The key role of blood pressure lowering in cardiovascular prevention irrespective of baseline blood pressure and risk profile

The meta-analysis performed by the Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC)1 was based on individual participant-level data for 344 716 participants from 48 randomized trials of pharmacological blood pressure (BP)-lowering medications vs. placebo or other classes of anti-hypertensive drugs, or between more vs. less intensive treatment regimens. The effects of BP-lowering treatment were stratified according to previous cardiovascular disease (CVD) (with and without previous CVD, 157 728 and 186 988, respectively; mean age at baseline, 65 years in both groups) and systolic BP categories (ranging from <120 to ≥170 mmHg). The primary outcome was a composite of major cardiovascular events (MACEs) consisting of fatal or non-fatal stroke, fatal or non-fatal myocardial infarction (MI) or ischaemic heart disease (IHD), or heart failure (HF) causing death or requiring hospital admission. After a median 4.2-year follow-up, MACEs occurred in 42 324 patients (12.3%), with an event rate of 3.2 in the comparator group vs. 2.6 per 100 person-years in the intervention group of participants without previous CVD, with corresponding figures of 4.0 vs. 3.6 in participants with previous CVD. On average, a 5-mmHg reduction in systolic BP produced a 10% decrease in the risk of MACEs in participants with and without previous CVD. The corresponding proportional risk reductions for stroke, HF, IHD, and cardiovascular death were 13%, 13%, 8%, and 5%, respectively. In stratified analyses, there was no apparent heterogeneity of treatment effects on MACEs by baseline CVD status or systolic BP categories. Comment on ‘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’, which was published in The Lancet, doi:10.1016/S0140-6736(21)00590-0. Although epidemiological studies have provided convincing evidence for a log-linear relationship between BP and risk of CVD across the physiological BP range, randomised trials, in which participants with normal and high-normal BP were either excluded or under-represented, and their tabular meta-analyses, have not provided a definite answer to the question of treatment effects at lower baseline BP thresholds in people with or without CVD.2–4 Most treatment guidelines define a ‘floor level’ for reducing BP, assuming that BP lowering below a certain threshold would be ineffective or produce a questionable or even detrimental effect.5–7 The meta-analysis by the BPLTTC1 (a group of the principal investigators of major randomized trials of pharmacological BP-lowering treatment) based on individual participant data has provided convincing evidence that relative reductions in MACEs were not significantly influenced by baseline BP levels, the benefits of a BP-lowering treatment being maintained in subjects with systolic BP <130 mmHg and even <120 mmHg. Indeed, there was no pattern of diminishing proportional effects in subgroups with lower BP. Although the benefits of anti-hypertensive treatment seemed to be greater in the highest risk categories, namely in those subjects with history of CVD, no significant heterogeneity of effect by CVD status was observed. This finding is reminiscent of the pivotal meta-analysis of the Cholesterol Treatment Trialists’ Collaboration, showing that statin therapy can reduce the 5-year incidence of major coronary events, coronary revascularization, and stroke by about one-fifth per mmol/L reduction in LDL cholesterol, largely irrespective of the initial lipid profile or other presenting characteristics,8 de-emphasizing the need to define a high-cholesterol threshold for initiating statin therapy or to establish a ‘floor level’ for cholesterol reduction. Furthermore, the present results do not support the concern over a J-shaped association between BP levels and Cardiovascular (CV) outcomes and challenge the concept that BP-lowering treatment is only effective when BP is above a certain threshold. Moreover, since the risk reductions were proportional to the magnitude of BP lowering, a more intensive therapeutic strategy might be supported. Major strengths of this meta-analysis are represented by the large sample size, the use of individual participant data and the adequate duration of follow-up. Some limitations should also be underlined. First, the 48 studies included in the meta-analysis were conducted over a very long time frame (between 1966 and 2019), during which major changes in therapeutic strategies have occurred in the management of frequent comorbidities, including dyslipidaemia and diabetes, as well as in the clinical handling of outcomes (e.g. non-fatal MI, stroke, and HF). As a consequence, the absolute CV benefits deriving from BP reduction may be influenced by a period-effect. Moreover, the results of the meta-analysis were not stratified according to age, diabetes, and chronic kidney disease, all conditions in which the benefits of a ‘the lower the better’ strategy may well be heterogeneous. Finally, the current meta-analysis does not provide information on the potential variable impact of different pharmacological strategies on CV outcomes. The authors of the BPLTTC meta-analysis advocate that for people at high risk of CVD, ‘pharmacological BP-lowering treatment should become a cornerstone of risk prevention irrespective of CVD status or BP’.1 Indeed, BP-lowering may act in concert with other pharmacological interventions (lipid-lowering, anti-thrombotic, and glucose-lowering drugs) as part of a multifactorial CV prevention strategy. Conflict of interest: M.V. reports personal fees for speaker bureau and/or consulting in Advisory Board from Amgen, Astra Zeneca, Daiichi-Sankyo, Menarini Int, MSD, Novartis Pharma, Novo Nordisk, outside the submitted work. C.P. reports personal fees from Acticor Biotech, Amgen, Bayer, GlaxoSmithKline, Tremeau, and Zambon; grants from AIFA (Italian Drug Agency) and European Commission; other from Scientific Advisory Board of the International Aspirin Foundation, outside the submitted work.