Magnitude of blood pressure reduction in the placebo arms of modern hypertension trials: implications for trials of renal denervation.
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.
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.
Hitesh C
HC
Patel
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.).
Carl
C
Hayward
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.).
Baris Ata
BA
Ozdemir
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.).
Stuart D
SD
Rosen
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.).
Henry
H
Krum
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.).
Alexander R
AR
Lyon
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.).
Darrel P
DP
Francis
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.).
Carlo
C
di Mario
D000577:Amides / Q000627:therapeutic use; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001562:Benzimidazoles / Q000627:therapeutic use; D001578:Benzopyrans / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D018660:Blood Pressure Monitoring, Ambulatory; D035061:Control Groups; D004311:Double-Blind Method; D004351:Drug Resistance; D000077545:Eplerenone; D004983:Ethanolamines / Q000627:therapeutic use; D005650:Fumarates / Q000627:therapeutic use; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology / Q000601:surgery; D007093:Imidazoles / Q000627:therapeutic use; D007668:Kidney / Q000294:innervation*; D000068577:Nebivolol; D010069:Oxadiazoles / Q000627:therapeutic use; D015990:Placebo Effect; D010919:Placebos; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D012044:Regression Analysis; D012107:Research Design; D013148:Spironolactone / Q000031:analogs & derivatives / Q000627:therapeutic use; D013562:Sympathectomy; D013777:Tetrazoles / Q000627:therapeutic use; D016896:Treatment Outcome
D000577:Amides; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001578:Benzopyrans; D004983:Ethanolamines; D005650:Fumarates; D007093:Imidazoles; D010069:Oxadiazoles; D010919:Placebos; D013777:Tetrazoles; D000068577:Nebivolol; D013148:Spironolactone; C446481:aliskiren; D000077545:Eplerenone; C437965:olmesartan; C521273:azilsartan
hypertension; meta-analysis; placebos; randomized controlled trial