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Benefits of more intensive versus less intensive blood pressure control. Updated trial sequential analysis

  • Author Footnotes
    1 These authors contributed equally this work.
    Gianpaolo Reboldi
    Footnotes
    1 These authors contributed equally this work.
    Affiliations
    Department of Medicine, Centro di Ricerca Clinica e Traslazionale (CERICLET), University of Perugia, Perugia, Italy
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  • Author Footnotes
    1 These authors contributed equally this work.
    Fabio Angeli
    Footnotes
    1 These authors contributed equally this work.
    Affiliations
    Department of Medicine and Surgery, University of Insubria, Varese and Department of Medicine and Cardiopulmonary Rehabilitation, Maugeri Care and Research Institute, IRCCS Tradate, Italy
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  • Giorgio Gentile
    Affiliations
    Royal Cornwall Hospitals, NHS Trust, Truro, Cornwall, United Kingdom

    University of Exeter Medical School, Exeter, United Kingdom
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  • Paolo Verdecchia
    Correspondence
    Corresponding author.
    Affiliations
    Fondazione Umbra Cuore e Ipertensione-ONLUS and Division of Cardiology, Hospital S. Maria della Misericordia, Perugia, Italy
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  • Author Footnotes
    1 These authors contributed equally this work.
Published:April 06, 2022DOI:https://doi.org/10.1016/j.ejim.2022.03.032

      Highlights

      • The conclusiveness of major RCTs on prognostic impact of a more intensive versus a less intensive BP control remains uncertain.
      • We undertook an updated cumulative meta-analysis of aggregated data and a trial sequential analysis.
      • A more intensive BP control was conclusively superior to a less intensive control for prevention of stroke, HF, and MI.
      • It also showed a significant benefit, albeit not yet conclusive, for prevention of cardiovascular death.

      Abstract

      Outcome data from randomized trials which compared different blood pressure (BP) targets grew impressively after publication of recent trials. We conducted a cumulative updated trial sequential analysis of studies which compared a more versus less intensive BP control strategy, for a total of 60,870 randomized patients. The compared BP targets differed across the trials. Outcome measures were stroke, heart failure, myocardial infarction and cardiovascular death. The average duration of follow-up was 3.95 years and achieved systolic BP was 7.69 mmHg lower with the more intensive than the less intensive BP control strategy. The more intensive BP control strategy significantly reduced the risk of stroke (OR 0.79; 95% CI 0.67–0.93), heart failure (OR 0.73; 95% CI 0.55–0.96), myocardial infarction (OR 0.81; 95% CI 0.73–0.91) and cardiovascular death (OR 0.81; 95% CI 0.68–0.98) as compared to the less intensive strategy. In a trial sequential analysis, the more intensive BP control strategy provided conclusive benefits over the less intensive strategy on the risk of stroke, heart failure and myocardial infarction by definitely crossing the efficacy monitoring boundary. For cardiovascular death, the cumulative Z-curve of the sequential analysis touched the efficacy monitoring boundary, but did not cross it. In conclusion, data accrued from randomized trials conclusively demonstrate the superiority of a more intensive over a less intensive BP control strategy for the prevention of stroke, heart failure and myocardial infarction. Results also suggest a significant benefit, albeit not yet conclusive, of a more intensive over a less intensive strategy for prevention of cardiovascular death.

      Graphical abstract

      Keywords

      Abbreviations:

      ACC (American College of Cardiology), AHA (American Heart Association), BP (Blood pressure), CI (Confidence interval), CMA (Cumulative meta-analysis), D2 (Diversity), ESC (European Society of Cardiology), ESH (European Society of Hypertension), HF (Heart failure), I2 (Inconsistency), IPD (Individual patient data), MI (Myocardial infarction), ONTARGET (Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial), OR (Odds ratio), PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyzes), RCT (Randomized controlled trial), RRR (Relative risk reduction), SHOT (Stroke in Hypertension Optimal Treatment), SPRINT (Systolic Blood Pressure Intervention Trial), STEP (Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients), TSA (Trial sequential analysis), VALUE (Valsartan Antihypertensive Long-Term Use Evaluation)

      Introduction

      High blood pressure (BP) remains a dominant risk factor for cardiovascular disease and death worldwide [
      • Carey R.M.
      • Muntner P.
      • Bosworth H.B.
      • Whelton P.K
      Prevention and control of hypertension: JACC health promotion series.
      ,
      • GBD 2017 Risk Factor Collaborators
      Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990–2015: a systematic analysis for the global burden of disease study 2015.
      ]. The progressive decline in the incidence of cardiovascular disease, particularly stroke, which occurred over the past 50 years, has been largely attributed to the progressive reduction of elevated BP levels at population level [
      • Lackland D.T.
      • Roccella E.J.
      • Deutsch A.F.
      • Fornage M.
      • George M.G.
      • Howard G.
      • et al.
      Factors influencing the decline in stroke mortality: a statement from the American heart association/American stroke association.
      ,
      • Lewington S.
      • Clarke R.
      • Qizilbash N.
      • Peto R.
      • Collins R.
      Prospective Studies Collaboration
      Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies.
      ]. However, despite the universal consensus on the importance of effective and persistent BP lowering [
      • Whelton P.K.
      • Carey R.M.
      • Aronow W.S.
      • Casey D.E.
      • Collins K.J.
      • Dennison Himmelfarb C.
      • et al.
      2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American college of cardiology/American heart association task force on clinical practice guidelines.
      ,
      • Williams B.
      • Mancia G.
      • Spiering W.
      • Agabiti Rosei E.
      • Azizi M.
      • Burnier M.
      • et al.
      2018 ESC/ESH guidelines for the management of arterial hypertension.
      ], the BP targets to achieve with treatment in the clinical practice are still object of debate [
      • Carey R.M.
      • Whelton P.K
      Evidence for the universal blood pressure goal of <130/80 mm Hg is strong: controversies in hypertension - pro side of the argument.
      ,
      • Kaul S
      Evidence for the universal blood pressure goal of <130/80mm Hg is strong: controversies in hypertension - con side of the argument.
      ]. The debate is synthetized by the different position of the American College of Cardiology (ACC)/American Heart Association (AHA) 2017 Guidelines, which recommend a general BP goal of <130/80 mmHg, [
      • Whelton P.K.
      • Carey R.M.
      • Aronow W.S.
      • Casey D.E.
      • Collins K.J.
      • Dennison Himmelfarb C.
      • et al.
      2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American college of cardiology/American heart association task force on clinical practice guidelines.
      ] and the European Society of Cardiology (ESC)/European Society of Hypertension (ESH) Guidelines which recommend a general BP goal of <140/90 mmHg, with lower goals in specific clinical scenarios [
      • Williams B.
      • Mancia G.
      • Spiering W.
      • Agabiti Rosei E.
      • Azizi M.
      • Burnier M.
      • et al.
      2018 ESC/ESH guidelines for the management of arterial hypertension.
      ].
      According to the general principles of evidence-based medicine, a final answer to the question of the most appropriate BP target can stem from randomized controlled trials in which different BP lowering strategies are compared in their effects on BP reduction and outcome. An alternative solution may be the comparison of subjects with different achieved BP levels from post-hoc analyzes of observational and trial databases which, however, may expose to inherent methodological bias.
      A few years ago, we published a trial sequential analysis of randomized trials with allocated patients to a more versus less intensive BP target [
      • Verdecchia P.
      • Angeli F.
      • Gentile G.
      • Reboldi G
      More versus less intensive blood pressure-lowering strategy: cumulative evidence and trial sequential analysis.
      ]. The analysis definitely supported the superiority of a more intensive over a less intensive BP lowering strategy to reduce the risk of stroke and myocardial infarction (MI), whereas the benefits on the risk of heart failure (HF) and death were still inconclusive [
      • Verdecchia P.
      • Angeli F.
      • Gentile G.
      • Reboldi G
      More versus less intensive blood pressure-lowering strategy: cumulative evidence and trial sequential analysis.
      ]. Subsequently, two important clinical trials have been published. The Final Report of the Systolic Blood Pressure Intervention Trial (SPRINT), published in year 2021 [
      • SPRINT Research Group
      • Lewis C.E.
      • Fine L.J.
      • Beddhu S.
      • Cheung A.K.
      • Cushman W.C.
      • et al.
      Final report of a trial of intensive versus standard blood-pressure control.
      ], provided additional adjudicated events to the previous publication [
      The SPRINT Research Group
      A randomized trial of intensive versus standard blood-pressure control.
      ]. In the same year, the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial [
      • Zhang W.
      • Zhang S.
      • Deng Y.
      • Wu S.
      • Ren J.
      • Sun G.
      • et al.
      Trial of intensive blood-pressure control in older patients with hypertension.
      ] provided further high-quality data in the comparison between different BP lowering strategies.
      In view of the important new contribution provided by these two reports, we undertook an updated cumulative meta-analysis (CMA) [
      • Lau J.
      • Antman E.M.
      • Jimenez-Silva J.
      • Kupelnick B.
      • Mosteller F.
      • Chalmers T.C
      Cumulative meta-analysis of therapeutic trials for myocardial infarction.
      ,
      • Lau J.
      • Schmid C.H.
      • Chalmers T.C
      Cumulative meta-analysis of clinical trials builds evidence for exemplary medical care.
      ] and a trial sequential analysis (TSA) [
      • Pogue J.M.
      • Yusuf S
      Cumulating evidence from randomized trials: utilizing sequential monitoring boundaries for cumulative meta-analysis.
      ,
      • Wetterslev J.
      • Thorlund K.
      • Brok J.
      • Gluud C
      Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis.
      ].

      Methods

      Study selection and outcome measures

      We addressed randomized controlled trials (RCTs) meeting all the following inclusion criteria: (a) comparison between different BP targets (more versus less intensive target), regardless of the specific BP goal; (b); stroke, MI, HF, or cardiovascular death as pre-specified outcome events, regardless of the definition of the primary end-point in each trial; (c) BP values measured both at baseline and at follow-up; (d) follow-up duration > 12 months with the exclusion of observational extensions phases; (e) publication before December 31th, 2021; (f) no age or language restriction, in order to avoid discriminating papers not written in English (‘tower of Babel bias’) [
      • Gregoire G.
      • Derderian F.
      • Le Lorier J.
      Selecting the language of the publications included in a meta-analysis: is there a tower of Babel bias?.
      ].

      Data sources and searches

      Candidate studies were searched through MEDLINE (from Jan 1, 1950, to Sept 30, 2021), Embase (from 1966 to Sept 30, 2021) and the Cochrane Central Register of Controlled Trials (up to Sept 30, 2021), using research Methodology Filters [
      • Haynes R.B.
      • Wilczynski N.
      • McKibbon K.A.
      • Walker C.J.
      • Sinclair J.C
      Developing optimal search strategies for detecting clinically sound studies in MEDLINE.
      ]. We limited the search to the randomized phase of controlled clinical trials with more than 12 months of follow-up and hence excluded post-randomized extensions phases. We made a further screening of review articles, published proceedings of conferences, and regulatory agencies files [
      • McAuley L.
      • Pham B.
      • Tugwell P.
      • Moher D
      Does the inclusion of grey literature influence estimates of intervention effectiveness reported in meta-analyses?.
      ] in order to identify other relevant studies. To focus our attention to cardiovascular outcome events, we excluded studies which reported all-cause mortality in the absence of data on different cardiovascular events or the possible cardiovascular origin of the death.

      Data synthesis and quality assessment

      Table 1 shows the trials identified on the basis of the above criteria. Overall, trials accrued 60,870 patients randomized to a more intensive or less intensive BP lowering strategy. The average duration of follow-up was 4.2 years. Fig. 1 shows the flow diagram with the criteria used for selection of trials. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) statement [
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      • Group P
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ]. Data were independently extracted by two authors (FA and PV) on the basis of an intention-to-treat approach. Disagreements were discussed in conference. In order to evaluate the methodological quality of trials (sequence generation of allocation, allocation concealment, masking of participants, personnel, and outcome assessors, incomplete outcome data, selective outcome reporting, and other sources of bias), we adopted the methods recommended by the Cochrane Collaboration [
      • Higgins J.
      • Green S
      Cochrane handbook for systematic reviews of interventions.
      ].
      Table 1. Main features of clinical trials included in the meta-analysis.
      StudyPublication YearBP Lowering Strategy, mmHgNumber of patientsFollow-up duration (years)Difference in SBP (mmHg) †
      More IntensiveLess IntensiveMore IntensiveLess Intensive
      HOT
      • Hansson L.
      • Zanchetti A.
      • Carruthers S.G.
      • Dahlof B.
      • Elmfeldt D.
      • Julius S.
      • et al.
      Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the hypertension optimal treatment (HOT) randomised trial. HOT study group.
      1998DBP < 80,85DBP < 9012,52662643.8−2.9
      UKPDS-38
      UK Prospective Diabetes Study Group
      Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38.
      1998BP < 150/85BP < 180/1057583908.4−9
      ABCD (H)
      • Estacio R.O.
      • Jeffers B.W.
      • Gifford N.
      • Schrier R.W
      Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes.
      2000DBP < 75DBP 80–892372335.0−5
      AASK
      • Wright J.T.
      • Bakris G.
      • Greene T.
      • Agodoa L.Y.
      • Appel L.J.
      • Charleston J.
      • et al.
      Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial.
      2002MBP < 92MAP 102–1075405543.8−20
      Schrier et al.
      • Schrier R.
      • McFann K.
      • Johnson A.
      • Chapman A.
      • Edelstein C.
      • Brosnahan G.
      • et al.
      Cardiac and renal effects of standard versus rigorous blood pressure control in autosomal-dominant polycystic kidney disease: results of a seven-year prospective randomized study.
      2002BP < 120/80BP 135–140/85–9041347.0−10
      ABCD (N)
      • Schrier R.W.
      • Estacio R.O.
      • Esler A.
      • Mehler P
      Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes.
      2002DBP drop 10DBP 80–902372435.3−11.5
      REIN-2
      • Ruggenenti P.
      • Perna A.
      • Loriga G.
      • Ganeva M.
      • Ene-Iordache B.
      • Turturro M.
      • et al.
      Blood-pressure control for renoprotection in patients with non-diabetic chronic renal disease (REIN-2): multicentre, randomised controlled trial.
      2005BP < 130/80DBP < 901691693.0−4.7
      JATOS
      JATOS Study Group
      Principal results of the Japanese trial to assess optimal systolic blood pressure in elderly hypertensive patients (JATOS).
      2008SBP < 140SBP < 160221222062.0−9.7
      Cardio-Sis
      • Verdecchia P.
      • Staessen J.A.
      • Angeli F.
      • de Simone G.
      • Achilli A.
      • Ganau A.
      • et al.
      Usual versus tight control of systolic blood pressure in non-diabetic patients with hypertension (Cardio-Sis): an open-label randomised trial.
      2009SBP < 130SBP < 1405585532.0−3.6
      ACCORD BP
      The ACCORD Study Group
      Effects of intensive blood-pressure control in type 2 diabetes mellitus.
      2010SBP < 120SBP < 140236223714.7−13.8
      VALISH
      • Ogihara T.
      • Saruta T.
      • Rakugi H.
      • Matsuoka H.
      • Shimamoto K.
      • Shimada K.
      • et al.
      Target blood pressure for treatment of isolated systolic hypertension in the elderly: valsartan in elderly isolated systolic hypertension study.
      2010SBP < 140SBP 140–149154515342.9−5.3
      HOMED-BP
      • Asayama K.
      • Ohkubo T.
      • Metoki H.
      • Obara T.
      • Inoue R.
      • Kikuya M.
      • et al.
      Cardiovascular outcomes in the first trial of antihypertensive therapy guided by self-measured home blood pressure.
      2012BP < 125/80BP 125–134/80–84175917595.3−1.1
      Wei et al.
      • Wei Y.
      • Jin Z.
      • Shen G.
      • Zhao X.
      • Yang W.
      • Zhong Y.
      • et al.
      Effects of intensive antihypertensive treatment on Chinese hypertensive patients older than 70 years.
      2013BP≤140/90BP≤150/903633614.0−14
      SPS3
      • Study Group S.P.S.
      Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial.
      2013SBP < 130SBP 130–149150115193.7−12.5
      SPRINT
      • SPRINT Research Group
      • Lewis C.E.
      • Fine L.J.
      • Beddhu S.
      • Cheung A.K.
      • Cushman W.C.
      • et al.
      Final report of a trial of intensive versus standard blood-pressure control.
      2021SBP < 120SBP < 140467846833.3−13.9
      STEP
      • Zhang W.
      • Zhang S.
      • Deng Y.
      • Wu S.
      • Ren J.
      • Sun G.
      • et al.
      Trial of intensive blood-pressure control in older patients with hypertension.
      2021SBP 110–129SBP 130–150424342683.3−9.2
      Abbreviations: BP = blood pressure; SBP = systolic blood pressure; DBP = diastolic blood pressure; MBP = mean blood pressure. † = baseline adjusted mean difference at follow-up.
      Fig 1
      Fig. 1. Criteria used for selection of trials.

      Data analysis

      We used the raw counts for each outcome event and calculated the cumulative odds ratios (ORs) and 95% confidence intervals (CIs) through a random-effects model. In case of multi-arm trials we analyzed the pre-specified comparisons as defined in the original design [
      • Sutton A.
      • Abrams K.
      • Jones D
      Methods for meta-analysis in medical research.
      ]. We tested the null hypothesis of homogeneity across individual trials by using the Q-test, and the I2 statistics to assess heterogeneity across pooled estimates. We tested the publication bias by a weighted regression test [
      • Higgins J.
      • Green S
      Cochrane handbook for systematic reviews of interventions.
      ,
      • Sterne J.A.
      • Sutton A.J.
      • Ioannidis J.P.
      • Terrin N.
      • Jones D.R.
      • Lau J.
      • et al.
      Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials.
      ].
      In order to evaluate to what extent the evidence changes over time, we undertook a CMA [
      • Lau J.
      • Antman E.M.
      • Jimenez-Silva J.
      • Kupelnick B.
      • Mosteller F.
      • Chalmers T.C
      Cumulative meta-analysis of therapeutic trials for myocardial infarction.
      ,
      • Lau J.
      • Schmid C.H.
      • Chalmers T.C
      Cumulative meta-analysis of clinical trials builds evidence for exemplary medical care.
      ]. CMA evaluate data from studies which are sequentially included according to the year in which they first became available. The earliest available study is entered into the analysis first. At each step of the CMA, one more study is added to the analysis, and the effect size and 95% CI are re-calculated. Hence, CMA of successive RCTs addresses the potential impact of more recent studies on prior pooled results. It can be used to settle whether enough evidence has been accrued comparing an intervention versus a control treatment, or whether a new RCT deserves to be initiated. Notably, no adjustment is made in CMA for repeatedly testing the null hypothesis.
      A cumulative TSA can be helpful to decide whether and when a firm and conclusive evidence favoring a specific intervention has been reached from data accrued so far [
      • Pogue J.M.
      • Yusuf S
      Cumulating evidence from randomized trials: utilizing sequential monitoring boundaries for cumulative meta-analysis.
      ,
      • Wetterslev J.
      • Thorlund K.
      • Brok J.
      • Gluud C
      Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis.
      ]. Cumulative TSA requires a pre-specified and clinically relevant estimate of the effect of intervention, as well as an overall estimate of the risk of type I error. In the present analysis we used the relative risk reductions (RRR) derived from CMA for each outcome event, with alpha set at 5% (two-sided) and a power of 80% considering early and repetitive testing. Based on this information we calculated a diversity adjusted required information size (i.e., the number of participants in the meta-analysis required to accept or reject the specific intervention effect) [
      • Wetterslev J.
      • Thorlund K.
      • Brok J.
      • Gluud C
      Estimating required information size by quantifying diversity in random-effects model meta-analyses.
      ]. Diversity (D2) is estimated as the percentage of the variability between trials (i.e., sum of the variability between trials). D2 differs from the adjusting factor based on the quantification of heterogeneity, the inconsistency (I2), which might underestimate the required information size [
      • Wetterslev J.
      • Thorlund K.
      • Brok J.
      • Gluud C
      Estimating required information size by quantifying diversity in random-effects model meta-analyses.
      ]. On the above basis, we built monitoring boundaries for benefit, harm, or futility with regard to the observed RRR to control the overall type I error as statistical tests were repeated throughout the accumulation of studies [
      • Lau J.
      • Schmid C.H.
      • Chalmers T.C
      Cumulative meta-analysis of clinical trials builds evidence for exemplary medical care.
      ,
      • Pogue J.M.
      • Yusuf S
      Cumulating evidence from randomized trials: utilizing sequential monitoring boundaries for cumulative meta-analysis.
      ,
      • Wetterslev J.
      • Thorlund K.
      • Brok J.
      • Gluud C
      Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis.
      ]. We generated cumulative Z-curves (i.e., Z-statistics after each trial) for each cumulative random-effects meta-analysis, and assessed its crossing of the conventional significance level and the monitoring boundaries. Of particular note, the efficacy monitoring boundaries should be crossed by the cumulative Z-curve to obtain firm evidence for a beneficial intervention effect. Crossing of Z = 1.96 provides a “conventionally” significant result, whereas crossing of the monitoring boundary denotes firm evidence adjusted for random error risk.
      Analyzes were performed using R version 4.1.2 (R Foundation for Statistical Computing, Vienna, Austria) and TSA software version 0.95 (Copenhagen Trial Unit, DK, http://www.ctu.dk/tsa/).

      Role of the funding source

      The funder of the study did not have any role in the design of the study, data collection, statistical analysis, interpretation of results and writing the manuscript. All the authors of this study had full access to data and share responsibility for their submission and dissemination.

      Results

      As shown in Fig. 1, literature search initially yielded 13,590 reports. After removal of duplicates and studies not focused on BP regulation, we reviewed 367 randomized studies in full text. Among these, we excluded 344 studies because of lack of data on the precise number of outcome events, no identification of BP lowering strategies or follow-up extension after the randomized phase. Among the remaining 23 studies, we removed 7 studies because of unclear reporting of outcome events, BP strategy based on ambulatory BP, or follow up time < 12 months. Thus, 16 trials entered the final analysis. Of these, 16 trials reported data on cardiovascular death, 14 on MI, 10 on congestive HF and 14 on stroke.
      In the included trials, a total of 61,916 patients were randomized and the average duration of follow-up was 3.95 years (244 568 patient-years of exposure). Baseline BP averaged 149/86 mmHg and 150/87 mmHg in the less intensive and more intensive arm, respectively. On follow-up, average BP was 138/81 mmHg and 129/76 mmHg in the less intensive and more intensive arm, respectively. The weighted BP difference between randomized strategies from baseline to follow-up (assessed by weighting the difference observed in each contributing trial by the number of randomized subjects) was 7.69 mmHg (95% CIs 7.64–7.71) for systolic BP and 4.29 mmHg (95% CIs 4.27–4.31) for diastolic BP. Overall, there were 1323 stroke events, 1403 MI events, 543 HF events and 959 cardiovascular deaths.
      The methodological quality varied across the trials, albeit most were at low risk of bias, and a formal test of plot asymmetry showed no evidence of publication bias (p-value = 0.208).
      Fig. 2 shows the cumulative MA of the examined studies. Overall, the more intensive BP lowering strategy was associated with a reduction in the cumulative risk of stroke (OR 0.79; 95% CI 0.67–0.93; p = 0.004), HF (OR 0.73; 95% CI 0.55–0.96; p = 0.025), MI (OR 0.81; 95% CI 0.73–0.91; p < 0.0001) and cardiovascular death (OR 0.81; 95% CI 0.66–0.98; p < 0.026) compared to the less intensive strategy. Notably, the heterogeneity across studies was moderate to null (I2 = 38% [p = 0.07], 44% [p = 0.07], 0% [p = 0.95] and 27% [p = 0.15] for stroke, HF, MI and cardiovascular death, respectively).
      Fig 2
      Fig. 2. Benefits of more intensive versus less intensive blood pressure control on the risk of stroke, heart failure, myocardial infarction and cardiovascular death. Diamonds represent the 95% confidence interval for pooled estimates.
      Results of TSA are shown in Figs. 3 and 4. For the outcome stroke (Fig. 3), the cumulative Z-curve reached the sequential monitoring boundary with the study by Wei et al. [
      • Wei Y.
      • Jin Z.
      • Shen G.
      • Zhao X.
      • Yang W.
      • Zhong Y.
      • et al.
      Effects of intensive antihypertensive treatment on Chinese hypertensive patients older than 70 years.
      ], crossed it after the SPRINT study [
      • SPRINT Research Group
      • Lewis C.E.
      • Fine L.J.
      • Beddhu S.
      • Cheung A.K.
      • Cushman W.C.
      • et al.
      Final report of a trial of intensive versus standard blood-pressure control.
      ] and fully maintained the trend after the STEP study, [
      • Zhang W.
      • Zhang S.
      • Deng Y.
      • Wu S.
      • Ren J.
      • Sun G.
      • et al.
      Trial of intensive blood-pressure control in older patients with hypertension.
      ] thus providing firm evidence of the beneficial effect of the intervention. For HF (Fig. 3), the cumulative Z-curve definitely crossed the conventional significance boundary after the SPRINT study [
      • SPRINT Research Group
      • Lewis C.E.
      • Fine L.J.
      • Beddhu S.
      • Cheung A.K.
      • Cushman W.C.
      • et al.
      Final report of a trial of intensive versus standard blood-pressure control.
      ]. As shown in Fig. 4, for the outcome MI the cumulative Z-curve reached the sequential monitoring boundary with the Cardio-Sis study [
      • Verdecchia P.
      • Staessen J.A.
      • Angeli F.
      • de Simone G.
      • Achilli A.
      • Ganau A.
      • et al.
      Usual versus tight control of systolic blood pressure in non-diabetic patients with hypertension (Cardio-Sis): an open-label randomised trial.
      ] and definitely crossed it after all the subsequent six studies. For cardiovascular death, the cumulative Z-curve reached the sequential monitoring boundary with the STEP study, without fully crossing it. Subsequently to the three latest trials (i.e., the study by Wei et al. [
      • Wei Y.
      • Jin Z.
      • Shen G.
      • Zhao X.
      • Yang W.
      • Zhong Y.
      • et al.
      Effects of intensive antihypertensive treatment on Chinese hypertensive patients older than 70 years.
      ] the SPRINT study [
      • SPRINT Research Group
      • Lewis C.E.
      • Fine L.J.
      • Beddhu S.
      • Cheung A.K.
      • Cushman W.C.
      • et al.
      Final report of a trial of intensive versus standard blood-pressure control.
      ] and the STEP study [
      • Zhang W.
      • Zhang S.
      • Deng Y.
      • Wu S.
      • Ren J.
      • Sun G.
      • et al.
      Trial of intensive blood-pressure control in older patients with hypertension.
      ]) the cumulative Z-curve for cardiovascular death moved far away from the futility area.
      Fig 3
      Fig. 3. Trial sequential analysis of more intensive versus less intensive blood pressure control on the risk of stroke and heart failure. The dashed red lines denote the sequential monitoring boundaries and the gray area the futility inner wedge.
      Fig 4
      Fig. 4. Trial sequential analysis of the effect of more intensive versus less intensive blood pressure control on the risk of myocardial infarction and cardiovascular death. The dashed red lines denote the sequential monitoring boundaries and the gray area the futility inner wedge.

      Discussion

      The present meta-analysis provides two clinically relevant findings. First, by including two recently published Reports from the large SPRINT [
      • SPRINT Research Group
      • Lewis C.E.
      • Fine L.J.
      • Beddhu S.
      • Cheung A.K.
      • Cushman W.C.
      • et al.
      Final report of a trial of intensive versus standard blood-pressure control.
      ] and the STEP [
      • Zhang W.
      • Zhang S.
      • Deng Y.
      • Wu S.
      • Ren J.
      • Sun G.
      • et al.
      Trial of intensive blood-pressure control in older patients with hypertension.
      ] trials, it consolidates evidence from available trials and meta-analyzes [
      • Verdecchia P.
      • Angeli F.
      • Gentile G.
      • Reboldi G
      More versus less intensive blood pressure-lowering strategy: cumulative evidence and trial sequential analysis.
      ,
      • Bangalore S.
      • Toklu B.
      • Gianos E.
      • Schwartzbard A.
      • Weintraub H.
      • Ogedegbe G.
      • et al.
      Optimal systolic blood pressure target after SPRINT: insights from a network meta-analysis of randomized trials.
      ,
      • Bundy J.D.
      • Li C.
      • Stuchlik P.
      • Bu X.
      • Kelly T.N.
      • Mills K.T.
      • et al.
      Systolic blood pressure reduction and risk of cardiovascular disease and mortality: a systematic review and network meta-analysis.
      ,
      • Ettehad D.
      • Emdin C.A.
      • Kiran A.
      • Anderson S.G.
      • Callender T.
      • Emberson J.
      • et al.
      Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis.
      ,
      • Law M.R.
      • Morris J.K.
      • Wald N.J
      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.
      ,
      • Reboussin D.M.
      • Allen N.B.
      • Griswold M.E.
      • Guallar E.
      • Hong Y.
      • Lackland D.T.
      • et al.
      Systematic review for the 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American college of cardiology/American heart association task force on clinical practice guidelines.
      ,
      • Sakima A.
      • Satonaka H.
      • Nishida N.
      • Yatsu K.
      • Arima H
      Optimal blood pressure targets for patients with hypertension: a systematic review and meta-analysis.
      ,
      • Thomopoulos C.
      • Parati G.
      • Zanchetti A
      Effects of blood pressure lowering on outcome incidence in hypertension: 7. Effects of more vs. less intensive blood pressure lowering and different achieved blood pressure levels - updated overview and meta-analyses of randomized trials.
      ,
      • Xie X.
      • Atkins E.
      • Lv J.
      • Bennett A.
      • Neal B.
      • Ninomiya T.
      • et al.
      Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis.
      ] with regard to the potential of a more intensive versus a less intensive BP lowering strategy for reducing the risk of stroke, HF, MI and cardiovascular death in hypertensive subjects. Second, our cumulative TSA showed that data accrued so far conclusively support the superiority of a more intensive BP control strategy for the prevention of stroke, HF and MI, whereas the benefits are not yet conclusive, although numerically significant from a statistic viewpoint, for prevention of cardiovascular death.
      The inclusion of the final data from SPRINT [
      • SPRINT Research Group
      • Lewis C.E.
      • Fine L.J.
      • Beddhu S.
      • Cheung A.K.
      • Cushman W.C.
      • et al.
      Final report of a trial of intensive versus standard blood-pressure control.
      ] and STEP [
      • Zhang W.
      • Zhang S.
      • Deng Y.
      • Wu S.
      • Ren J.
      • Sun G.
      • et al.
      Trial of intensive blood-pressure control in older patients with hypertension.
      ] in the meta-analysis allowed to conclude that a more intensive BP lowering strategy specifically reduces the risk of stroke, HF, MI and cardiovascular death by 21% (p = 0.004), 27% (p = 0.025), 19% (p < 0.0001) and 19% (p = 0.026), respectively. Of note, the risk of stroke showed a non-significant 19% reduction in the intensive strategy arm in SPRINT and a 33% reduction in STEP (Hazard Ratio [HR] 0.67; 95% CI 0.47–0.97). Conversely, the risk of cardiovascular death showed a significant 42% reduction in the intensive strategy arm in SPRINT, but a non-significant 28% reduction in STEP (HR 0.72; 95% CI 0.39–1.32).
      In a comprehensive meta-analysis, which did not include SPRINT and STEP, a more intensive BP target was associated with a significant 22% reduction in the risk of stroke and a significant 13% reduction in the risk of MI, along with a non-significant reduction in the risk of HF (15%) and cardiovascular death (9%) [
      • Xie X.
      • Atkins E.
      • Lv J.
      • Bennett A.
      • Neal B.
      • Ninomiya T.
      • et al.
      Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis.
      ].
      Since SPRINT contributed 173 new cases of HF, by 37% less frequent in the more intensive arm [
      • SPRINT Research Group
      • Lewis C.E.
      • Fine L.J.
      • Beddhu S.
      • Cheung A.K.
      • Cushman W.C.
      • et al.
      Final report of a trial of intensive versus standard blood-pressure control.
      ], and STEP contributed 14 new cases of HF (by 73% less frequent in the more intensive arm) [
      • Zhang W.
      • Zhang S.
      • Deng Y.
      • Wu S.
      • Ren J.
      • Sun G.
      • et al.
      Trial of intensive blood-pressure control in older patients with hypertension.
      ], inclusion of the two latter trials consolidated the overall benefit on HF in the more intensive arm. Similarly, SPRINT contributed 112 new cases, and STEP 43 new cases, of cardiovascular death which was less frequent by 42% and 28%, respectively, in the more intensive arm of the SPRINT and STEP [
      • SPRINT Research Group
      • Lewis C.E.
      • Fine L.J.
      • Beddhu S.
      • Cheung A.K.
      • Cushman W.C.
      • et al.
      Final report of a trial of intensive versus standard blood-pressure control.
      ,
      • Zhang W.
      • Zhang S.
      • Deng Y.
      • Wu S.
      • Ren J.
      • Sun G.
      • et al.
      Trial of intensive blood-pressure control in older patients with hypertension.
      ].
      We used a cumulative TSA of randomized trials to estimate whether the evidence progressively accrued on pivotal specific outcomes may be considered strong and conclusive [
      • Wetterslev J.
      • Thorlund K.
      • Brok J.
      • Gluud C
      Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis.
      ,
      • Wetterslev J.
      • Thorlund K.
      • Brok J.
      • Gluud C
      Estimating required information size by quantifying diversity in random-effects model meta-analyses.
      ]. The logic of ‘early stopping rules’ used in the management of randomized intervention trials to evaluate whether it is still ethical to continue a trial on the basis of data accrued so far, can be applied to a TSA to understand whether the accrued data are definitive and no further studies are needed [
      • Wetterslev J.
      • Thorlund K.
      • Brok J.
      • Gluud C
      Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis.
      ,
      • Wetterslev J.
      • Thorlund K.
      • Brok J.
      • Gluud C
      Estimating required information size by quantifying diversity in random-effects model meta-analyses.
      ]. In our analysis, the cumulative Z-curves for the hypotheses of a 20%, 25% and 18% relative risk reduction for stroke, HF and MI, respectively, in the intensive strategy arm crossed not only the conventional Z = 1.96 (P < 0.05) boundary, but also the monitoring boundaries, thereby providing firm and conclusive evidence of benefit. The monitoring boundaries were definitely crossed after the SPRINT trial for stroke, and after the STEP trial for HF. For MI, the monitoring boundaries were definitely crossed with the ACCORD study and the trend consolidated after the subsequent trials.
      For cardiovascular death, the benefit associated to the intensive strategy crossed the conventional Z = 1.96 (P < 0.05) boundary after SPRINT [
      • SPRINT Research Group
      • Lewis C.E.
      • Fine L.J.
      • Beddhu S.
      • Cheung A.K.
      • Cushman W.C.
      • et al.
      Final report of a trial of intensive versus standard blood-pressure control.
      ] and STEP [
      • Zhang W.
      • Zhang S.
      • Deng Y.
      • Wu S.
      • Ren J.
      • Sun G.
      • et al.
      Trial of intensive blood-pressure control in older patients with hypertension.
      ]. However, the efficacy monitoring boundary was touched, but not crossed, after STEP. Hence, albeit significant from a statistic viewpoint, the benefit of an intensive BP lowering strategy for prevention of cardiovascular death may not yet been considered conclusive.
      Several methodological aspects suggest that meta-analyzes should be interpreted with some more caution in comparison with well-designed and rigorously conducted controlled randomized clinical trials [
      • Pogue J.M.
      • Yusuf S
      Cumulating evidence from randomized trials: utilizing sequential monitoring boundaries for cumulative meta-analysis.
      ,
      • Brunstrom M.
      • Thomopoulos C.
      • Carlberg B.
      • Kreutz R.
      • Mancia G
      Methodological aspects of meta-analyses assessing the effect of blood pressure-lowering treatment on clinical outcomes.
      ]. Unfortunately, however, several randomized intervention trials may have been underpowered to robustly test the superiority of intensive BP control strategies on organ-specific outcomes, thus justifying meta-analyzes of aggregated and individual data, as well as further trials [
      • Kjeldsen S.E.
      • Lund-Johansen P.
      • Nilsson P.M.
      • Mancia G
      Unattended blood pressure measurements in the systolic blood pressure intervention trial. implications for entry and achieved blood pressure values compared with other trials.
      ].
      In the ongoing Stroke in Hypertension Optimal Treatment (SHOT) trial, promoted by the European Society of Hypertension and the Chinese Hypertension League, hypertensive patients with a history of stroke or transient ischemic are being randomized to different systolic BP targets [
      • Zanchetti A.
      • Liu L.
      • Mancia G.
      • Parati G.
      • Grassi G.
      • Stramba-Badiale M.
      • et al.
      Continuation of the ESH-CHL-SHOT trial after publication of the SPRINT: rationale for further study on blood pressure targets of antihypertensive treatment after stroke.
      ]. The present analysis suggests that the primary outcome of the Stroke in Hypertension Optimal Treatment (SHOT) study, a composite of fatal and non-fatal stroke, will be likely to be observed, while further important evidence will be accrued in relation to cardiovascular death and other secondary outcomes of the study [
      • Zanchetti A.
      • Liu L.
      • Mancia G.
      • Parati G.
      • Grassi G.
      • Stramba-Badiale M.
      • et al.
      Continuation of the ESH-CHL-SHOT trial after publication of the SPRINT: rationale for further study on blood pressure targets of antihypertensive treatment after stroke.
      ].
      In the present meta-analysis of aggregated data, we found that achieved BP was around 8/4 mmHg lower in the more intensive than in the less intensive BP lowering arm, with at least eight studies targeting a systolic BP level < 130 mmHg and a diastolic target < 80 mmHg in the more intensive arm. These data support the view that a universal BP target <130/80 mmHg is strong and that, in general, hypertension guidelines should reconsider the BP targets moving towards lower values [
      • Ettehad D.
      • Emdin C.A.
      • Kiran A.
      • Anderson S.G.
      • Callender T.
      • Emberson J.
      • et al.
      Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis.
      ,
      • Xie X.
      • Atkins E.
      • Lv J.
      • Bennett A.
      • Neal B.
      • Ninomiya T.
      • et al.
      Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis.
      ,
      • Touyz R.M.
      • Dominiczak A.F
      Hypertension guidelines: is it time to reappraise blood pressure thresholds and targets?.
      ,
      • Esler M
      SPRINT, or false start, toward a lower universal treated blood pressure target in hypertension.
      ,
      • Kjeldsen S.E.
      • Oparil S.
      • Narkiewicz K.
      • Hedner T
      The J-curve phenomenon revisited again: SPRINT outcomes favor target systolic blood pressure below 120 mmHg.
      ,
      • Perkovic V.
      • Rodgers A
      Redefining blood-pressure targets–SPRINT starts the marathon.
      ,
      • Chobanian A.V
      Time to reassess blood-pressure goals.
      ,
      • Jones D.W.
      • Weatherly L.
      • Hall J.E
      SPRINT: what remains unanswered and where do we go from here?.
      ,
      Blood Pressure Lowering Treatment Trialists Collaboration
      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.
      ]. However, disagreement remains on this point [
      • Kaul S
      Evidence for the universal blood pressure goal of <130/80mm Hg is strong: controversies in hypertension - con side of the argument.
      ,
      • Brunstrom M.
      • Thomopoulos C.
      • Carlberg B.
      • Kreutz R.
      • Mancia G
      Methodological aspects of meta-analyses assessing the effect of blood pressure-lowering treatment on clinical outcomes.
      ]. In particular, some authors believe that an excessive BP reduction may exert an adverse impact on coronary flow and myocardial perfusion in patients with coronary artery disease [
      • Chalmers J
      Is a blood pressure target of <130/80 mm Hg still appropriate for high-risk patients?.
      ,
      • Messerli F.H.
      • Mancia G.
      • Conti C.R.
      • Hewkin A.C.
      • Kupfer S.
      • Champion A.
      • et al.
      Dogma disputed: can aggressively lowering blood pressure in hypertensive patients with coronary artery disease be dangerous?.
      ,
      • Cruickshank J.M.
      • Thorp J.M.
      • Zacharias F.J
      Benefits and potential harm of lowering high blood pressure.
      ]. In a post-hoc analysis of the Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) study, we investigated 19,102 patients with coronary artery disease at baseline and did not find any excess risk of myocardial infarction after adjustment for potential determinants of reverse causality including cancer and heart failure [
      • Verdecchia P.
      • Reboldi G.
      • Angeli F.
      • Trimarco B.
      • Mancia G.
      • Pogue J.
      • et al.
      Systolic and diastolic blood pressure changes in relation with myocardial infarction and stroke in patients with coronary artery disease.
      ]. Notably, an achieved BP of 118/68 mmHg was associated with a markedly reduced risk of stroke, without any significant increase in the risk of myocardial infarction [
      • Verdecchia P.
      • Reboldi G.
      • Angeli F.
      • Trimarco B.
      • Mancia G.
      • Pogue J.
      • et al.
      Systolic and diastolic blood pressure changes in relation with myocardial infarction and stroke in patients with coronary artery disease.
      ]. These results have been confirmed by a post-hoc analysis of the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial, in which there was no evidence of an excess risk of major events with lower achieved BP values [
      • Kjeldsen S.E.
      • Berge E.
      • Bangalore S.
      • Messerli F.H.
      • Mancia G.
      • Holzhauer B.
      • et al.
      No evidence for a J-shaped curve in treated hypertensive patients with increased cardiovascular risk: the VALUE trial.
      ]. Overall, these data suggest that the so called ‘J-curve phenomenon’ might mostly result from reverse causality induced by some coexistent diseases associated with low BP and poor outcome (i.e., cancer, heart failure, etc.), rather than any direct effect of BP lowering per se [
      • Xie X.
      • Atkins E.
      • Lv J.
      • Bennett A.
      • Neal B.
      • Ninomiya T.
      • et al.
      Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis.
      ].
      The present analysis was not designed to investigate safety issues. However, despite the evidence of episodes of hypotension, electrolyte abnormalities and renal failure associated with a more intensive control of BP [
      • Xie X.
      • Atkins E.
      • Lv J.
      • Bennett A.
      • Neal B.
      • Ninomiya T.
      • et al.
      Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis.
      ,
      • Wright J.T.
      • Bakris G.
      • Greene T.
      • Agodoa L.Y.
      • Appel L.J.
      • Charleston J.
      • et al.
      Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial.
      ,
      • Peralta C.A.
      • McClure L.A.
      • Scherzer R.
      • Odden M.C.
      • White C.L.
      • Shlipak M.
      • et al.
      Effect of intensive versus usual blood pressure control on kidney function among individuals with prior lacunar stroke: a post hoc analysis of the secondary prevention of small subcortical strokes (SPS3) randomized trial.
      ], the bulk of evidence suggests that the benefits of a more intensive BP control in terms of prevention of major cardiovascular disease and death outweigh the risk of adverse events. We recognize that the magnitude of treatment benefit and the risk of adverse events may depend on the age of initiation, especially if therapies are intended for life-long use. Specifically, younger patients have a lower risk of adverse events and longer projected survival times and longer anticipated exposure to BP lowering treatments over their lifetime.
      In other words, it remains to be fully determined whether intensive BP lowering is well-tolerated and if its effects are uniform across the age spectrum.

      Limitations of the study

      Our aggregate meta-analysis lacks individual patient data (IPD), which would have probably allowed a better precision of estimates. However, the superiority of IPD analyzes on aggregate meta-analyzes has been questioned [
      • Brunstrom M.
      • Thomopoulos C.
      • Carlberg B.
      • Kreutz R.
      • Mancia G
      Methodological aspects of meta-analyses assessing the effect of blood pressure-lowering treatment on clinical outcomes.
      ]. Our analysis shares the major limitations of systematic reviews including publication bias, different inclusion and exclusion criteria in the individual trials, different adjudication of major outcome events, different follow-up duration, and different methodological quality of the original studies. By using the Cochrane Collaboration's tool for assessing risk of bias, we found no evidence of heterogeneity between higher and lower quality trials. Finally, our aggregate analysis could not investigate the prognostic impact of more versus less intensive strategies across different strata of cardiovascular risk. Similarly, we could not assess the potential interactions between the intensity of BP control and long-term BP variability [
      • Del Pinto R.
      • Pietropaoli D.
      • Dobre M.
      • Ferri C
      Prognostic importance of long-term SBP variability in high-risk hypertension.
      ].

      Conclusion

      Our meta-analysis and TSA of aggregate data from randomized clinical trials conclusively demonstrate that a more intensive BP control strategy is superior to a less intensive control strategy for prevention of stroke, HF and MI. We also found a significant benefit, albeit not conclusive, of a more intensive over a less intensive strategy for prevention of cardiovascular death. These data support the view that hypertension guidelines should reconsider lower BP targets in the management of hypertension.

      Sources of funding

      This study has been funded in part by the no-profit Fondazione Umbra Cuore e Ipertensione – ONLUS, Perugia, Italy.

      Disclosures

      None.

      Appendix. Supplementary materials

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