Placebo responses in blinded hypertension RCTs
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Magnitude of blood pressure reduction in the placebo arms of modern hypertension
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trials: Implications for trials of renal denervation.
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Running Title: Placebo responses in blinded hypertension RCTs
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Hitesh C Patel,1,2,* Carl Hayward,1,2,* Baris Ata Ozdemir,3 Stuart D Rosen,2,4 Henry Krum,5
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Alexander R Lyon,1,2 Darrel P Francis,2 Carlo di Mario1,2
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1
NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, UK
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2
National Heart and Lung Institute, Imperial College, London, UK
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3
Department of Outcomes Research, St. George’s Vascular Institute, St George’s University,
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London, UK
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4
Department of Cardiology, Ealing Hospital NHS Trust, Southall, London, UK
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5
Monash Centre of Cardiovascular Research and Education in Therapeutics, School of
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Public Health and Preventive Medicine, Monash University, Alfred Hospital, Melbourne,
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VIC, Australia
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*HP and CH contributed equally to the manuscript
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Corresponding Author:
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Dr Hitesh Patel, Cardiology Research Fellow
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Cardiovascular BRU, Royal Brompton Hospital
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London UK, SW3 6NP
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Tel: +44 207 352 8121 x2920
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Fax: +44 207 351 8184
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Email: h.patel3@rbht.nhs.uk
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Placebo responses in blinded hypertension RCTs
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Abstract
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Early phase studies of novel interventions for hypertension, such as renal sympathetic
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denervation, are sometimes single-armed (uncontrolled). We explored the wisdom of this by
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quantifying the blood pressure fall in the placebo arms of contemporary trials of
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hypertension.
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We searched Medline up to June 2014 and identified blinded, randomized trials of
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hypertension therapy in which the control arm received placebo medication or a sham
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(placebo) procedure. For non-resistant hypertension, we identified all such trials of drugs
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licensed by the US Food and Drug Administration since 2000 (five drugs). This US Food and
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Drug Administration related restriction was not applied to resistant hypertension trials. This
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produced 7451 patients who were allocated to a blinded control from 52 trials of non-resistant
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hypertension, and 694 patients from 8 trials of resistant hypertension (three drugs and two
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interventions).
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Systolic blood pressure fell by 5.92mmHg (95% confidence interval: 5.14-6.71; p<0.0001) in
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the non-resistant cohort and by 8.76 mmHg (95% confidence interval: 4.83-12.70; p<0.0001)
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in the resistant cohort. Using meta-regression, the falls were larger in trials that did not use
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ambulatory blood pressure monitoring as an inclusion criterion (z=2.84, p=0.0045), in those
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with higher baseline blood pressures (z=-0.3, p=0.0001) and those where the patients were
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prescribed a continuous background of anti-hypertensives (z=-2.72, p=0.0065).
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The non-trivial magnitude of these apparent blood pressure reductions with perfectly
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ineffective intervention (placebo) illustrates that efficacy explorations of novel therapies for
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hypertension, once safety is established, should be performed with a randomized,
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appropriately controlled and blinded design.
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Keywords: Hypertension; Randomized controlled trial; Renal denervation; Placebo;
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Meta-analysis
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Placebo responses in blinded hypertension RCTs
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Magnitude of blood pressure reduction in the placebo arms of modern hypertension
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trials: implications for trials of renal denervation
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Introduction
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The sham arm of the SYMPLICITY HTN-3 trial reported a reduction in systolic blood
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pressure of 11.8mmHg which was not significantly different from the active arm.1 This led to
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a widespread moratorium on renal sympathetic denervation as a treatment for resistant
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hypertension. The placebo arm results of SYMPLICITY HTN-3 were a surprise to those
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expecting to replicate SYMPLICITY HTN-2 in which the open-control arm had a 1mmHg
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increase in systolic blood pressure.2 In this article we analyse whether the results from the
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placebo arm of SYMPLICITY HTN-3 are out of keeping with findings from the placebo
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arms of other hypertension trials.
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Methods
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Resistant hypertension is a term applied to a cohort of patients in whom a combination of
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three or more anti-hypertensives (one of which is a diuretic) has failed to control their blood
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pressure.3 Though commonly overlooked, white coat hypertension4 and non-compliance need
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to be excluded to confirm the diagnosis. 5 Important differences exist between resistant and
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non-resistant hypertensives, with the former associated with a higher prevalence of obesity,
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longer duration of hypertension and more end organ damage.6 As such, we performed a meta-
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analysis of a series of hypertension trials, considering the resistant and non-resistant subjects
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separately. To minimise bias we included only those trials that have a randomized,
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placebo/sham controlled and blinded design.
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Search strategy, eligibility criteria and data extraction
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The United States Food and Drug Administration (FDA) has approved five drugs for
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hypertension since 2000 (azilsartan, aliskiren, nebivolol, eplerenone and olmesartan). We
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restricted our analysis of trials of non-resistant hypertension to those involving these licensed
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drugs. We searched Pubmed for trials using the following criteria: (((([Drug name]) AND
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Random*) AND Control*) AND Blind*). We also searched the FDA Medical Reviews for
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each of the drugs (listed on the Drugs@FDA database). To identify trials of resistant
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hypertension, the following search fields were used: ((((Resistant) AND Hypertension) AND
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Control*) AND Random*). searches were limited to ‘humans’, in English language and with
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date ranging from the start of PubMed to June 2014. We also performed a manual search of
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citation lists, review articles and PubMed links to related citations.
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Two reviewers independently scrutinised the search results (HP and CH). Trials were
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selected if their design was randomized, controlled (placebo or sham), parallel group and
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blinded. Data on baseline demographics, blood pressure inclusion criteria, trial duration (time
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in weeks from randomisation to planned final follow-up) and change in systolic and diastolic
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blood pressures in the placebo/sham arms were extracted. Where this was not possible, the
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trial was excluded from the pooled series. When blood pressure changes were reported at
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multiple time points, we used the time that was stated as the primary outcome. Discrepancies
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were resolved by discussion and consensus.
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Statistics
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To compare the baseline characteristics of the non-resistant and resistant hypertension trials,
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the independent sample t-test was used to compare sample size-weighted continuous
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variables and Fisher’s exact test was used to compare categorical data. Standard deviations
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(SD) and standard errors (SE) are quoted as appropriate. A meta-analysis was conducted for
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the selected trials, weighting the effect size estimates by the inverse variance. We pooled the
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data on office blood pressure effect size using a random effects model and present them as
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weighted mean differences with 95% confidence intervals. Trial heterogeneity is expressed
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using Chi2 and I2.
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To explore any heterogeneity in the trials, a multi-variable meta-regression analysis was
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applied to the non-resistant hypertension trials. The best model was described using R2, the
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unstandardised beta coefficient and the standardised coefficient to rank the relative
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contribution of each covariate to the model. Data analysis was carried out with Review
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Manager (v5.3, The Cochrane Collaboration) and the programme R using the metafor
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package.7 All analyses were performed independently by two authors (HP and BO) with
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discrepancies in findings resolved by discussion.
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Results
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Non-resistant Hypertension Trials
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Fifty-two trials fulfilled our inclusion criteria, involving 7451 patients who were allocated to
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blinded placebo (online supplement- figure S1). The key characteristics of each trial are
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summarised in the online supplement- figure S2. All but eight of the trials recruited patients
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using only diastolic blood pressure cut-offs. Thirteen trials had more stringent inclusion
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criteria, which required not only elevated office blood pressure measurements but also
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elevated ambulatory measurements. Thirty-eight trials mandated that patients should be on no
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therapy for hypertension at the time of randomisation (i.e. patients underwent a complete
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drug washout phase).
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There was a significant blood pressure reduction in the control arm, 5.92mmHg (95% CI:
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5.14, 6.71; p<0.0001) systolic and 5.40mmHg (95% CI: 4.80, 6.01; p<0.0001) diastolic
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(Figure 1). The sample size weighted baseline blood pressure for these trials was 155/98
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mmHg with a mean study period of 8.5 weeks (Table 1).There was significant heterogeneity
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in trial characteristics, with an I2 value of 0.71 for the systolic blood pressure effect,
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suggesting that 71% of the observed variance could be explained by differences between the
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studies and hence might be explained by study-level covariates. For diastolic blood pressure
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change, the I2 was 80%.
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For systolic blood pressure, meta-regression analysis (Table 2) found that the predictors of
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the fall in the placebo arm were, in decreasing order of importance, baseline blood pressure,
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the use of ambulatory blood pressure monitor readings as an inclusion criterion and the
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number of anti-hypertensive medications being taken at randomisation. The reduction in
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blood pressure in the control arm was less in trials that used ambulatory monitoring. Trials of
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patients with higher baseline systolic blood pressures and those with patients on anti-
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hypertensives at randomisation observed a greater fall in pressure in the control arm. The
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overall R2 was 0.38 (i.e. the model accounts for 38% of the heterogeneity). The
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unstandardized regression coefficient for baseline office systolic blood pressure was -0.3,
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which equates to an additional 0.3mmHg blood pressure reduction (in the placebo arm) for
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every 1mmHg higher baseline systolic blood pressure. Similarly, for every additional blood
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pressure tablet taken at baseline, there is an expected further 2.43mmHg decrease with
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placebo. The use of ambulatory monitoring as an inclusion criterion is a categorical variable
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(no/yes) as opposed to a continuous one, which changes the interpretation of its
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unstandardized regression coefficient. Where ambulatory monitoring is used there is an
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associated 2.48mmHg reduction in the magnitude of systolic blood pressure reduction with
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placebo.
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Trials which used ambulatory blood pressure monitor measurements as well as office blood
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pressure recordings (on separate days) as an inclusion criterion (online supplement- S2) had
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smaller reductions in blood pressure in the placebo arm than those in studies based solely on
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measurement of office blood pressure (systolic blood pressure effect: 3.37mmHg (SE= 0.93)
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vs. 6.76mmHg (SE= 0.39), p<0.0001 for difference between groups.
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For diastolic blood pressure, the use of ambulatory blood pressure monitors for recruitment
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and baseline diastolic blood pressure associated significantly with the magnitude of blood
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pressure reduction in the placebo arm (R2 of 0.50) (Table 2). The direction of change was as
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described for systolic blood pressure responses earlier.
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Age, trial duration, washout/run-in period duration and drop-out rate (which includes
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protocol violations, unsatisfactory therapeutic effects, adverse events, withdrawal of patient
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consent and loss to follow-up) were not significantly associated with either systolic or
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diastolic placebo responses and were consequently removed from the models.
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Resistant Hypertension Trials
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The literature search algorithm yielded 236 potential studies of resistant hypertension (online
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supplement- figure S1). After applying our inclusion criteria, all but 8 trials were excluded,
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and these studies randomized a total of 694 subjects to the control arm (online supplement-
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figure S2). The average number of antihypertensives consumed at baseline was 4.1 (Table 1).
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Diuretics were taken by 98% of patients, inhibitors of the renin-angiotensin system by 97%,
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calcium channel blockers by 72% and beta-blockers by 68%. Two of the trials were non-
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pharmacological, investigating renal sympathetic denervation1 and baroreceptor activation8 as
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therapies.
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There was a significant blood pressure reduction in the control arms; 8.76 mmHg (95% CI:
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4.83, 12.70, p<0.0001) systolic and 3.56 mmHg (95% CI: 1.45, 5.95, p=0.001) diastolic
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(Figure 1). The sample size weighted baseline blood pressure for these trials was 160/91 with
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mean study period of 17.6 weeks (Table 1). There was significant heterogeneity between the
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trials. The I2 was 77% with respect to systolic blood pressure response and 79% with diastolic
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blood pressure.
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Invasive placebo procedures showed a non-significant trend towards a greater placebo
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response on systolic blood pressure than medication in the treatment of resistant hypertension
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(-13.2 ±2.4 (SE) mmHg vs -7.24 ±2.4 (SE) mmHg, p=0.102).
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Differences between the trials of non-resistant and resistant hypertension
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There are key differences in study design and patient related features between the two sets of
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trials (Table 1). The placebo/sham systolic blood pressure response size was significantly
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greater in the resistant hypertension trials by 2.84 mmHg (95% CI: 5.67, 0.00, p=0.0497).
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There was no difference between the two groups with respect to diastolic blood pressure (-
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1.7mmHg 95% CI: -0.41, 3.81, p=0.114).
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Discussion
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On average, systolic blood pressure falls by ~6mmHg in the placebo/sham arms in trials of
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non-resistant hypertension and ~9mmHg in the trials of resistant hypertension. Blood
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pressure reductions of this size are not trivial and, if genuine, would deliver a 14% decrease
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in stroke and 7% reduction in mortality.9
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It seems very unlikely that there is a genuine biological effect of the placebo on blood
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pressure. More likely, there are three broad contributors to the reduction in blood pressure
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seen in the placebo arm of hypertension trials.12
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Regression to the mean
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Registries have repeatedly demonstrated that the higher the baseline blood pressure, the
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bigger the fall after intervention.10,11 This effect occurs whenever a variable has inherent
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biological variability and patients are selected on the basis of recording a high value.
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Statistically, it is known as regression to the mean. We have previously suggested an informal
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term, “big-day bias”.12 In short, if the selection process preferentially selects patients on a
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big-day, subsequent measurements are pre-destined to be lower. The larger the spontaneous
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temporal biological variability, and the more intense the selection, the larger the statistical
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expectation of fall in the variable, without any intervention.
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Indeed our pooled data showed evidence of regression to the mean at the study level; those
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studies with higher starting baseline blood pressures demonstrated greater responses in the
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placebo group. Measures to reduce regression to the mean include taking multiple blood
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pressure measurements across several weeks prior to randomising patients. Our data support
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this notion as those studies that used ambulatory monitoring to determine eligibility displayed
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smaller placebo responses.
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Unintentional bias by clinical observers
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The second source may be related to clinicians and their training to use all clinical
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information in making decisions. There may therefore be a temptation (“check-once-more
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bias”) to re-measure values that seem superficially inconsistent with what the clinician
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knows. For example, imagine a patient enrolled in a double-blind trial is having a follow up
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blood pressure measurement. Suppose the patient is receiving placebo, although of course the
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clinician is unaware of the study arm allocation. If the pressure is by chance an unusually low
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value, the clinician might accept this (recognising that some patients are having efficacious
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therapy). If, in contrast, the pressure is an unusually high value, the clinician (knowing that
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neither arm is receiving a blood-pressure raising therapy) might be more likely to consider
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the value erroneous and in need of repeating. The net effect would be to trend blood pressure
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measurements downwards.13
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A previous comparison of office and ambulatory blood pressure reduction in randomized
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placebo-controlled blinded drug trials may be instructive.14 While the effects beyond placebo
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were identical regardless of whether documented by staff (office blood pressure) or
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documented by machine (ambulatory blood pressure), the effects within the placebo arm
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were significantly larger when documented by staff than by machine. This suggested a ~2.9
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mmHg artificial appearance of pressure drop with staff-documented blood pressures.
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Ambulatory monitoring should be considered not only to reduce bias in patient selection for a
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trial but also to monitor their response to therapy. This approach has been shown to be useful
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in recent head to head trials15 as well as placebo controlled ones.16
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Improvement in Compliance
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The third source is the potential for patients to increase compliance to antihypertensive
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medications when participating in a trial due to patient observation and education. Poor
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compliance with medications has long been shown to contribute to uncontrolled
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hypertension. Studies employing high-performance liquid chromatography-tandem mass
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spectrometry urine analysis have demonstrated full or partial drug non-compliance in up to
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53% of resistant hypertensives5 and 25% of all patients in a specialist hypertension clinic.17
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Longitudinal studies to objectively ascertain changes in compliance with hypertension
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medications over time are lacking but there is evidence linking poor adherence to increased
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risk of stroke in both the short and long term.18
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Our study found that the greater the number of anti-hypertensive medications prescribed at
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baseline, the greater the drop in blood pressure in the control group. This would be expected
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if trial participation resulted in increased compliance. One approach to minimizing this in
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trials is to replace the prior medications with a single blind inert tablet in a phase known as
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run-in prior to randomisation. Some non-resistant hypertension trials have chosen to give an
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active drug during the single blind run-in period. In contrast, all the trials of resistant
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hypertension continued prior medications, which may have contributed to the larger
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reductions in blood pressure observed in the placebo arm of these trials. In addition to
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improved compliance, patient education and observation can reduce their level of anxiety,
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which might contribute to a reduction in blood pressure.
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Procedural versus medical placebo
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There has been a suggestion that trials which involve an elaborate or invasive sham procedure
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are prone to larger placebo effects.19,20,21 Our pooling of data from resistant hypertension
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trials was underpowered but it did show a trend that might support this notion. This
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phenomenon was particularly visible in the RHEOS Pivotal Trial8 in which 322 patients with
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resistant hypertension were implanted with baroreceptor stimulators. The patients were
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monitored for a month with the device in situ (turned off) and then randomized 2:1 in a
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blinded fashion to device on or off. An 8mmHg drop in blood pressure was seen after
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implantation, before the device was even turned on.
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A contributor to the greater effect seen in the trials of invasive sham might be that they had
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greater scope for regression to the mean bias, since they had a higher enrolment threshold
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systolic blood pressure, at 160 mmHg versus the 140 mmHg of other resistant hypertension
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trials.
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Limitations
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We have restricted our analysis to contemporary data. Global awareness of hypertension has
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improved over the last 20 years, not just for physicians but also for patients. Using historic
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trials would therefore not be representative. For the second analysis we identified all trials
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that treated patients with resistant hypertension using placebo/sham control and blinding.
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This excluded several trials including SYMPLICITY HTN-2, reducing further the number of
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trials in the resistant hypertension group. However, inclusion of these unblinded studies
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would not have answered our study question of the size of the fall in pressure in an
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appropriately blinded placebo arm.
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The majority of the trials did not clearly state the proportion of patients in the placebo group
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who may have received additional anti-hypertensive drugs during follow-up as a result of
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protocol violation. However 50/52 non-resistant hypertension trials did report the study
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withdrawal rate, which we used as a surrogate. This was not found to be an important
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modifier of fall in blood pressure in the control group.
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We performed meta-regression analysis as a hypothesis generating exercise to try and
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understand the factors (at the trial-level) that affect the placebo response. We cannot imply
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causality in any of our assertions. We did not perform meta-regression on the resistant
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hypertension trials as the number of available trials is small.22 This paucity of robust clinical
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trials on resistant hypertension also has implications in clinical practice, with little guidance
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on how to manage this challenging medical condition. Statistically, our findings from the
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non-resistant hypertension meta-analysis should not be extrapolated to the resistant
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hypertension trials due to the large differences between the populations.
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Perspectives
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The 11.7mmHg reduction in systolic blood pressure in SYMPLICITY HTN-3 should not be
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considered surprisingly large. The only other anti-hypertensive sham-controlled device trial
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observed a systolic blood pressure drop of 17mmHg. Placebo arms in drug trials also
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demonstrate a non-trivial reduction in blood pressure of the order of 6mmHg. When the
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genuine effect of an interventional therapy may be similar in magnitude to this, we suggest
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that in future it is unwise to design a trial that is unable to distinguish the genuine effect of
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the intervention from the placebo response. When novel therapies for hypertension undergo
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exploration for efficacy, we recommend from the outset a study design with appropriate
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randomisation and blinding.
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Funding
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HP and CH are supported by the National Institute of Health Research (NIHR)
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Cardiovascular Biomedical Research Unit at the Royal Brompton Hospital, London. DPF is
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supported by a British Heart Foundation Senior Research Fellowship (FS/10/038). ARL is
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supported by a British Heart Foundation Intermediate Research Fellowship.
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Disclosures
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HK, DPF, CDM have received honoraria and travel support from Medtronic Inc. HK has
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additionally consulted for Merck, Pfizer, Mesoblast, Novartis, Roche, Schering Plough,
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Servier and Gilead Sciences.
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benign hypertensive disease. Circulation. 1956;14:260-264.
22
Baker W, White M, Cappelleri J, Kluger J, Coleman C, From the Health Outcomes, Policy,
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Placebo responses in blinded hypertension RCTs
HYPE201404640 R2
Novelty and Significance
What is new?

The expected magnitude of the fall in blood pressure in the control arm of robustly
designed clinical trials has not been adequately reported.
What is relevant?

There is an average 6mmHg drop in systolic blood pressure in the control arm of clinical
trials of non-resistant hypertension and 9mmHg in trials of resistant hypertension, which
is useful information to those planning a trial.
Summary
This meta-analysis included 52 trials of non-resistant hypertension and 8 trial of resistant
hypertension with a total of 8145 patients allocated to placebo or sham control. There is a
non-trivial reduction in blood pressure in control arms of clinical trials. Explanations for this
include several biases which are discussed. If an investigator seeks to prove efficacy of a
novel therapy in hypertension, it is paramount that the trial be randomized, blinded and
appropriately controlled.
Table and Figure Legends:
Table 1: Sample size weighted summaries of key characteristics of the trials of nonresistant and resistant hypertension (HTN). Continuous data is presented as mean
(standard deviation) and count data as number (%). SBP= systolic blood pressure;
DBP= diastolic blood pressure; ABPM= ambulatory blood pressure monitoring.
Table 2: Summary of the meta-regression model for blood pressure effects. SBP=
systolic blood pressure; DBP= diastolic blood pressure; ABPM= ambulatory blood
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Placebo responses in blinded hypertension RCTs
HYPE201404640 R2
pressure monitor. The larger the modulus of the z-value the greater the influence of the
co-variate on the dependent variable.
Figure 1: Forest Plots for systolic blood pressure (SBP) effects [left] and diastolic blood
pressure (DBP) effects [right] for non-resistant hypertension trials [white background]
and resistant hypertension trials [grey background].
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