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Effects of Blood Pressure Reduction in Mild Hypertension: A Systematic Review and Meta-analysisEffects of Blood Pressure Reduction in Mild Hypertension

Johan Sundström, MD, PhD; Hisatomi Arima, MD, PhD; Rod Jackson, MBChB, PhD; Fiona Turnbull, MBChB, MPH (Hons), PhD; Kazem Rahimi, MD; John Chalmers, MD, PhD; Mark Woodward, PhD; Bruce Neal, MBChB, PhD, on behalf of the Blood Pressure Lowering Treatment Trialists' Collaboration*
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* For a list of the members of the Blood Pressure Lowering Treatment Trialists' Collaboration, see the Appendix.

This article was published online first at www.annals.org on 23 December 2014.


From Uppsala University, Uppsala, Sweden; Sydney University, Sydney, Australia; University of Auckland, Auckland, New Zealand; University of Oxford, Oxford, United Kingdom; and Imperial College, London, United Kingdom.

Note: The authors had access to all of the study data, take responsibility for the accuracy of the analysis, and had authority over manuscript preparation and the decision to submit the manuscript for publication.

Financial Support: Dr. Sundström was funded by the Swedish Heart-Lung Foundation (grant 20041151), Kjell och Märta Beijers Stiftelse, and the Swedish Research Council (grants 2007-5942 and 2010-1078). Dr. Rahimi was funded by the U.K. National Institute for Health Research (NIHR Oxford Biomedical Research Centre and NIHR Career Development Fellowship). Dr. Neal is supported by an Australian Research Council Future Fellowship, and Dr. Neal and Dr. Woodward are supported by National Health and Medical Research Council of Australia Senior Research Fellowships. This work received partial funding support from a National Health and Medical Research Council of Australia Program Grant. The BPLTTC received funding from the following sources at its initiation: Astra Hässle, Bayer, British Heart Foundation, Bristol-Myers Squibb, Glaxo Wellcome, Hoechst Marion Roussel, Knoll, Merck & Co., Pfizer, Searle, and Institut de Recherches Internationales Servier.

Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-0773.

Requests for Single Reprints: Kazem Rahimi, MD, The George Institute for Global Health, c/o Oxford Martin School, University of Oxford, 34 Broad Street, Oxford OX1 3BD, United Kingdom.

Current Author Addresses: Dr. Sundström: Department of Medical Sciences & Uppsala Clinical Research Center, Uppsala University, SE-75185 Uppsala, Sweden.

Drs. Arima, Turnbull, Chalmers, Woodward, and Neal: The George Institute for Global Health, PO Box M201, Missenden Road, Camperdown, Sydney, NSW 2050, Australia.

Dr. Jackson: Section of Epidemiology and Biostatistics, School of Population Health, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.

Dr. Rahimi: The George Institute for Global Health, c/o Oxford Martin School, University of Oxford, 34 Broad Street, Oxford OX1 3BD, United Kingdom.

Author Contributions: Conception and design: J. Sundström, H. Arima, R. Jackson, F. Turnbull, M. Woodward, B. Neal.

Analysis and interpretation of the data: J. Sundström, H. Arima, F. Turnbull, K. Rahimi, J. Chalmers, M. Woodward, B. Neal.

Drafting of the article: J. Sundström, K. Rahimi, B. Neal.

Critical revision of the article for important intellectual content: H. Arima, R. Jackson, F. Turnbull, K. Rahimi, J. Chalmers, M. Woodward, B. Neal.

Final approval of the article: J. Sundström, H. Arima, R. Jackson, F. Turnbull, K. Rahimi, M. Woodward, B. Neal.

Provision of study materials or patients: J. Sundström, K. Rahimi, J. Chalmers.

Statistical expertise: J. Sundström, H. Arima, M. Woodward.

Obtaining of funding: J. Sundström.

Administrative, technical, or logistic support: B. Neal.

Collection and assembly of data: J. Sundström, H. Arima, F. Turnbull, M. Woodward.


Ann Intern Med. 2015;162(3):184-191. doi:10.7326/M14-0773
Text Size: A A A

Background: Effects of blood pressure reduction in persons with grade 1 hypertension are unclear.

Purpose: To investigate whether pharmacologic blood pressure reduction prevents cardiovascular events and deaths in persons with grade 1 hypertension.

Data Sources: Trials included in the BPLTTC (Blood Pressure Lowering Treatment Trialists' Collaboration) and trials identified from a previous review and electronic database searches.

Study Selection: Patients without cardiovascular disease with blood pressures in the grade 1 hypertension range (140 to 159/90 to 99 mm Hg) who were randomly assigned to an active (antihypertensive drug or more intensive regimen) or control (placebo or less intensive regimen) blood pressure–lowering regimen.

Data Extraction: Individual-patient data from BPLTTC trials and aggregate data from other trials were extracted. Risk of bias was assessed for all trials.

Data Synthesis: Individual-patient data involved 10 comparisons from trials where most patients had diabetes, and aggregate data involved 3 comparisons from trials of patients without diabetes. The average blood pressure reduction was about 3.6/2.4 mm Hg. Over 5 years, odds ratios were 0.86 (95% CI, 0.74 to 1.01) for total cardiovascular events, 0.72 (CI, 0.55 to 0.94) for strokes, 0.91 (CI, 0.74 to 1.12) for coronary events, 0.80 (CI, 0.57 to 1.12) for heart failure, 0.75 (CI, 0.57 to 0.98) for cardiovascular deaths, and 0.78 (CI, 0.67 to 0.92) for total deaths. Results were similar in secondary analyses. Withdrawal from treatment due to adverse effects was more common in the active groups.

Limitation: Blood pressure reductions and numbers of events were small.

Conclusion: Blood pressure–lowering therapy is likely to prevent stroke and death in patients with uncomplicated grade 1 hypertension.

Primary Funding Source: Swedish Heart-Lung Foundation, Swedish Research Council, Australian Research Council, and National Health and Medical Research Council of Australia.

Figures

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Appendix Figure 1.

Summary of evidence search and selection.

BPLTTC = Blood Pressure Lowering Treatment Trialists' Collaboration.

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Figure.

Main treatment effects.

The difference in average achieved blood pressure between active and control groups in the BPLTTC studies was 3.6/2.4 mm Hg. ABCD = Appropriate Blood Pressure Control in Diabetes; ACEI = angiotensin-converting enzyme inhibitor; ADVANCE = Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation; ANBP = Australian National Blood Pressure Study; BENEDICT = Bergamo Nephrologic Diabetes Complications Trial; BPLTTC = Blood Pressure Lowering Treatment Trialists' Collaboration; CCB = calcium-channel blocker; CVD = cardiovascular disease; DIABHYCAR = Non-insulin-dependent Diabetes, Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril; H = hypertensive sample; MRC = Medical Research Council Trial of Treatment of Mild Hypertension; N = normotensive sample; NA = not applicable; OR = odds ratio; PART-2 = Prevention of Atherosclerosis with Ramipril; PREVEND IT = Prevention of Renal and Vascular End-Stage Disease Intervention Trial; SCAT = Simvastatin/Enalapril Coronary Atherosclerosis Trial; UKPDS = U.K. Prospective Diabetes Study; VA-NHLBI = Veterans Administration-National Heart, Lung, and Blood Institute Feasibility Trial.

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Appendix Figure 2.

Treatment effects in subgroups.

Analyses based on BPLTTC status, BP-lowering drugs, and diabetes included all trials; those based on age, sex, and CVD risk included only BPLTTC trials. Data on heart failure and cardiovascular deaths were available only in the BPLTTC trials. BP = blood pressure; BPLTTC = Blood Pressure Lowering Treatment Trialists' Collaboration; CVD = cardiovascular disease; OR = odds ratio.

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Appendix Figure 3.

Risk of bias within studies.

Plus sign denotes low risk. Minus sign denotes high risk. Question mark denotes unclear risk. ABCD = Appropriate Blood Pressure Control in Diabetes; ADVANCE = Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation; ANBP = Australian National Blood Pressure Study; BENEDICT = Bergamo Nephrologic Diabetes Complications Trial; DIABHYCAR = Non-insulin-dependent Diabetes, Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril; H = hypertensive sample; MRC = Medical Research Council Trial of Treatment of Mild Hypertension; N = normotensive sample; PART-2 = Prevention of Atherosclerosis with Ramipril; PREVEND IT = Prevention of Renal and Vascular End-Stage Disease Intervention Trial; SCAT = Simvastatin/Enalapril Coronary Atherosclerosis Trial; UKPDS = U.K. Prospective Diabetes Study; VA-NHLBI = Veterans Administration-National Heart, Lung, and Blood Institute Feasibility Trial.

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Apples Added to Oranges
Posted on February 10, 2015
Stephen A. Martin, MD, EdM
Department of Family Medicine and Community Health; University of Massachusetts Medical School
Conflict of Interest: None Declared
In their paper “Effects of Blood Pressure Reduction in Mild Hypertension: A Systematic Review and Meta-analysis,” Sundström et al conclude that drug treatment “in the primary preventive setting is likely to reduce the risk for several important adverse health outcomes” (1). This is an interesting finding given that the 2012 Cochrane review they cite (2) found no evidence of mortality or morbidity benefit in drug treatment of mild hypertension. What changed?

The authors explain the different conclusions this way: “Besides the inclusion of persons with diabetes or prior antihypertensive treatment, the disparity between the conclusions of this review and the one immediately preceding it is primarily attributable to statistical power. The present review nearly doubled the number of patients, quadrupled the number of cardiovascular events, and provides data on end points not available in the prior meta-analysis.”

Having recently examined this literature (3), my interpretation is different. In order to gain statistical power, the new review combined high-risk and low-risk patients with mild hypertension. This is equivalent of mixing apples—i.e., higher-risk people with diabetes and prior treatment—with oranges—people without diabetes or prior treatment of hypertension.

To summarize the systematic review a bit differently, I used the Appendix Table 3 (http://annals.org/data/Journals/AIM/0/190tta3.jpeg) to compare trial participants as being oranges (Cochrane) or apples (BPLTTC Trials). 96% of patients in the BPLTTC Trials had diabetes and 62% had previous antihypertensive treatment compared with 0% for both in the Cochrane review, making the relative difference (96/0 and 62/0) infinite. Discrete outcomes including total deaths, strokes, and coronary events were higher by a factor of 3.8, 13, and 2.1 times in the BPLTTC Trials group. (Comparison of cardiovascular deaths and heart failure could not be compared due to a lack of data.)

There is hope yet. The paper buries a worthy point when it concludes that “… estimation of cardiovascular risk may aid prioritization in this patient group.” Rather than combining apples and oranges, we need to treat them as different fruit. Apples may benefit from drug treatment of mild hypertension while oranges do not. Blending them serves neither fruit well.


1. Sundström J, Arima H, Jackson R, Turnbull F, Rahimi K, Chalmers J, et al. Effects of Blood Pressure Reduction in Mild Hypertension: A Systematic Review and Meta-analysis. Ann Intern Med. 2014 Dec 23;

2. Diao D, Wright JM, Cundiff DK, Gueyffier F. Pharmacotherapy for mild hypertension. Cochrane Database Syst Rev. 2012/08/17 ed. 2012 Jan;8:CD006742.

3. Martin SA, Boucher M, Wright JM, Saini V. Mild hypertension in people at low risk. BMJ. 2014 Jan;349:g5432.

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