Magnitude of Blood Pressure Reduction in the Placebo Arms of Modern Hypertension Trials

Abstract

Early phase studies of novel interventions for hypertension, such as renal sympathetic denervation, are sometimes single-armed (uncontrolled). We explored the wisdom of this by quantifying the blood pressure fall in the placebo arms of contemporary trials of hypertension. We searched Medline up to June 2014 and identified blinded, randomized trials of hypertension therapy in which the control arm received placebo medication or a sham (placebo) procedure. For nonresistant hypertension, we have identified all such trials of drugs licensed by the US Food and Drug Administration since 2000 (5 drugs). This US Food and Drug Administration–related restriction was not applied to resistant hypertension trials. This produced 7451 patients, who were allocated to a blinded control from 52 trials of nonresistant hypertension and 694 patients from 8 trials of resistant hypertension (3 drugs and 2 interventions). Systolic blood pressure fell by 5.92 mm Hg (95% confidence interval, 5.14–6.71; P <0.0001) in the nonresistant cohort and by 8.76 mm Hg (95% confidence interval, 4.83–12.70; P <0.0001) in the resistant cohort. Using metaregression, the falls were larger in trials that did not use ambulatory blood pressure monitoring as an inclusion criterion ( z =2.84; P =0.0045), in those with higher baseline blood pressures ( z =−0.3; P =0.0001), and in those where the patients were prescribed a continuous background of antihypertensives ( z =−2.72; P =0.0065). The nontrivial magnitude of these apparent blood pressure reductions with perfectly ineffective intervention (placebo) illustrates that efficacy explorations of novel therapies for hypertension, once safety is established, should be performed with a randomized, appropriately controlled, and blinded design.

A Network Meta-Analysis of Clinical Management Strategies for Treatment-Resistant Hypertension: Making Optimal Use of the Evidence

“…, 58 At the same time, the effects of MRAs on SBP reduction did not differ from the effects of a sham procedure, another kind of placebo. While this may sound counterintuitive, these results are consistent with the literature as far as the difference in effect size between sham procedures and medication placebo both in this population and in general,30 , 59 , 60 while both have a marked effect on blood pressure reduction 30. It is possible that the enhanced clinical routine61 surrounding a sham procedure increases adherence to the background medications in these patients.…”

“…Using GRADE, results for the office SBP/DBP outcome were downgraded mainly due to imprecision and inconsistency (heterogeneity) across studies. This imprecision may be due to the fact that office blood pressure values are not particularly reliable, and are prone to be influenced by white-coat effects 30. In addition, inconsistency (heterogeneity) in office SBP and DBP was substantial or considerable,31 leading to unreliable conclusions.…”

“…Therefore, barostimulation therapy could not be compared in the main analysis, nor could we include the alpha blocker doxazosin or the beta blocker bisoprolol reported in the recent PATHWAY-2 study 57. At the same time, we are confident that we have been able to include all relevant studies reporting 24-h ABPM on MRAs, RDN and particularly placebo-controlled studies on any treatment strategy30 in the ATRHTN group, and were thus able to make indirect comparisons between these major strategies for the treatment of ATRHTN.…”

“…Records were assessed for eligibility and were excluded in the case of disease condition other than ATRHTN, studies not reporting primary clinical data, or case studies. In addition, two recent systematic reviews on MRAs,28 , 29 four recent meta-analyses of RDN17 , 21 – 23 and one meta-analysis on placebo effect in the ATRHTN population30 were checked for relevant references. PM and KJ independently extracted relevant data using a pre-specified form.…”

“…We used a Bayesian random effects network meta-analysis approach to analyze the data, and meta-regression adapted for multiple treatment comparisons. Using meta-regressions, we controlled for the effect of differences in the previously identified variables baseline blood pressure and number of medications used 30. Based on the search, the main treatment strategies assigned to the network nodes were: RDN, MRAs (spironolactone and eplerenone), placebo, sham, darusentan, CAA and regimens having more than 3 medications without an add-on.…”