Magnitude of blood pressure reduction in the placebo arms of modern hypertension
trials: implications for trials of renal denervation.
Author(s): Patel HC(1), Hayward C(2), Ozdemir BA(2), Rosen SD(2), Krum H(2), Lyon AR(2),
Francis DP(2), di Mario C(2).
Affiliation(s): Author information:
(1)From the National Institute of Health Research Cardiovascular Biomedical
Research Unit, Department of Cardiology, Royal Brompton Hospital, London, United
Kingdom (H.C.P., C.H., A.R.L., C.d.M.); Faculty of Medicine, National Heart and
Lung Institute, Imperial College, London, United Kingdom (H.C.P., C.H., S.D.R.,
A.R.L., D.P.F., C.d.M.); Department of Outcomes Research, St. George's Vascular
Institute, St George's University, London, United Kingdom (B.A.O.); Department of
Cardiology, Ealing Hospital NHS Trust, Southall, London, United Kingdom (S.D.R.);
and Monash Centre of Cardiovascular Research and Education in Therapeutics,
School of Public Health and Preventive Medicine, Monash University, Alfred
Hospital, Melbourne, Victoria, Australia (H.K.). h.patel3@rbht.nhs.uk. (2)From
the National Institute of Health Research Cardiovascular Biomedical Research
Unit, Department of Cardiology, Royal Brompton Hospital, London, United Kingdom
(H.C.P., C.H., A.R.L., C.d.M.); Faculty of Medicine, National Heart and Lung
Institute, Imperial College, London, United Kingdom (H.C.P., C.H., S.D.R.,
A.R.L., D.P.F., C.d.M.); Department of Outcomes Research, St. George's Vascular
Institute, St George's University, London, United Kingdom (B.A.O.); Department of
Cardiology, Ealing Hospital NHS Trust, Southall, London, United Kingdom (S.D.R.);
and Monash Centre of Cardiovascular Research and Education in Therapeutics,
School of Public Health and Preventive Medicine, Monash University, Alfred
Hospital, Melbourne, Victoria, Australia (H.K.).
Publication date & source: 2015, Hypertension. , 65(2):401-6
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.
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