension (with almost half thenumber of years of antihypertensive treatment amongsuch individuals) among those who subsequentlyachieved their individual BP target during the 28-dayrun-in period. Alternatively, participants with persis-tently elevated BP following the run-in period and

therefore randomized into the VIPER-BP study hadhigher baseline BP values and, in turn, higher absolutecardiovascular risk scores and potential to develop type2 diabetes (with almost double the number of pre-existing cases).

The Figure shows the overall pattern of BP responsefor the 3 different BP target groups (initial targets set bythe GP at the start of the run-in period) among early BPresponders 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 reachtheir individual target, a total of 22 of 299 participants(7.4%) achieved their BP target. This compared with116 of 861 (13.5%) in the <130/80 mm Hg BP targetgroup and 278 of 818 (34.0%) in the <140/90 mm Hggroup. There were similar changes in BP across all 3 BPtarget 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 whoachieved their BP target. A similar (but less pronouncedin 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 theBP target groups among those randomized on the basisof not achieving their individual BP target.

Table II shows the pattern of BP change from baselineto 14 and 28 days for men and women separatelyaccording to their BP status at the end of the study run-in. Overall, women had lower systolic BP values thanmen and the greatest differences were observed at14 days. Among those who achieved their individual BPtarget, women had the greatest decline in mean BPvalues (>4 mm Hg in systolic BP [P<.001] and1 mm Hg in diastolic BP [P<.05]) from baseline to28 days.

FIGURE. Change in mean systolic and diastolic blood pressure (BP) according to initial BP target and final 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.



Independent Correlates of Achieving Individual BPTargetAdjusting for demographic and clinical profile, womenwere almost 1.5-fold more likely than men to achievetheir individual BP target (24.1% vs 19.0% men:adjusted OR, 1.41; 95% CI, 1.10–1.80; P=.007) whileobese participants were less likely (16.9% vs 25.0%nonobese: OR, 0.63; 95% CI, 0.50–0.81; P<.001). Forevery 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 wereless likely to achieve their BP target. As hypothesized,patients already taking ≥1 more antihypertensive agentprior to study enrollment (13.7% vs the rest 32.6%:OR, 0.33; 95% CI, 0.25–0.42; P<.001) and/or pre-scribed combination therapy (7.0% vs the rest 22.9%:OR, 0.36; 95% CI, 0.20–0.62; P<.001) were also lesslikely to achieve their target BP during this timeframe.Overall, compared with those not taking prior antihy-pertensive treatment, participants prescribed one agentwere around one half less likely to achieve their BPtarget during run-in (OR, 0.51; 95% CI, 0.40–0.66;P<.001) and around one quarter likely than those taking2 agents (OR, 0.24; 95% CI, 0.14–0.42).

The duration of prescribed antihypertensive therapywas also important, with those treated for longer beingless 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 estab-lished at baseline, the more likely a participant achievedthe BP goal (OR, 2.01, 95% CI, 1.23–3.29; P<.005 andOR, 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 corre-lates of achieving individual BP target were found inmen and women, with one notable exception: marriedwomen were around 2-fold less likely to achieve theirBP target (adjusted OR, 0.49; 95% CI, 0.26–0.93 vsnonmarried women; P=.028).

DISCUSSIONWhen designing the VIPER-BP study, we hypothesizedthat a maximum of 1 in 10 patients being managed forhypertension in the primary care, when challenged witha standardized period of clinical profiling and low-doseARB therapy, would achieve their individualized BPtarget. In reality, excluding those who withdrew fromthe early stages of the study for other reasons (around1 in 3 participants) had a positive BP response, withalmost 1 in 5 participants overall achieving theirindividual 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 amean fall of 22/14 mm Hg in systolic and diastolic BPand in women an even greater mean fall of 26/15 mm Hg. Alternatively, for a majority of those whoremained 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) witha mean overall fall in systolic and diastolic BP of 4/3 mm Hg. On an adjusted basis, early BP responderswere more likely to be women (1.5-fold more likely toachieve their BP target compared with men), althoughmarried women were less likely to have an early BPresponse compared with nonmarried women. Early BPresponders had a lower presenting systolic and/ordiastolic 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 assignedan initial BP target of ≤140/90 mm Hg compared withthe more stringent targets. In both sexes, there was aclear gradient in respect to BP control according to morestringent targets. Ultimately, this meant that the run-inperiod of the VIPER-BP study truly represented a“wheat from the chaff” process that meant that partic-ipants with both persistently elevated BP and morestringent BP targets based on absolute risk wererandomized 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 149.3�10.4 148.9�12.5 154.1�13.0 152.7�13.5

Diastolic BP mm Hg 88.5�9.9 88.5�10.2 91.5�11.3 89.7�10.8

Achieved BP target – – – –

14 days (n=1794)

Systolic BP mm Hg 129.5�7.4 125.5�8.4 150.2�16.7 147.9�17.1


Mean BP change mm Hg �19.3/�11.4 �20.8/�10.0 – –

28 days (n=1734)

Systolic BP mm Hg 127.9�7.1 126.3�9.6 150.2�16.4 148.8�17.1


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.



translation perspective, these data reinforce the poten-tial to achieve early BP control, particularly amongwomen, nonobese individuals, and those with a recenthistory of hypertension (as reflected in both the durationand intensity of prior treatment) via a fairly simpleprocess of structured care and treatment (in this case, alow-dose ARB). Individuals previously prescribed 2antihypertensive agents were least likely to respond(<1 in 10) to this strategy, while positive BP responseswere broadly apparent within 14 days and sustained upto 28 days.

It is important to emphasize that the study run-inperiod with multiple BP measuring points undoubtedlyunmasked the phenomenon of “regression to themean”11 with relatively small changes in BP valuesenabling 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 ARBtherapy, occurred in 40% of participants. However,the almost immediate impact of standardized profilingand management with a low-dose ARB (valsartan80 mg/d) in this large study cohort, among a predom-inance of individuals with a long history of persistentlyelevated BP, is of clinical importance. These datareinforce the potential to reassess the need for higherdoses and combination antihypertensive therapy in asignificant proportion of treated individuals who areassumed to have persistently elevated BP. This is notunprecedented given reports from the Second Austra-lian National Blood Pressure Study (ANBP II), whichdemonstrated 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 thatresulted in only 4% of participants requiring a rescuerandomization for markedly elevated BP in addition toa further 10% who withdrew from the study for otherreasons. Such an approach (ie, structured profiling andinitial BP management) that has been shown toimprove outcomes when applying more intensive anti-hypertensive management6,13 has equivalent potentialto identify those who may respond to lower doses ofantihypertensive therapy or even cease active pharma-cotherapy, with the need for only routine surveillancethereafter to ensure a more intensive approach isn’trequired in time. At the very least, the results of therandomized component of the VIPER-BP study (whereindividual BP targets proved difficult to achieve)8

demonstrated that the standardized run-in period waseffective in selecting a higher-risk group of participantswho truly required a more intensive approach to BPmanagement. Given the enormous primary care burdenof hypertension and its associated costs,14 such anapproach to sorting the wheat from the chaff has thepotential to not only save costs (pending a formalhealth economic analysis of study data) but ensurevaluable time and services are reserved for those whoneed it most.

STUDY LIMITATIONSBeyond the issue of regression to the mean, there are anumber of study limitations that require comment.Firstly, given that this was a clinical trial, with pressureto recruit eligible patients, it is certainly possible thatinitial recruitment of participants with only slightlyelevated BP (above their initial BP target) occurred. BPtargets also became more stringent during the run-inperiod as more definitive profiling of diabetes status andrenal function were undertaken with the proportion ofrandomized participants with an initial vs finalized BPtarget of <140/90 mm Hg changing from 34% to 29%.Consistent with recently updated National Institute ofClinical Excellence recommendations in the UnitedKingdom,15 it might be argued that the lower and morestringent risk-based BP targets will soon be replacedwith historically higher BP targets. As in most clinicalsettings, we relied on office BP measurements (withstrict protocols) but not 24-hour ambulatory BP mon-itoring or home BP monitoring, which may well havereduced the number of eligible participants by revealinga greater component of underlying white-coat hyper-tension.4 We also relied on self-reported adherence toprescribed therapy. Moreover, as a nonblinded study,we cannot determine whether a placebo arm wouldhave had a similar impact, although everyone receivedthe standardized therapy and there appeared to be amarked, dichotomous response. We also do not haveextended follow-up for nonrandomized participants,nor did we examine potential changes in lifestyle duringthis period (although these are unlikely to explain themajor changes in BP profile over 28 days). Finally, asthis was a clinical trial cohort being managed with theAustralian health care system and being treated withthe same ARB therapy, all interpretation of study dataand its implications for other clinical settings needs tobe applied cautiously, particularly as patient visitsand drug treatment are provided free or are heavilysubsidized.

CONCLUSIONSDespite these limitations, however, these data derivedfrom one of the largest trials of BP management inprimary care demonstrate a clear potential to “sort thewheat from the chaff” in respect to the need for lessrather than more intensive antihypertensive therapy insome individuals. The relatively simple act of providingmore care and attention (particularly among womenand those with a BP close to their ideal target) appearsto provide a therapeutic response in up to one fifth ofindividuals with elevated BP.

AUTHOR CONTRIBUTIONSAll authors were involved in the original design,conduct, and interpretation of the VIPER-BP study.Data were generated from the original study datasetunder the supervision of MC and SS. SS wrote the firstdraft of the manuscript and all authors contributed



to data interpretation and finalizing the submittedmanuscript.

Acknowledgments: We gratefully acknowledge all GP investigators8 and studynurse coordinators for participating in the VIPER-BP study. VIPER-BP wasdesigned by Baker IDI Heart and Diabetes Institute (Simon Stewart, MelindaCarrington, 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, NigelStocks).

Sources of funding: SS and MC are supported by the National Health andMedical Research Council of Australia. This research was sponsored byNovartis Pharmaceuticals Australia Pty Ltd. It was also supported in part bythe Victorian Governments Operational Infrastructure Support Program.

Disclosures: This research was sponsored by Novartis PharmaceuticalsAustralia Ltd (*did not receive funding). The study was designed by theVIPER-BP investigators in consultation with the sponsors.

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determinants of achieving early blood pressure control with monotherapy in a primary care setting

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