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Articles Effects of Intensive Blood Pressure Lowering On Articles Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis Xinfang Xie, Emily Atkins, Jicheng Lv, Alexander Bennett, Bruce Neal, Toshiharu Ninomiya, Mark Woodward, Stephen MacMahon, Fiona Turnbull, Graham S Hillis, John Chalmers, Jonathan Mant, Abdul Salam, Kazem Rahimi, Vlado Perkovic, Anthony Rodgers Summary Background Recent hypertension guidelines have reversed previous recommendations for lower blood pressure Published Online targets in high-risk patients, such as those with cardiovascular disease, renal disease, or diabetes. This change November 6, 2015 http://dx.doi.org/10.1016/ represents uncertainty about whether more intensive blood pressure-lowering strategies are associated with greater S0140-6736(15)00805-3 reductions in risk of major cardiovascular and renal events. We aimed to assess the efficacy and safety of intensive See Online/Comment blood pressure-lowering strategies. http://dx.doi.org/10.1016/ S0140-6736(15)00816-8 Methods For this updated systematic review and meta-analysis, we systematically searched MEDLINE, Embase, and Renal Division, Department of the Cochrane Library for trials published between Jan 1, 1950, and Nov 3, 2015. We included randomised controlled Medicine, Peking University trials with at least 6 months’ follow-up that randomly assigned participants to more intensive versus less intensive First Hospital, Beijing, China (X Xie MD, Prof J Lv MD); The blood pressure-lowering treatment, with different blood pressure targets or different blood pressure changes from George Institute for Global baseline. We did not use any age or language restrictions. We did a meta-analysis of blood pressure reductions on Health, The University of relative risk (RR) of major cardiovascular events (myocardial infarction, stroke, heart failure, or cardiovascular death, Sydney, Sydney, NSW, Australia separately and combined), and non-vascular and all-cause mortality, end-stage kidney disease, and adverse events, as (E Atkins BHlthSc, Prof J Lv, A Bennett BMedSc, well as albuminuria and progression of retinopathy in trials done in patients with diabetes. Prof B Neal MBChB, Prof M Woodward PhD, Findings We identified 19 trials including 44 989 participants, in whom 2496 major cardiovascular events were recorded Prof S MacMahon PhD, during a mean 3·8 years of follow-up (range 1·0–8·4 years). Our meta-analysis showed that after randomisation, F Turnbull PhD, Prof J Chalmers MBBS, patients in the more intensive blood pressure-lowering treatment group had mean blood pressure levels of A Salam MPharm, 133/76 mm Hg, compared with 140/81 mm Hg in the less intensive treatment group. Intensive blood pressure-lowering Prof V Perkovic MBBS, treatment achieved RR reductions for major cardiovascular events (14% [95% CI 4–22]), myocardial infarction (13% Prof A Rodgers MBChB); The George Institute for Global [0–24]), stroke (22% [10–32]), albuminuria (10% [3–16]), and retinopathy progression (19% [0–34]). However, more Health, Nuffield Department of intensive treatment had no clear effects on heart failure (15% [95% CI –11 to 34]), cardiovascular death (9% [–11 to 26]), Population Health, University total mortality (9% [–3 to 19]), or end-stage kidney disease (10% [–6 to 23]). The reduction in major cardiovascular events of Oxford, Oxford, UK (Prof was consistent across patient groups, and additional blood pressure lowering had a clear benefit even in patients with M Woodward, Prof S MacMahon, Prof K Rahimi PhD); Department systolic blood pressure lower than 140 mm Hg. The absolute benefits were greatest in trials in which all enrolled of Medicine and Clinical Science, patients had vascular disease, renal disease, or diabetes. Serious adverse events associated with blood pressure lowering Graduate School of Medical were only reported by six trials and had an event rate of 1·2% per year in intensive blood pressure-lowering group Sciences, Kyushu University, participants, compared with 0·9% in the less intensive treatment group (RR 1·35 [95% CI 0·93–1·97]). Severe Japan (Prof T Ninomiya PhD); Department of Cardiology, hypotension was more frequent in the more intensive treatment regimen (RR 2·68 [1·21–5·89], p=0·015), but the Royal Perth Hospital, absolute excess was small (0·3% vs 0·1% per person-year for the duration of follow-up). Wellington Street, Perth, WA, Australia (Prof G S Hillis MBChB); Interpretation Intensive blood pressure lowering provided greater vascular protection than standard regimens. In Primary Care Unit, Department of Public Health and Primary high-risk patients, there are additional benefits from more intensive blood pressure lowering, including for those Care, University of Cambridge, with systolic blood pressure below 140 mmHg. The net absolute benefits of intensive blood pressure lowering in Cambridge, UK (Prof J Mant MD) high-risk individuals are large. Correspondence to: Prof Anthony Rodgers, Funding National Health and Medical Research Council of Australia. The George Institute for Global Health, The University of Sydney, PO Box M201, Missenden Road, Introduction Joint National Commitee guideline raised the target blood Sydney, NSW 2050, Australia Several major hypertension guidelines have recently pressure level for individuals older than 60 years of age to [email protected] raised target blood pressures for some high-risk patient 150/90 mm Hg.1 Globally, just under half of the total or 1–3 Prof Jicheng Lv, Renal Division, populations. Previous guidelines recommended target blood pressure-attributable disease burden occurs in Department Of Medicine, Peking blood pressure levels of around 130/85 mm Hg for people with systolic blood pressure lower than University First Hospital, Beijing, patients with cerebrovascular disease, coronary heart 140 mm Hg4 and most cardiovascular events occur in China disease, renal disease, and diabetes, whereas these people who have had a previous event.5 Therefore, [email protected] guidelines now recommend target levels of 140/90 mm Hg recommendations for treatment initiation, intensification, in these patient populations. Additionally, the Eighth or maintenance for high-risk patients who have systolic www.thelancet.com Published online November 6, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00805-3 1 Articles blood pressure levels below 140 mm Hg carry substantial Data extraction and quality assessment clinical and public health importance. Published reports were obtained for each trial and The most frequently cited reason for the change in standard information was extracted and placed into a guideline recommendations for high-risk patients was spreadsheet. The data extracted from each paper included the findings from the ACCORD trial,6 which randomly baseline patient characteristics (age, sex, mean systolic assigned 4733 patients with type 2 diabetes to intensive and diastolic blood pressure levels, history of diabetes, or standard blood pressure-lowering therapy (target history of hypertension, and chronic kidney disease), systolic blood pressure <120 mm Hg vs <140 mm Hg) blood pressure control target in each group, blood and did not report a significant difference in overall pressure-lowering agents used, follow-up duration, mean cardiovascular event rates associated with a 14 mm Hg reduction of systolic and diastolic blood pressure during mean difference in systolic blood pressure. By contrast, a the trial, outcome events, and adverse events. We judged systematic review of trials of more versus less blood study quality by evaluating trial procedures for pressure lowering did note a significant reduction in randomisation, concealment of treatment allocation, major vascular events.7 In view of the uncertainty and the completeness of follow-up, and use of intention-to-treat completion of several additional trials8–10 (Mant J, analysis. The Cochrane Collaboration’s tool was used to University of Cambridge, personal communication), we assess risk of bias. Any disagreements in abstracted data sought to undertake an updated systematic review of all were adjudicated by a third reviewer (AR). trials comparing different blood pressure targets, with a particular focus on the efficacy and safety of additional Outcomes blood pressure lowering in high-risk individuals whose Outcomes of interest were: major cardiovascular events, systolic blood pressure is lower than 140 mm Hg. defined as a myocardial infarction, stroke, heart failure, or cardiovascular death, separately and combined; non- Methods vascular and all-cause mortality; end-stage kidney disease; Search strategy and selection criteria and adverse events. Progression of albuminuria (defined as We did an update of a systematic review7 of the literature, new onset of micro-albuminuria/macro-albuminuria or a using the same methods and to allow the reporting change from micro-albuminuria to macro-albuminuria) standards recommended by the PRISMA statement for and retinopathy (retinopathy progression of two or more See Online for appendix meta-analyses of intervention studies (appendix pp 11–13).11 steps) were also recorded for trials that were done in We identified relevant studies by searching the following patients with diabetes. databases using Ovid: MEDLINE (from Jan 1, 1950, to Nov 3, 2015), Embase (from 1966 to Nov 3, 2015) and the Statistical analysis Cochrane Library database (on Nov 3, 2015), using relevant For each study, we calculated individual relative risks (RRs) keywords and medical subject headings that included
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