Elsevier

The Lancet

Volume 387, Issue 10022, 5–11 March 2016, Pages 957-967
The Lancet

Articles
Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis

https://doi.org/10.1016/S0140-6736(15)01225-8Get rights and content

Summary

Background

The benefits of blood pressure lowering treatment for prevention of cardiovascular disease are well established. However, the extent to which these effects differ by baseline blood pressure, presence of comorbidities, or drug class is less clear. We therefore performed a systematic review and meta-analysis to clarify these differences.

Method

For this systematic review and meta-analysis, we searched MEDLINE for large-scale blood pressure lowering trials, published between Jan 1, 1966, and July 7, 2015, and we searched the medical literature to identify trials up to Nov 9, 2015. All randomised controlled trials of blood pressure lowering treatment were eligible for inclusion if they included a minimum of 1000 patient-years of follow-up in each study arm. No trials were excluded because of presence of baseline comorbidities, and trials of antihypertensive drugs for indications other than hypertension were eligible. We extracted summary-level data about study characteristics and the outcomes of major cardiovascular disease events, coronary heart disease, stroke, heart failure, renal failure, and all-cause mortality. We used inverse variance weighted fixed-effects meta-analyses to pool the estimates.

Results

We identified 123 studies with 613 815 participants for the tabular meta-analysis. Meta-regression analyses showed relative risk reductions proportional to the magnitude of the blood pressure reductions achieved. Every 10 mm Hg reduction in systolic blood pressure significantly reduced the risk of major cardiovascular disease events (relative risk [RR] 0·80, 95% CI 0·77–0·83), coronary heart disease (0·83, 0·78–0·88), stroke (0·73, 0·68–0·77), and heart failure (0·72, 0·67–0·78), which, in the populations studied, led to a significant 13% reduction in all-cause mortality (0·87, 0·84–0·91). However, the effect on renal failure was not significant (0·95, 0·84–1·07). Similar proportional risk reductions (per 10 mm Hg lower systolic blood pressure) were noted in trials with higher mean baseline systolic blood pressure and trials with lower mean baseline systolic blood pressure (all ptrend>0·05). There was no clear evidence that proportional risk reductions in major cardiovascular disease differed by baseline disease history, except for diabetes and chronic kidney disease, for which smaller, but significant, risk reductions were detected. β blockers were inferior to other drugs for the prevention of major cardiovascular disease events, stroke, and renal failure. Calcium channel blockers were superior to other drugs for the prevention of stroke. For the prevention of heart failure, calcium channel blockers were inferior and diuretics were superior to other drug classes. Risk of bias was judged to be low for 113 trials and unclear for 10 trials. Heterogeneity for outcomes was low to moderate; the I2 statistic for heterogeneity for major cardiovascular disease events was 41%, for coronary heart disease 25%, for stroke 26%, for heart failure 37%, for renal failure 28%, and for all-cause mortality 35%.

Interpretation

Blood pressure lowering significantly reduces vascular risk across various baseline blood pressure levels and comorbidities. Our results provide strong support for lowering blood pressure to systolic blood pressures less than 130 mm Hg and providing blood pressure lowering treatment to individuals with a history of cardiovascular disease, coronary heart disease, stroke, diabetes, heart failure, and chronic kidney disease.

Funding

National Institute for Health Research and Oxford Martin School.

Introduction

Elevated blood pressure is the most important risk factor for death and disability worldwide, affecting more than one billion individuals and causing an estimated 9·4 million deaths every year.1 Prospective cohort studies have reported a continuous log-linear association between blood pressure and vascular events to a blood pressure of 115/75 mm Hg, with no apparent threshold.2 This association seems to exist across large and diverse population groups, including men and women, individuals aged 40–89 years, from different ethnicities, with and without established vascular disease.2, 3, 4 Despite this robust observational evidence, whether blood pressure lowering treatment reduces the risk of cardiovascular disease in all patient populations remains unclear.

Although the benefits of blood pressure lowering have long been established in randomised trials of patients with substantially raised blood pressures,5, 6, 7, 8 evidence for the protective effects of pharmacologically-induced blood pressure reduction in individuals with lower blood pressure or with comorbidities, have been less certain.9, 10, 11, 12 Furthermore, the best approach to reduce blood pressure remains subject to controversy.13, 14, 15, 16

Research in context

Evidence before this study

Although the benefits of blood pressure lowering treatment for prevention of cardiovascular disease are well established, the extent to which these effects differ by baseline blood pressure, presence of comorbidities, or drug class is less clear.

Added value of this study

Our study provides a comprehensive systematic review and meta-analysis of all available large-scale blood pressure lowering randomised trials. Our findings show that pharmacological blood pressure lowering results in similar proportional reductions in risk of cardiovascular disease and death to a mean baseline systolic blood pressure of less than 130 mm Hg. Furthermore, we noted that proportional risk reductions are broadly similar among individuals with or without major cardiovascular comorbidities. Finally, our findings emphasise the fact that, despite the general efficacy of commonly prescribed blood pressure lowering drug classes in preventing cardiovascular disease, there are some significant differences among them in the reduction of risk of specific clinical outcomes. For example, calcium channel blockers seem to be more effective than other classes of drugs for stroke prevention, and diuretics are more effective for prevention of heart failure.

Implications of all the available evidence

Our study has several implications for clinical practice. First, our findings suggest that blood pressure lowering to levels below those recommended in current guidelines (ie, systolic blood pressure of less than 140 mm Hg) will reduce the risk of cardiovascular disease. Second, by showing no evidence for a threshold below which blood pressure lowering ceases to work, the findings call for blood pressure lowering based on an individual's potential net benefit from treatment rather than treatment of the risk factor to a specific target. Third, the broad consistency of the findings across patients with or without prior vascular disease could help to simplify clinical guidelines for use of blood pressure lowering drugs. Fourth, the differences we identified between classes of drugs support more targeted drug use for individuals at high risk of specific outcomes (eg, calcium channel blocker therapy for individuals at high risk of stroke).

Recent major guidelines have reversed a trend toward lower blood pressure thresholds and targets, recommending higher targets and threshold for blood pressure lowering than have previous guidelines.14, 17, 18 The SPRINT trial12 reported the benefits of blood pressure lowering to 120 mm Hg in some high-risk groups of patients. However uncertainty remains as to whether such benefits hold for high-risk individuals excluded from the trial, especially those with diabetes or cerebrovascular disease.12

In this systematic review and meta-analysis, we aimed to combine data from all published large-scale blood pressure lowering trials to quantify the effects of blood pressure reduction on cardiovascular outcomes and death across various baseline blood pressure levels, major comorbidities, and different pharmacological interventions.

Section snippets

Search strategy and selection criteria

The systematic review and tabular meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for meta-analyses of interventional studies.19 We searched MEDLINE from Jan 1, 1966, to July 7, 2015, using an existing search strategy16 with the terms “anti-hypertensive agents” or “hypertension” or “diuretics”, “thiazide”, or “angiotensin-converting enzyme” or “angiotensin-converting enzyme inhibitors” or “receptors, angiotensin/antagonists &

Results

In total, we screened 11 428 abstracts, of which 350 were eligible for full-text review (figure 1). Of the 134 randomised controlled trials identified, 123 trials with 613 815 participants were eligible for inclusion in the meta-analysis. 92 studies were deemed to be trials of blood pressure lowering because they compared either blood pressure lowering drugs to placebo (78 trials) or different blood pressure lowering targets (14 trials; appendix pp 1–6, 10). 43 trials compared different drug

Discussion

In this meta-analysis, blood pressure lowering treatment significantly reduced the risk of cardiovascular disease and death in various populations of patients. Overall, a 10 mm Hg reduction in systolic blood pressure reduced the risk of major cardiovascular disease events by 20%, coronary heart disease by 17%, stroke by 27%, heart failure by 28%, and all-cause mortality by 13%. The size of these proportional reductions was broadly consistent across several major high-risk groups of patients,

References (70)

  • L Hansson et al.

    Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial

    Lancet

    (1999)
  • H Ogawa et al.

    Angiotensin II receptor blocker-based therapy in Japanese elderly, high-risk, hypertensive patients

    Am J Med

    (2012)
  • A Helgeland

    Treatment of mild hypertension: a five year controlled drug trial. The Oslo study

    Am J Med

    (1980)
  • J Coresh et al.

    Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey

    Am J Kidney Dis

    (2003)
  • V Perkovic et al.

    High prevalence of chronic kidney disease in Thailand

    Kidney Int

    (2008)
  • A global brief on hypertension

    (2013)
  • S Lewington et al.

    Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies

    Lancet

    (2002)
  • CMM Lawes et al.

    Blood pressure and cardiovascular disease in the Asia Pacific region

    J Hypertens

    (2003)
  • Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP)

    JAMA

    (1991)
  • NS Beckett et al.

    Treatment of hypertension in patients 80 years of age or older

    N Engl J Med

    (2008)
  • Randomised trial of a perindopril- based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack

    Lancet

    (2001)
  • S Yusuf et al.

    Effects of an Angiotensin-Converting-Enzyme Inhibitor, Ramipril, on Cardiovascular Events in High-Risk Patients

    N Engl J Med

    (2000)
  • JTJ Wright et al.

    A randomized trial of intensive versus standard blood-pressure control

    N Engl J Med

    (2015)
  • C Emdin et al.

    Blood pressure lowering in type 2 diabetes

    JAMA

    (2015)
  • P James et al.

    2014 Evidence-based guideline for the management of high blood pressure in adults report from the panel members appointed to the Eighth Joint National Committee (JNC 8)

    JAMA

    (2014)
  • JT Wright et al.

    Evidence supporting a systolic blood pressure goal of less than 150 mm Hg in patients aged 60 years or older: the minority view

    Ann Intern Med

    (2014)
  • MR Law et al.

    Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies

    BMJ

    (2009)
  • G Mancia et al.

    2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC)

    Eur Heart J

    (2013)
  • The clinical management of primary hypertension in adults: clinical guideline 127

    (2011)
  • A Liberati et al.

    The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions

    PLoS Med

    (2009)
  • LL Kjaergard et al.

    Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses

    Ann Intern Med

    (2001)
  • Protocol for prospective collaborative overviews of major randomized trials of blood-pressure lowering treatments

    J Hypertens

    (1998)
  • I Annesi et al.

    Efficiency of the logistic regression and Cox proportional hazards models in longitudinal studies

    Stat Med

    (1989)
  • JPT Higgins et al.

    Measuring inconsistency in meta-analyses

    BMJ

    (2003)
  • Cited by (2346)

    View all citing articles on Scopus
    View full text