Pharmacological blood pressure lowering for primary and secondary prevention of cardiovascular disease across different levels of blood pressure: an individual participant-level data meta-analysis

Abstract

Background: The effects of pharmacological blood pressure lowering at normal or high-normal blood pressure ranges in people with or without pre-existing cardiovascular disease remains uncertain. We analysed individual participant data from randomised trials to investigate the effects of blood pressure lowering treatment on the risk of major cardiovascular events by baseline levels of systolic blood pressure.

Methods: We did a meta-analysis of individual participant-level data from 48 randomised trials of pharmacological blood pressure lowering medications versus placebo or other classes of blood pressure-lowering medications, or between more versus less intensive treatment regimens, which had at least 1000 persons-years of follow-up in each group. Trials exclusively done with participants with heart failure or short-term interventions in participants with acute myocardial infarction or other acute settings were excluded. Data from 51 studies published between 1972 and 2013 were obtained by the Blood Pressure Lowering Treatment Trialists' Collaboration (Oxford University, Oxford, UK). We pooled the data to investigate the stratified effects of blood pressure-lowering treatment in participants with and without prevalent cardiovascular disease (ie, any reports of stroke, myocardial infarction, or ischaemic heart disease before randomisation), overall and across seven systolic blood pressure categories (ranging from <120 to ≥170 mm Hg). The primary outcome was a major cardiovascular event (defined as a composite of fatal and non-fatal stroke, fatal or non-fatal myocardial infarction or ischaemic heart disease, or heart failure causing death or requiring admission to hospital), analysed as per intention to treat.

Findings: Data for 344 716 participants from 48 randomised clinical trials were available for this analysis. Pre-randomisation mean systolic/diastolic blood pressures were 146/84 mm Hg in participants with previous cardiovascular disease (n=157 728) and 157/89 mm Hg in participants without previous cardiovascular disease (n=186 988). There was substantial spread in participants' blood pressure at baseline, with 31 239 (19·8%) of participants with previous cardiovascular disease and 14 928 (8·0%) of individuals without previous cardiovascular disease having a systolic blood pressure of less than 130 mm Hg. The relative effects of blood pressure-lowering treatment were proportional to the intensity of systolic blood pressure reduction. After a median 4·15 years' follow-up (Q1-Q3 2·97-4·96), 42 324 participants (12·3%) had at least one major cardiovascular event. In participants without previous cardiovascular disease at baseline, the incidence rate for developing a major cardiovascular event per 1000 person-years was 31·9 (95% CI 31·3-32·5) in the comparator group and 25·9 (25·4-26·4) in the intervention group. In participants with previous cardiovascular disease at baseline, the corresponding rates were 39·7 (95% CI 39·0-40·5) and 36·0 (95% CI 35·3-36·7), in the comparator and intervention groups, respectively. Hazard ratios (HR) associated with a reduction of systolic blood pressure by 5 mm Hg for a major cardiovascular event were 0·91, 95% CI 0·89-0·94 for partipants without previous cardiovascular disease and 0·89, 0·86-0·92, for those with previous cardiovascular disease. In stratified analyses, there was no reliable evidence of heterogeneity of treatment effects on major cardiovascular events by baseline cardiovascular disease status or systolic blood pressure categories.

Interpretation: In this large-scale analysis of randomised trials, a 5 mm Hg reduction of systolic blood pressure reduced the risk of major cardiovascular events by about 10%, irrespective of previous diagnoses of cardiovascular disease, and even at normal or high-normal blood pressure values. These findings suggest that a fixed degree of pharmacological blood pressure lowering is similarly effective for primary and secondary prevention of major cardiovascular disease, even at blood pressure levels currently not considered for treatment. Physicians communicating the indication for blood pressure lowering treatment to their patients should emphasise its importance on reducing cardiovascular risk rather than focusing on blood pressure reduction itself.

Funding: British Heart Foundation, UK National Institute for Health Research, and Oxford Martin School.

Figure 1

Rates of major cardiovascular events per 5 mm Hg reduction in systolic blood pressure, stratified by treatment allocation and cardiovascular disease status at baseline Major cardiovascular events were defined as a composition of fatal or non-fatal stroke, fatal or non-fatal myocardial infarction or ischaemic heart disease, or heart failure causing death or requiring admission to hospital. HR=hazard ratio.

Figure 2

Association between the intensity of blood pressure reduction and relative treatment effects for prevention of major cardiovascular events The centre of the bubbles indicates the HR for each trial, with the size of the bubble inversely proportional to the respective SE. The solid red line is the fitted regression line; the dashed blue lines indicate 95% CI; and the dashed grey line indicates HR=1·0. HR=hazard ratio. *Excluding the first 12 months after randomisation.

Figure 3

Effects of blood pressure-lowering treatment on primary and secondary outcomes, by cardiovascular disease status at baseline Forest plot shows the HRs and 95% CIs per 5 mm Hg reduction in systolic blood pressure, separately for each outcome. Adjusted p_interaction values were adjusted for multiple testing using Hommel's method. Unadjusted p_interaction values were not adjusted for multiple testing. HR=hazard ratio. CVD=cardiovascular disease.

Figure 4

Effects of blood pressure-lowering treatment on primary and secondary outcomes, by cardiovascular disease status and systolic blood pressure at baseline Forest plot shows the HRs and 95% CIs per 5 mm Hg systolic blood pressure reduction, separately for each outcome. Adjusted p_interaction values were adjusted for multiple testing using Hommel's method. Unadjusted p_interaction values were unadjusted for multiple testing. HR=hazard ratio. CVD=cardiovascular disease.

Figure 4

Effects of blood pressure-lowering treatment on primary and secondary outcomes, by cardiovascular disease status and systolic blood pressure at baseline Forest plot shows the HRs and 95% CIs per 5 mm Hg systolic blood pressure reduction, separately for each outcome. Adjusted p_interaction values were adjusted for multiple testing using Hommel's method. Unadjusted p_interaction values were unadjusted for multiple testing. HR=hazard ratio. CVD=cardiovascular disease.