Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis

Transcription

1 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 targets in high-risk patients, such as those with cardiovascular disease, renal disease, or diabetes. This change represents uncertainty about whether more intensive blood pressure-lowering strategies are associated with greater reductions in risk of major cardiovascular and renal events. We aimed to assess the efficacy and safety of intensive blood pressure-lowering strategies. Methods For this updated systematic review and meta-analysis, we systematically searched MEDLINE, Embase, and the Cochrane Library for trials published between Jan 1, 1950, and Nov 3, We included randomised controlled trials with at least 6 months follow-up that randomly assigned participants to more intensive versus less intensive blood pressure-lowering treatment, with different blood pressure targets or different blood pressure changes from baseline. We did not use any age or language restrictions. We did a meta-analysis of blood pressure reductions on relative risk (RR) of major cardiovascular events (myocardial infarction, stroke, heart failure, or cardiovascular death, separately and combined), and non-vascular and all-cause mortality, end-stage kidney disease, and adverse events, as well as albuminuria and progression of retinopathy in trials done in patients with diabetes. Findings We identified 19 trials including participants, in whom 2496 major cardiovascular events were recorded during a mean 3 years of follow-up (range years). Our meta-analysis showed that after randomisation, patients in the more intensive blood pressure-lowering treatment group had mean blood pressure levels of 133/6 mm Hg, compared with 140/1 mm Hg in the less intensive treatment group. Intensive blood pressure-lowering treatment achieved RR reductions for major cardiovascular events (14% [95% CI 4 22]), myocardial infarction (13% [0 24]), stroke (22% [10 32]), albuminuria (10% [3 16]), and retinopathy progression (19% [0 34]). However, more intensive treatment had no clear effects on heart failure (15% [95% CI 11 to 34]), cardiovascular death (9% [ 11 to 26]), total mortality (9% [ 3 to 19]), or end-stage kidney disease (10% [ 6 to 23]). The reduction in major cardiovascular events was consistent across patient groups, and additional blood pressure lowering had a clear benefit even in patients with systolic blood pressure lower than 140 mm Hg. The absolute benefits were greatest in trials in which all enrolled patients had vascular disease, renal disease, or diabetes. Serious adverse events associated with blood pressure lowering were only reported by six trials and had an event rate of 1 2% per year in intensive blood pressure-lowering group participants, compared with 0 9% in the less intensive treatment group (RR 1 35 [95% CI ]). Severe hypotension was more frequent in the more intensive treatment regimen (RR 2 6 [ ], p=0 015), but the absolute excess was small (0 3% vs 0 1% per person-year for the duration of follow-up). Interpretation Intensive blood pressure lowering provided greater vascular protection than standard regimens. In high-risk patients, there are additional benefits from more intensive blood pressure lowering, including for those with systolic blood pressure below 140 mmhg. The net absolute benefits of intensive blood pressure lowering in high-risk individuals are large. Funding National Health and Medical Research Council of Australia. Introduction Several major hypertension guidelines have recently raised target blood pressures for some high-risk patient populations. 1 3 Previous guidelines recommended target blood pressure levels of around 130/5 mm Hg for patients with cerebrovascular disease, coronary heart disease, renal disease, and diabetes, whereas these guidelines now recommend target levels of 140/90 mm Hg in these patient populations. Additionally, the Eighth Joint National Commitee guideline raised the target blood pressure level for individuals older than 60 years of age to 150/90 mm Hg. 1 Globally, just under half of the total blood pressure-attributable disease burden occurs in people with systolic blood pressure lower than 140 mm Hg 4 and most cardiovascular events occur in people who have had a previous event. 5 Therefore, recommendations for treatment initiation, intensification, or maintenance for high-risk patients who have systolic Published Online November 6, S (15) See Online/Comment S (15)0016- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China (X Xie MD, Prof J Lv MD); The George Institute for Global Health, The University of Sydney, Sydney, NSW, Australia (E Atkins BHlthSc, Prof J Lv, A Bennett BMedSc, Prof B Neal MBChB, Prof M Woodward PhD, Prof S MacMahon PhD, F Turnbull PhD, Prof J Chalmers MBBS, A Salam MPharm, Prof V Perkovic MBBS, Prof A Rodgers MBChB); The George Institute for Global Health, Nuffield Department of Population Health, University of Oxford, Oxford, UK (Prof M Woodward, Prof S MacMahon, Prof K Rahimi PhD); Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Japan (Prof T Ninomiya PhD); Department of Cardiology, Royal Perth Hospital, Wellington Street, Perth, WA, Australia (Prof G S Hillis MBChB); Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK (Prof J Mant MD) Correspondence to: Prof Anthony Rodgers, The George Institute for Global Health, The University of Sydney, PO Box M201, Missenden Road, Sydney, NSW 2050, Australia arodgers@georgeinstitute.org or Prof Jicheng Lv, Renal Division, Department Of Medicine, Peking University First Hospital, Beijing, China jichenglv5@gmail.com Published online November 6,

2 See Online for appendix blood pressure levels below 140 mm Hg carry substantial clinical and public health importance. The most frequently cited reason for the change in guideline recommendations for high-risk patients was the findings from the ACCORD trial, 6 which randomly assigned 433 patients with type 2 diabetes to intensive or standard blood pressure-lowering therapy (target systolic blood pressure <120 mm Hg vs <140 mm Hg) and did not report a significant difference in overall cardiovascular event rates associated with a 14 mm Hg mean difference in systolic blood pressure. By contrast, a systematic review of trials of more versus less blood pressure lowering did note a significant reduction in major vascular events. In view of the uncertainty and the completion of several additional trials 10 (Mant J, University of Cambridge, personal communication), we sought to undertake an updated systematic review of all trials comparing different blood pressure targets, with a particular focus on the efficacy and safety of additional blood pressure lowering in high-risk individuals whose systolic blood pressure is lower than 140 mm Hg. Methods Search strategy and selection criteria We did an update of a systematic review of the literature, using the same methods and to allow the reporting standards recommended by the PRISMA statement for meta-analyses of intervention studies (appendix pp 11 13). 11 We identified relevant studies by searching the following databases using Ovid: MEDLINE (from Jan 1, 1950, to Nov 3, 2015), Embase (from 1966 to Nov 3, 2015) and the Cochrane Library database (on Nov 3, 2015), using relevant keywords and medical subject headings that included all spellings of antihypertensive agents, target blood pressure, intensive blood pressure treatment, intensive blood pressure control, strict blood pressure treatment, strict blood pressure control, tight blood pressure treatment, and tight blood pressure control (appendix pp 21 25). Trials were eligible for inclusion if they had different blood pressure targets or different blood pressure changes between the more versus less blood pressure-treated groups. Our search was limited to randomised controlled trials with at least 6 months follow-up, but we did not use any age or language restrictions. Reference lists from identified trials and review articles were manually scanned to identify any other relevant studies. We also searched the ClinicalTrials.gov website for randomised trials that were registered as completed but not yet published. The updated literature search, data extraction, and quality assessment were done independently by two authors (XX and AB) using a standardised approach (see appendix pp 2 10, 21 25). All completed randomised controlled trials that compared more versus less intensive blood pressure targets with pharmacological blood pressure-lowering agents were eligible for inclusion, including those that enrolled participants with hypertension, at high risk of cardiovascular or renal disease, or both. Data extraction and quality assessment Published reports were obtained for each trial and standard information was extracted and placed into a spreadsheet. The data extracted from each paper included baseline patient characteristics (age, sex, mean systolic and diastolic blood pressure levels, history of diabetes, history of hypertension, and chronic kidney disease), blood pressure control target in each group, blood pressure-lowering agents used, follow-up duration, mean reduction of systolic and diastolic blood pressure during the trial, outcome events, and adverse events. We judged study quality by evaluating trial procedures for randomisation, concealment of treatment allocation, completeness of follow-up, and use of intention-to-treat analysis. The Cochrane Collaboration s tool was used to assess risk of bias. Any disagreements in abstracted data were adjudicated by a third reviewer (AR). Outcomes Outcomes of interest were: major cardiovascular events, defined as a myocardial infarction, stroke, heart failure, or cardiovascular death, separately and combined; nonvascular and all-cause mortality; end-stage kidney disease; and adverse events. Progression of albuminuria (defined as new onset of micro-albuminuria/macro-albuminuria or a change from micro-albuminuria to macro-albuminuria) and retinopathy (retinopathy progression of two or more steps) were also recorded for trials that were done in patients with diabetes. Statistical analysis For each study, we calculated individual relative risks (RRs) and 95% CIs for each outcome before pooling. We obtained summary estimates of RRs by using a random-effects DerSimonian model, with secondary analyses as a fixedeffects model. For blood pressure, we used the mean difference between the groups who received intensive versus standard blood pressure-lowering treatment during the trial. We estimated the percentage of variability across studies attributable to heterogeneity beyond chance using the I² statistic. 12 We assessed small study bias by stratifying treatment effects by sample size. We explored evidence for heterogeneity in estimates of treatment effect attributable to the baseline characteristics of the trials by comparing summary results obtained from subsets of studies grouped by number of patients, cardiovascular event rate, age, diabetes, blood pressure target, and blood pressure level at baseline. We also explored potential heterogeneity using univariate meta-regression. A two-sided p value less than 0 05 was regarded as statistically significant. Stata version 13.0 was used for all statistical analyses. Role of the funding source The funders of the study had no role in study design; in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit for publication. XX, EA, JL, and AR had full access to all the data, and XX 2 Published online November 6,

3 and AR were responsible for the decision to submit for publication. Results Our search strategy found 4300 records. Once duplicates had been removed, 299 abstracts were screened, and 95 publications were selected for full-text review. This process yielded 21 publications from 19 trials (figure 1) 6, 10,13 26 (Mant J, personal communication). These trials included participants with 2496 major cardiovascular events (14 studies), 162 all-cause deaths (19 studies), and 514 end-stage kidney disease events (eight studies; appendix pp 2 ). All the trials had an openlabel design with very few patients lost to follow-up (0 4 9%). Mean follow-up was 3 years (range years). The risk of bias varied substantially across the studies (appendix pp 9 10). Of the 19 trials, five (6960 participants) enrolled only patients with diabetes, 6,15 1,22 and six specifically recruited participants with chronic kidney disease (209 participants). 13,1 21,25 One of the studies was done in children with chronic kidney disease and hypertension (35 participants, with a mean age of 11 5 years). 25 Two trials (609 participants) recruited patients with diabetes but without hypertension, who had a mean baseline blood pressure of 136/4 mm Hg 1 and 126/4 mm Hg. 22 The other 1 trials (44 30 participants) recruited mostly patients with hypertension and vascular disease, kidney disease, diabetes, or other risk factors. The mean baseline blood pressure levels in the trials of adults were between 123 and 12 mm Hg for systolic blood pressure and between 6 and 105 mm Hg for diastolic blood pressure, with an overall mean of 159/92 mm Hg. The mean follow-up blood pressure levels in the less intensive blood pressure-lowering regimen group were 140/1 mm Hg, compared with 133/6 mm Hg in the more intensive treatment group. The blood pressure targets varied across the trials, and some trials had change in blood pressure as the target endpoint, whereas others had a mixture of target level and change in blood pressure. Several trials had intensive group targets of lower than mm Hg systolic blood pressure and lower than 5 90 mm Hg diastolic blood pressure, 10,15,23,26 whereas in other studies, which tended to be more recent, systolic blood pressure targets in the intensive groups were were mm Hg below these levels. 6,9,1,21,24 Eight trials had diastolic blood pressure targets below 0 mm Hg.,13,14,16 1,21,22 However, many trials did not achieve these targets for most patients; as appendix pp 2 show, the mean follow-up blood pressure was above the trial target in the more intensive group for eight (42%) of the 19 trials and was above target in the less intensive group in two (16%) of the 19 trials (data were unavailable for one trial). Across all trials, the weighted mean follow-up difference in blood pressure between the intensive versus less intensively treated groups was 6 /3 5 mm Hg. 3 more articles from other sources 4300 articles found in database searches 1 MEDLINE 2105 Embase 40 Cochrane 299 abstracts reviewed 95 full-text articles reviewed 21 publications (19 trials) included 1321 duplicates excluded Figure 1: Study selection The diagram summarises search results between Jan 1, 1950, and July 31, The search was updated on Nov 3, 2015, with results restricted to papers published from 2014 to that date. MEDLINE found 133 records, Embase 50 records, and Cochrane Central 6 records. All 251 records were screened for eligibility, but no new studies meeting the inclusion criteria were identified. Data about the effects of intensive blood pressure lowering on major cardiovascular events were available from 14 trials including participants and 2496 cardiovascular events 6, 10,14 1,19,21,23,24,26 (Mant J, personal communication; figure 2A). Overall, more intensive blood pressure-lowering regimens reduced the risk of major cardiovascular events by 14% (95% CI 4 22) compared with less intensive regimens, without evidence of major heterogeneity in the size of effect across included studies (figure 2A). Myocardial infarction was reported in 13 trials including participants, in whom 64 events were recorded 6, 10,14 1,21,23,24,26 (Mant J, personal communication; figure 2B). More intensive blood pressure-lowering therapy reduced the risk of myocardial infarction by 13% (95% CI 0 24) compared with less intensive regimens. 14 trials (43 43 participants) reported 1099 stroke events, and more intensive blood pressure-lowering regimens were associated with a 22% reduction (95% CI 10 32) in the risk of stroke compared with less intensive regimens 6, 10,14 1,19,21,23,24,26 (Mant J, personal communication; figure 2C). The magnitude of the risk reductions recorded for stroke and myocardial infarction in this meta-analysis 2 excluded 1136 not original investigations 20 not randomised controlled trials 261 did not assess blood pressure lowering 1122 did not assess a different target or relevant outcome 1 trials of hypertension in pregnancy 16 not human studies 54 other publications from the same trial 4 excluded not randomised controlled trials 5 not original investigations 46 did not assess a different target or relevant outcome 13 other publications from the same trial 2 follow-up of <6 months Published online November 6,

4 A Blood pressure difference (mm Hg) Relative risk (95% CI) Weight (%) HOT (199) / 3 1 UKPDS-HDS (199) / 5 0 ABCD (H) (2000) / 0 ABCD (N) (2001) 1 9 0/ 6 0 REIN-2 (2005) / 2 JATOS (200) 23 9 / 3 3 Cardio-Sis (2009) 24 3 / 1 5 VANLISH (2010) / 1 AASK (2010) / 0 ACCORD (2010) / 6 HOMED-BP (2012) 1 3/ 0 SPS3 (2013) /NA Wei et al (2013) / 5 9 PAST-BP (2015)* 2 0/ 2 4 Overall 6 / 3 5 Events/population: 1090/16 vs 1406/2416 I 2 =22 4%, p=0 21 Fixed-effects model 0 (95% CI ), p< ( ) 0 69 ( ) 0 91 ( ) 0 9 ( ) 0 0 ( ) 1 05 ( ) 0 53 ( ) 0 ( ) 1 09 ( ) 0 ( ) 1 04 ( ) 0 6 ( ) 0 59 ( ) 0 22 ( ) 0 6 (0 0 96), p= B Figure 2: Effects of intensive blood pressure lowering on risk of cardiovascular outcomes Forest plots showing the effects of intensive versus less intensive blood pressure-lowering regimens on major cardiovascular events (A), myocardial infarction (B), and stroke (C). NA=not available. *Mant J, personal communication. A p value <0 05 represents a significant pooled point estimate of relative risk. Boxes and horizontal lines represent relative risk and 95% CI for each trial. The vertical dashed line on each plot represents the point estimate of overall relative risk. The size of each box is proportional to weight of that trial result. Diamonds represent the 95% CI for pooled estimates of effect and are centred on pooled relative risk. HOT (199) / 3 1 UKPDS-HDS (199) / 5 0 ABCD (H) (2000) / 0 ABCD (N) (2001) 1 9 0/ 6 0 REIN-2 (2005) / 2 JATOS (200) 23 9 / 3 3 Cardio-Sis (2009) 24 3 / 1 5 VANLISH (2010) / 1 ACCORD (2010) / 6 HOMED-BP (2012) 1 3/ 0 SPS3 (2013) /NA Wei et al (2013) / 5 9 PAST-BP (2015)* 2 0/ 2 4 Overall 6 6/ 3 4 Events/population: 39/122 vs 46/24162 I 2 =0 0%, p=0 99 Fixed-effects model 0 (95% CI ), p=0 042 C HOT (199) / 3 1 UKPDS-HDS (199) / 5 0 ABCD (H) (2000) / 0 ABCD (N) (2001) 1 9 0/ 6 0 REIN-2 (2005) / 2 JATOS (200) 23 9 / 3 3 Cardio-Sis (2009) 24 3 / 1 5 VANLISH (2010) / 1 AASK (2010) / 0 ACCORD (2010) / 6 HOMED-BP (2012) 1 3/ 0 SPS3 (2013) /NA Wei et al (2013) / 5 9 PAST-BP (2015)* 2 0/ 2 4 Overall 6 / 3 5 Events/population: 44/16 vs 651/2416 I 2 =12 %, p=0 32 Fixed-effects model 0 9 (95% CI ), p< Favours more intensive blood pressure control Favours less intensive blood pressure control 0 2 ( ) 0 0 ( ) 1 12 ( ) 1 30 ( ) 1 00 ( ) 1 00 ( ) 0 66 ( ) 1 25 ( ) 0 ( ) 0 1 ( ) 0 91 ( ) 0 99 ( ) 1 0 ( ) 0 ( ), p= ( ) 0 5 ( ) 0 9 ( ) 0 32 ( ) 0 33 ( ) 1 04 ( ) 0 44 ( ) 0 0 ( ) 0 96 ( ) 0 5 ( ) 1 25 ( ) 0 3 ( ) 0 5 ( ) 0 00 ( ) 0 ( ), p= Published online November 6,

5 Coronary heart disease Observed in current meta-analysis of trials of more vs less intensive blood pressure-lowering treatment 13% 22% Observed* in blood pressure difference trials 2 16% 31% Observed* in trials of blood pressure lowering vs control, in non-hypertensive patients with cardiovascular disease 29 20% 23% Expected* from cohort studies for people with systolic blood pressure >140 mm Hg 2 19% 26% Expected* from cohort studies for people with systolic blood pressure mm Hg 2 19% 26% *The associations observed in cohort studies for participants aged years 2 and the reductions shown in trials of blood pressure lowering vs control 2 are shown, standardised to the mm Hg systolic blood pressure difference recorded in the present meta-analysis (eg, previous blood pressure difference trials showed a relative risk for stroke of 0 59 with a 10 mm Hg systolic blood pressure reduction, 2 so one would expect a 31% reduction for mm Hg lower systolic blood pressure, because 0 59 /10 =0 69 and the relation between blood pressure change and relative risk is log-linear). The exception is for data from Thompson and colleagues study, 29 in which the overall systolic blood pressure difference was not available. Table 1: Comparison of expected and observed effects of a mm Hg systolic blood pressure decrease on coronary heart disease and stroke outcomes Stroke Trials (n) Events (n)/patients (n) Mean blood pressure difference (mm Hg) Relative risk (95% CI) Other major vascular events and renal outcomes Heart failure End-stage kidney disease Albuminuria Retinopathy Mortality /13 69 vs 221/ /4533 vs 266/ /2661 vs 9/ /1421 vs 351/1244 Cardiovascular death Non-cardiovascular death Overall mortality /1209 vs 446/ /1 02 vs 46/ /1953 vs 96/ / / / / / / / ( ) 0 90 (0 1 06) 0 90 ( ) 0 1 ( ) 0 91 ( ) 0 9 ( ( ) Favours more intensive blood pressure control Favours less intensive blood pressure control Figure 3: Effect of intensive versus less intensive blood pressure lowering on the risk of other major vascular events, renal outcomes, and mortality Weights are from random-effects analysis. Diamonds represent the 95% CI for pooled estimates of effect. were similar to those anticipated from large cohort studies 2 and with those in a meta-analysis of a broader set of all blood pressure difference trials (ie, treatment vs control and more intensive vs less intensive; 2 see table 1). Ten trials ( participants) reported 410 occurrences of heart failure, 6,10,14 1,19,21,23,24 with a non-significant reduction in this outcome in patients allocated to intensive blood pressure-lowering regimens compared with less intensive regimens (p=0 24; figure 3, appendix p 14). Eight trials including 690 participants recorded 514 end-stage kidney disease outcomes. 6,13,15,1 21,25 Compared with less intensive blood pressure lowering, the more intensive regimen did not significantly affect the risk of end-stage kidney disease (p=0 22; figure 3, appendix p 15). Three trials 6,15,16 reported data about progression of albuminuria (5224 participants and 1924 events) and showed that more intensive blood pressure control reduced the risk of albuminuria progression by 10% (95% CI 3 16) compared with less intensive control (p=0 004; figure 3) with no evidence of heterogeneity (I²=0 0%, p=0 65; appendix p 16). Progression of retinopathy was reported by four trials with 2665 participants and 693 events. 6,15 1 A borderline significant reduction in retinopathy occurred with more intensive blood pressure lowering (p=0 04, figure 3) but substantial heterogeneity in the magnitude of the effect across the included studies (I²=63 %, p=0 041, appendix p 1) which is mostly attributable to the result of the ACCORD study. 6 A sensitivity analysis excluding ACCORD resulted in a risk reduction of 25% (RR 0 5 [95% CI ], p<0 0001) with a much reduced I² value of 1 1%. Notably, there were significant imbalances in several of the baseline characteristics between randomised groups in this substudy of ACCORD. 6 Our analysis showed no clear effect of more intensive blood pressure lowering on the risk of cardiovascular death (p=0 36; figure 3, appendix p 1), 6, 10,14 1,19,21,23,26 (Mant J, personal communication), non-cardiovascular death (p=0 02; figure 3, appendix p 19), 6, 10,14 1,19,21,23,26 or all-cause death (p=0 135; figure 3, appendix p 20) 6, 10,13 26 (Mant J, personal communication) as compared with less intensive blood pressure control, with confidence intervals that were compatible with modest effects in either direction. No evidence suggests that the observed effects of more intensive blood pressure-lowering regimens on major vascular events differed across trial subgroups defined according to a broad range of baseline characteristics (p values for heterogeneity all greater than 0 05; figure 4). In particular, there was no clear evidence that the benefits of more intensive blood pressure lowering varied by the starting mean baseline blood pressure of the trial Published online November 6,

6 Subgroup of major cardiovascular events Trials (n) Relative risk (95% CI) p value for heterogeneity Sample size (n) < Mean age (years) <62 62 Follow-up (years) <4 4 Cardiovascular event rate <2 2% 2 2% Diabetes mellitus Yes No or mixture Chronic kidney disease Yes No or mixture Baseline systolic blood pressure (mm Hg) >160 Target blood pressure (mm Hg) Systolic blood pressure <130 and/or diastolic blood pressure <0 Systolic blood pressure 130 or diastolic blood pressure 0 Blood pressure targets met by most patients Yes No Target systolic blood pressure in intensive group <140 or <150 mm Hg <120 <130 mm Hg or diastolic target Mean follow-up systolic blood pressure (mm Hg) Systolic blood pressure difference (mm Hg) <6 6 Jadad score < ( ) 0 91 ( ) 0 91 ( ) 0 1 ( ) 0 92 ( ) 0 1 ( ) 0 92 ( ) 0 1 ( ) 0 3 ( ) 0 ( ) 1 0 ( ) 0 4 ( ) 0 9 ( ) 0 3 ( ) 0 9 ( ) 0 9 ( ) 0 1 ( ) 0 2 ( ) 0 94 ( ) 0 6 ( ) 0 91 ( ) 0 91 ( ) 0 2 ( ) 0 ( ) 0 6 ( ) 0 9 ( ) 0 5 ( ) Overall (0 0 96) Favours more intensive blood pressure control Favours less intensive blood pressure control Figure 4: Effects of intensive blood pressure lowering on the risk of major cardiovascular events in subgroups of trials Weights are from random-effects analysis. Boxes and horizontal lines represent relative risk and 95% CI for each trial. The vertical dashed line represents the overall point estimate relative risk according to the horizontal axis. The size of each box is proportional to weight of that trial result. The diamond represents the 95% CI for pooled estimates of effect and is centred on pooled relative risk. participants, the absolute level of the systolic or diastolic target set for the intensive group, or the mean follow-up blood pressure in the control group. After excluding the four trials with relatively high systolic blood pressure targets in the intensive group (150 mm Hg in one trial 15 and 140 mm Hg in three trials 10,23,26 ), the reduction in major vascular events was still evident (RR 0 91 [95% CI ]). Univariate meta-regression of intensive blood pressure lowering on major cardiovascular outcomes according to the baseline characteristics also showed no evidence of heterogeneity (appendix p 10). As a result of the consistent proportional reductions, absolute benefits were proportional to absolute risk. For trials in which all patients had vascular disease, renal disease, or diabetes at baseline, the average control group rate of major vascular events was 2 9% per year compared with 0 9% per year in other trials, 6 Published online November 6,

7 Serious adverse events associated with blood pressure lowering* Trials (n) Participants (n) Total events, n (event rate per person-year, %) More intensive regimen Less intensive regimen Relative risk (95% CI) p value (1 2%) 211 (0 9%) 1 35 ( ) Severe hypotension (0 3%) 23 (0 1%) 2 6 ( ) Dizziness (3 1%) 536 (2 %) 1 11 ( ) Adverse events leading to discontinuation of treatment (1 0%) 14 (1 0%) 0 96 ( ) 0 *For three trials, total serious adverse events are reported, whereas for the other three trials, serious adverse events associated with blood pressure lowering were reported. Table 2: Adverse events occurring in more intensive versus less intensive blood pressure-lowering trials and the numbers needed to treat were 94 (95% CI 44 2) in these trials versus 16 (10 0) in all other trials. Data for adverse effects potentially associated with treatment were reported inconsistently by individual trials. Table 2 summarises the data that were available. Six trials 6,9,21,25,26 (Mant J, personal communication) reported data for severe adverse events associated with blood pressure lowering ( participants and 491 events), showing no clear effect of more intensive versus less intensive blood pressure lowering on severe adverse events associated with blood pressure lowering (table 2). Five trials 6,9,20,24,25 reported severe hypotension outcomes (10 09 participants, with 61 events in the more intensive blood pressure-lowering treatment regimen vs 23 in the less intensive regimen) with more intensive blood pressure control almost tripling the risk of hypotension (p=0 015). More intensive blood pressure control led to a trend to an increased risk of dizziness (five trials with 9 participants and 1125 events [Mant J, personal communication]; 6,9,24,25 table 2). Finally, the rate of drug discontinuation did not differ between the more intensively and less intensively treated groups in the four trials 6,22,23,25 that reported data (9665 participants and 343 events; table 2). Discussion Our updated systematic review and meta-analysis shows reductions in major cardiovascular events from more intensive blood pressure-lowering treatment regimens aiming for lower blood pressure targets. These beneficial effects were consistent across major patient subgroups and types of interventions and significant gains could be achieved from further lowering of systolic blood pressure to lower than 140 mm Hg. Although an increase in hypotension occurred as a result of more intensive blood pressure lowering, including serious hypotensive events, there was no suggestion that these adverse effects would outweigh the benefits of treatment in high-risk patient populations. One of the main limitations of this review is the lack of individual participant data, which would have allowed a more reliable assessment of treatment effects in different patient groups. Additionally, there were few cause-specific events, such as fewer than 1000 myocardial infarction outcomes. To maximise power, we assessed major cardiovascular events as a whole, but the makeup of this composite outcome can vary by factors like patient group and blood pressure level. However, our review was comprehensive and increased the numbers of events available for analysis by 29% compared with our previous review by including four new trials (Mant J, personal communication). 10 A key issue in this topic is that few trials have simultaneously achieved large blood pressure separations between randomised groups and recorded large numbers of events. In such a setting, equivocal results can be expected from individual trials as a result of low statistical power and even meta-analyses if they are based on only a subset of all trials. 30 This situation is especially true for outcomes such as myocardial infarction, which is less strongly associated with blood pressure than is stroke, 2 and also for composite outcomes such as all cardiovascular events because these will comprise quite a high proportion of coronary heart disease events at lower blood pressure levels. However, this review showed clearly that the relative risk reductions for stroke and coronary heart disease were consistent with those expected for blood pressure differences of about mm Hg systolic. 2 Prospective observational studies in people without major illness at baseline consistently show that that the association of blood pressure with risk for cardiovascular events is direct and continuous at blood pressure levels of 115/5 mm Hg or higher. 2,31,32 However, several publications in recent years, derived from non-randomised studies in people with vascular disease, have suggested a J-curve association between blood pressure and outcome. 33 This finding has led to concern that excessive lowering of blood pressure could increase the risk of cardiovascular events. The results of the present meta-analysis support the idea that those observations were probably a result of uncontrolled confounding, and especially reverse causation, whereby major illness is itself a cause of low blood pressure, rather than a consequence. Similar concerns were voiced in the 190s and 1990s about the associations of low cholesterol levels with adverse outcomes, 34 but these were dispelled when large Published online November 6,

8 randomised trials of intensive cholesterol lowering refuted increases in outcomes such as cancer. 35 The higher potency of statins compared with blood pressure-lowering drugs is probably the main reason why this issue was resolved several decades earlier for lipids than for blood pressure. Contrary to some expectations, this meta-analysis provides evidence that intensive blood pressure lowering reduces cardiovascular events, although it also shows that an intensive strategy does increase the risk of some adverse effects. A definite increase in hypotension occurred in patients receiving the more intensive blood pressure-lowering regimen, including severe episodes of hypotension. Side-effects and quality-of-life data were incompletely and inconsistently collected across the contributing studies, which makes interpretation of these findings challenging. However, no evidence suggested an increase in fatal or life-threatening events, or other adverse events that were of similar severity to major cardiorenal events. Although the data about falls and fractures were scarce, the incidence rate would have been low in these generally less elderly patient populations, and reassuring data are available from more vulnerable, elderly patients. 36,3 In patient populations at high risk of vascular disease, the absolute benefits of treatment will comfortably surpass the absolute harms. Several research questions arise from this work, perhaps the most important of which is how best to achieve and maintain greater reductions in blood pressure given the relatively modest blood pressure differences seen in these trials. Combination therapy will be an important part of this solution, 3 40 but other approaches to improve treatment rates and adherence will be needed. The application of non-pharmacological approaches, such as weight loss and dietary sodium restriction, might help but will also be insufficient for most patients. In conclusion, this review and meta-analysis provides clear evidence of the benefits of more intensive blood pressure lowering, including in high-risk patients whose systolic blood pressure is lower than 140 mm Hg. Existing clinical guidelines 1 3 should be revised accordingly, to recommend more intensive blood pressure-lowering treatment in high-risk patient groups. Contributors AR, XX, JL, and VP conceived and designed the study. XX, AB, EA, JL, and AR did the study. XX analysed the data. AR wrote the first draft of the report, and AR, XX, EA, and JL helped to write the final version. All authors read and met the ICMJE criteria for authorship. All authors agree with the results and conclusions of the report. Declaration of interests EA has received grants from the National Health and Medical Research Council, during the conduct of the study. BN has received grants from Jannsen, Abbvie, Dr Reddy s Laboratories, Merck Schering Plough, and Roche, and honoraria or travel reimbursement from Abbott, Novartis, Pfizer, Servier, Roche, and Janssen, outside the submitted work. MW has received personal fees from Amgen and Novartis, and grants and personal fees from Roche, outside the submitted work. JC has received grants from the National Health and Medical Research Council of Australia Program Grant, during the conduct of the study, and grants and personal fees from Servier International, outside the submitted work. AS has received grants from the National Health and Medical Research Council of Australia, during the conduct of the study. KR has received grants from NIHR Oxford Biomedical Research Centre, Oxford Martin School, and NIHR Career Development Fellowship, during the conduct of the study. VP has received grants from Abbvie, Baxter, and Janssen; has received personal fees from Merck and Servier; has been on the steering committee for Astellas; has been on the steering commiteee or advisory board for GSK, Bristol-Myers Squibb, and Janssen; has received honoraria for speaking at science symposia from Eli Lilly, Pfizer, and Astra Zeneca; and has been on the steering committee and received honoraria for scientific presentations from Boehringer Ingleheim, outside the submitted work. AR has received grants from Servier outside the submitted work and also receives salary support in part from The George Institute for Global Health. George Health Enterprises, the social enterprise section of The George Institute, has received investment for the development of fixed-dose combination therapy containing statin, aspirin, and blood pressure-lowering drugs. XX, JL, AB, TN, SM, FT, GSH, and JM declare no competing interests. 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