Over the past 20 years, several outcome-based intervention trials have compared a more intensive with a less intensive
strategy of blood pressure (BP) reduction in patients with high BP. For the practical management of hypertensive patients, information from strategy trials is independent and comple-mentary to that stemming from trials in which different drug treatments and similar BP-lowering strategies are compared with their effects on BP reduction and vascular outcome.1,2
The last strategy trial published to date, the SPRINT (Systolic Blood Pressure Intervention Trial), showed a sig-nificant 25% reduction of the primary outcome (a compos-ite of myocardial infarction [MI], acute coronary syndromes, stroke, heart failure [HF], or cardiovascular death), a 43% reduction of cardiovascular death, a 27% reduction of all-cause death, and a 38% reduction of hospitalizations for HF in the group allocated to a more intensive (<120 mm Hg) than to a less intensive (<140 mm Hg) systolic BP reduction.3 However, the risk of stroke and coronary artery disease, 2 end
points associated with BP reduction,4–6 did not significantly differ between the 2 groups.3 Several other strategy trials were underpowered to demonstrate the efficacy of a more intensive BP-lowering strategy on specific vascular end points.
In view of the uncertainty surrounding the role of a more versus a less intensive BP control in reducing the risk of mortality and organ-specific cardiovascular outcomes, we undertook a cumulative meta-analysis (CMA)7,8 and a trial sequential analysis (TSA).9,10 Beyond the inherent clinical value of cumulative estimates arising from chronologically ordered studies,11 TSA can firmly establish whether such evidence can be considered conclusive.9,10
Methods
Study Selection and Outcome MeasuresWe extracted data from prospective controlled trials with a parallel design, which met the following selection criteria: (1) comparison
Abstract—Several randomized trials compared a more versus less intensive blood pressure–lowering strategy on the risk of major cardiovascular events and death. Cumulative meta-analyses and trial sequential analyses can establish whether and when firm evidence favoring a specific intervention has been reached from accrued literature. Therefore, we conducted a cumulative trial sequential analysis of 18 trials that randomly allocated 53 405 patients to a more or less intensive blood pressure–lowering strategy. We sought to ascertain the extent to which trial evidence added to previously accrued data. Outcome measures were stroke, myocardial infarction, heart failure, cardiovascular death, and all-cause death. Achieved blood pressure was 7.6/4.5 mm Hg lower with the more intensive than the less intensive blood pressure–lowering strategy. For stroke and myocardial infarction, the cumulative Z curve crossed the efficacy monitoring boundary solely after the SPRINT (Systolic Blood Pressure Intervention Trial) study, thereby providing firm evidence of superiority of a more intensive over a less intensive blood pressure–lowering strategy. For cardiovascular death and heart failure, the cumulative Z curve crossed the conventional significance boundary, but not the sequential monitoring boundary, after SPRINT. For all-cause death, the SPRINT trial pushed the cumulative Z curve away from the futility area, without reaching the conventional significance boundary. We conclude that evidence accrued to date strongly supports the superiority of a more intensive versus a less intensive blood pressure–lowering strategy for prevention of stroke and myocardial infarction. Cardiovascular death and heart failure are likely to be reduced by a more intensive blood pressure–lowering strategy, but evidence is not yet conclusive. (Hypertension. 2016;68:00-00. DOI: 10.1161/HYPERTENSIONAHA.116.07608.) • Online Data Supplement
Received March 28, 2016; first decision April 20, 2016; revision accepted May 19, 2016.From the Department of Medicine, Hospital of Assisi, Italy (P.V.); Cardiology and Cardiovascular Pathophysiology, Hospital S.M. della Misericordia,
Perugia, Italy (F.A.); Royal Cornwall Hospitals, NHS Trust, Truro, Cornwall, UnitedKingdom (G.G.); and Department of Medicine, University of Perugia, Italy (G.R.).
*These authors contributed equally to this work.The online-only Data Supplement is available at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.116.07608/-/DC1.Correspondence to Paolo Verdecchia, Department of Medicine, Hospital of Assisi, Via Valentin Muller 1, 06081 Assisi, Italy. E-mail [email protected]
More Versus Less Intensive Blood Pressure–Lowering Strategy
Cumulative Evidence and Trial Sequential Analysis
Paolo Verdecchia,* Fabio Angeli, Giorgio Gentile, Gianpaolo Reboldi*
between a more intensive and a less intensive BP-lowering strat-egy independently of the specific BP target; (2) publication before December 31, 2015; (3) stroke, MI, HF, cardiovascular death, all-cause death as prespecified end points, regardless of the definition of the primary end point in each trial; (5) systolic BP values both at baseline and at follow-up; (6) duration of follow-up of >12 months excluding observational extensions phases.
Data Sources and SearchesWe searched for relevant studies through MEDLINE (from January 1, 1950, to December 31, 2015), Embase (from 1966 to December 31, 2015) and the Cochrane Central Register of Controlled Trials (up to December 31, 2015), using research Methodology Filters (Table S1 in the online-only Data Supplement).12 Our search was limited to reports of the randomized phase of controlled clinical trials with >12 months of follow-up excluding observational exten-sions phases. We did not use any age or language restriction to avoid discriminating papers not written in the English language (tower of Babel bias).13 Reference lists from identified trials and review articles were further screened along with hand-searching of con-ference proceedings and regulatory agencies files14 to identify any other relevant study.
Data Synthesis and Quality AssessmentOn the basis of the above criteria, we identified 18 trials (Table), for a total of 53 405 patients and 199 336 patient-year of exposure.3,15–32
Figure 1 shows the flow diagram with information about the selected, included, and excluded trials. The flow diagram was prepared accord-ing to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.33 Two reviewers (F.A. and G.G.) indepen-dently extracted data on the basis of an intention-to-treat approach, and disagreements were discussed and resolved in conference. The methodological quality of trials was assessed by the methods recom-mended by the Cochrane Collaboration (Table S2).34 The criteria used for quality assessment were sequence generation of allocation; allo-cation concealment; masking of participants, personnel, and outcome assessors; incomplete outcome data; selective outcome reporting; and other sources of bias.
Data AnalysisUsing raw counts for each outcome, we calculated the cumulative odds ratios (ORs) and 95% confidence intervals (CIs) using a ran-dom-effects model. For multiarm trials, we analyzed only the pre-planned comparisons, as defined in the original study design.35 The null hypothesis of homogeneity across individual trials was tested by using the Q-test. Pooled estimates were assessed for heterogene-ity by using the I2 statistics. Publication bias was tested by visual inspection of the funnel plot and, more formally, with a weighted regression test.34,36
We used CMA to evaluate how evidence has developed over time.7,8 In CMA, outcome data from all available studies were in-cluded sequentially according to the year in which they first became available. The earliest available study was entered into the analysis
Table. Main Features of Clinical Trials Included in the Meta-Analysis
Study Publication Year
BP-Lowering Strategy No. of PatientsFollow-Up Duration, y
Difference in SBP/DBP, mm Hg*More Intensive Less Intensive More Intensive Less Intensive
MDRD15,16 1995 MAP≤92† MAP≤107‡ 432 408 2.2 −8/−4
Toto et al17 1995 DBP 65–80 DBP 85–95 42 35 3.4 −7/−5
AASK indicates African-American Study of Kidney Disease and Hypertension; ABCD, Appropriate Blood Pressure Control in Diabetes; ACCORD-BP, Action to Control Cardiovascular Risk in Diabetes Blood Pressure; BP, blood pressure;Cardio-Sis, Italian Study on the Cardiovascular Effects of Systolic Blood Pressure Control; DBP, diastolic blood pressure; HOMED-BP, Hypertension Objective Treatment Based on Measurement by Electrical Devices of Blood Pressure; HOT, Hypertension Optimal Treatment; JATOS, Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients; MAP, mean blood pressure; MDRD, Modification of Diet in Renal Disease; REIN-2, Renoprotection in Patients with Non-diabetic chronic renal disease; SBP, systolic blood pressure;SPRINT, Systolic Blood Pressure Intervention Trial; SPS3, Secondary Prevention of Small Subcortical Strokes; UKPDS, UK Prospective Diabetes Study; and VALISH, Valsartan in Elderly Isolated Systolic Hypertension.
*Baseline adjusted mean difference at follow-up.†≤98 mm Hg if age ≥61 y.‡≤113 mm Hg if age ≥61 y.
by guest on June 30, 2018http://hyper.ahajournals.org/
Verdecchia et al Intensive Blood Pressure Reduction and Outcome 3
first. At each step of the CMA, one more study was added to the analysis, and the effect size and 95% CI were recalculated. CMA of successive randomized controlled trials addresses the impact of new studies on previous pooled results, and it can be used to decide whether enough evidence has been obtained comparing a control and an intervention treatment, or whether a new randomized con-trolled trial should be initiated. However, in CMA, no adjustment is made for repeatedly testing the null hypothesis on cumulative data. Conversely, sequential analysis applied to meta-analysis,9,11,37 and specifically cumulative TSA,10,38 can establish whether and when firm evidence favoring a specific intervention has been reached in the literature collected to date. To investigate the conclusiveness of the available evidence, we defined a single-study domain: randomized controlled trials comparing more versus less intensive BP-lowering strategies independently of study-specific targets. Cumulative TSA requires a prespecified and clinically relevant intervention effect, as well as an overall risk of type I error to be maintained. We used the relative risk reductions derived from CMA for each outcome, with α set at 5% (2 sided) and a power of 80% considering early and repetitive testing. We then proceeded to the estimation of the re-quired information size, ie, the required number of patients, for a re-liable and conclusive meta-analysis. In the absence of heterogeneity,
required information size equals the sample size required to detect a significant intervention effect in a large, reasonably powered trial.9 However, our meta-analyses showed varying degrees of heterogene-ity (between-trial variation), and because increased variation could decrease the precision of results, we incorporated heterogeneity in the estimated required information size.10,39 We used diversity (D2) as heterogeneity-adjustment factor to calculate the adjusted required information size (ie, a heterogeneity inflated number of participants required to accept or reject the specific intervention effect) with D2 being the relative variance reduction when the meta-analysis model is changed from a random-effects model to a fixed-effects model.38 D2 is an estimate of sampling error, and it is different from the intui-tively obvious adjusting factor based on the common quantification of heterogeneity, the inconsistency (I2), which might underestimate the required information size.38 Then, we constructed monitoring boundaries for benefit, harm, or futility for the observed relative risk reductions to control the overall type I error as statistical tests were repeated throughout the accumulation of studies.8–10 Statistical sig-nificance testing was performed using the Z statistic that is equal to the intervention effect (ie, the log OR in our case) divided by its SE. We then constructed the cumulative Z curve (ie, Z statistics af-ter each trial) for each cumulative random-effects meta-analysis and
Figure 1. Criteria for selection of trials. AASK indicates African-American Study of Kidney Disease and Hypertension; ABCD, Appropriate Blood Pressure Control in Diabetes; ACCORD-BP, Action to Control Cardiovascular Risk in Diabetes Blood Pressure; BP, blood pressure; Cardio-Sis, Italian Study on the Cardiovascular Effects of Systolic Blood Pressure Control; DBP, diastolic blood pressure; HOMED-BP, Hypertension Objective Treatment Based on Measurement by Electrical Devices of Blood Pressure; HOT, Hypertension Optimal Treatment; JATOS, Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients; MAP, mean blood pressure; MDRD, Modification of Diet in Renal Disease; REIN-2, Renoprotection in Patients with Non-diabetic chronic renal disease; SBP, systolic blood pressure; SPRINT, Systolic Blood Pressure Intervention Trial; SPS3, Secondary Prevention of Small Subcortical Strokes; UKPDS, UK Prospective Diabetes Study; and VALISH, Valsartan in Elderly Isolated Systolic Hypertension.
by guest on June 30, 2018http://hyper.ahajournals.org/
assessed its crossing of the conventional significance level and the monitoring boundaries. 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 conven-tionally significant result, while crossing of the monitoring boundary denotes firm evidence adjusted for random error risk. Cumulative Z curves not crossing Z=1.96 indicate the absence of evidence if the information size is not reached or lack of the specific intervention effect if the information size is reached.
Analyses were performed using R version 3.2.3 (R Foundation for Statistical Computing, Vienna, Austria) and TSA software version 0.9 (Copenhagen Trial Unit, DK, http://www.ctu.dk/tsa/).
Role of the Funding SourceThe 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 article. All the authors of this study had full access to data and share responsibility for their submission and dissemination.
ResultsAs shown in Figure 1, literature search initially yielded 8977 reports. After removal of duplicates and studies lacking out-come data, 130 randomized studies were reviewed in full text. Of these, 110 were excluded either because of lack of information about the number of events during follow-up or because of unclear identification of BP-lowering strategies. After exclusion of 2 additional studies, we selected 18 trials for final analysis. Definition of BP targets differed across the studies. Targets were based on systolic BP alone in 6 studies, diastolic BP alone in 5 studies, systolic and diastolic BP in 5 studies, and mean BP in 2 studies. At baseline, aver-age BP was 148.4/85.6 mm Hg and 148.5/85.8 mm Hg in the less intensive and more intensive arm, respectively. On fol-low-up, average BP was 137.9/80.8 mm Hg and 129.4/75.9 mm Hg in the less intensive and more intensive arm, respec-tively. The average duration of follow-up was 3.98 years. The weighted BP difference between randomized strategies from baseline to follow-up (calculated by weighting the dif-ference observed in each contributing trial by the number of randomized subjects) was 7.6 mm Hg (95% CIs, 5.1–10.2) for systolic BP and 4.5 mm Hg (95% CIs 3.2–5.7) for dia-stolic BP. Overall, there were 1189 stroke events, 1234 MI events, 518 HF events, 906 cardiovascular deaths, and 2 207 all-cause deaths.
The methodological quality varied across the studies (Table S2), but most studies were at low risk of bias. Neither the visual inspection of the funnel plot (Figure S1) nor a for-mal test of plot asymmetry (weighted linear regression test P=0.896) showed evidence of publication bias.
Figure 2 shows the cumulative MA of the 13 studies that reported about stroke and MI, and the 9 studies that reported about HF. Overall, the more intensive BP-lowering strategy was associated with a significant reduction in the cumulative risk of stroke (OR, 0.802; 95% CI, 0.676–0.952; P=0.011), MI (OR, 0.853; 95% CI, 0.760–0.957; P=0.019), and HF (OR, 0.754; 95% CI, 0.573–0.992; P=0.044). Notably, there was no significant heterogeneity across the studies (I2=39.7% [P=0.069], 0.0% [P=0.994], and 42.8% [P=0.082] for stroke, MI, and HF, respectively).
Figure 3 shows the cumulative MA of the 15 studies that reported about cardiovascular death, and the 18 stud-ies that reported about all-cause death. The more intensive BP-lowering strategy was associated with a significant reduc-tion in the risk of cardiovascular death (OR, 0.816; 95% CI, 0.674–0.988; P=0.037), but not of all-cause death (OR, 0.888; 95% CI, 0.772–1.021; P=0.094). Heterogeneity across the studies was not significant for cardiovascular death (I2=32.1%; P=0.112), but significant for all-cause death (I2=40.9%; P=0.037).
Results of sequential meta-analysis are shown in Figures 4 through 6. For both stroke and MI (Figure 4), the cumulative Z curve crossed the sequential monitoring boundary only after the SPRINT study, thus providing firm evidence of the beneficial effect of the intervention. For HF (Figure 5), the cumulative Z curve crossed the conventional significance boundary after the SPRINT study, albeit not reaching the sequential monitoring boundary. As shown in Figure 6, for the outcome cardiovascular death, the cumu-lative Z curve crossed the conventional significance bound-ary, but not the sequential monitoring boundary, solely after SPRINT. For all-cause death, the cumulative Z curve failed to cross the conventional significance boundary. However, after adding the 2 latest trials (ie, the study by Wei et al31 and the SPRINT study3), the cumulative Z curve moved far away from the futility area.
DiscussionTo the best of our knowledge, this is the first CMA of trials comparing different BP-lowering strategies that included the SPRINT study,3 the second largest randomized study in this field after the HOT (Hypertension Optimal Treatment).18 Compared to SPRINT, the HOT study achieved lower BP gradients between the groups, ie, ≈4 mm Hg for both systolic and diastolic BP between the groups randomized to ≤80 versus ≤90 mm Hg.18 Inclusion of SPRINT in the meta-analysis allowed us to reach conclusive evidence that a more intensive BP-lowering strategy reduces the risk of stroke by 20% and that of MI by 15% when compared with a less intensive strategy. Surprisingly, none of these 2 key outcomes was significantly reduced in the intensive treat-ment arm in SPRINT.3 However, the cumulative Z curve of meta-analysis crossed the sequential monitoring boundary for both stroke and MI solely after SPRINT, with a total of 51 946 patients.
Our estimates are in keeping with the 22% reduction in the risk of stroke, and the 13% reduction in the risk of MI, noted in a recent analytic meta-analysis, conducted by Xie et al,40 of randomized studies comparing different BP targets that, however, did not include SPRINT. Notably, the evidence that a more intensive BP control reduces the risk of MI is par-ticularly appealing in view of the epidemiological evidence of a less steep relation between usual BP and the risk of MI, as compared with the steeper relation between BP and the risk of stroke.41
A second key finding of our study regards the risk of HF and cardiovascular death. In the meta-analysis by Xie et al,40 the risk of HF was reduced by only 15% in the more intensive BP-lowering strategy, a reduction that failed to
by guest on June 30, 2018http://hyper.ahajournals.org/
Verdecchia et al Intensive Blood Pressure Reduction and Outcome 5
reach statistical significance.40 SPRINT contributed 162 new cases of HF, which was by 38% less frequent in the more intensive than in the less intensive treatment arm.3
Addition of SPRINT led to a cumulative 25% lower risk of HF for effect of the more intensive BP reduction, with the Z curve crossing the conventional monitoring boundaries.
Figure 2. Effect of more intensive versus less intensive blood pressure reduction on the risk of stroke, myocardial infarction, and heart failure. Weights are from random-effect analysis and diamonds represent the 95% confidence interval (CI) for pooled estimate of effect. AASK indicates African-American Study of Kidney Disease and Hypertension; ABCD, Appropriate Blood Pressure Control in Diabetes; ACCORD-BP, Action to Control Cardiovascular Risk in Diabetes Blood Pressure; BP, blood pressure; Cardio-Sis, Italian Study on the Cardiovascular Effects of Systolic Blood Pressure Control; DBP, diastolic blood pressure; HOMED-BP, Hypertension Objective Treatment Based on Measurement by Electrical Devices of Blood Pressure; HOT, Hypertension Optimal Treatment; JATOS, Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients; MAP, mean blood pressure; MDRD, Modification of Diet in Renal Disease; OR, odds ratio; REIN-2, Renoprotection in Patients with Non-diabetic chronic renal disease; RRR, relative risk reduction; SBP, systolic blood pressure; SPRINT, Systolic Blood Pressure Intervention Trial; SPS3, Secondary Prevention of Small Subcortical Strokes; UKPDS, UK Prospective Diabetes Study; and VALISH, Valsartan in Elderly Isolated Systolic Hypertension.
by guest on June 30, 2018http://hyper.ahajournals.org/
As for cardiovascular death, the meta-analysis by Xie et al40 found a nonsignificant 9% reduction in the risk of cardio-vascular death. SPRINT added 102 new cases of cardiovas-cular death, which was by 43% less frequent in the more intensive BP-lowering arm. As for HF, addition of SPRINT to previous studies led to a significant 18% lower risk of cardiovascular death with the more intensive BP-lowering strategy that, however, did not cross the sequential monitor-ing boundaries. Therefore, despite the substantial reduction in the risk of HF and cardiovascular death in the SPRINT trial,3 the evidence that a more aggressive strategy (ie, one targeting lower BP values) is superior to a less aggressive strategy in reducing the risk of these 2 important end points is not yet conclusive.
In this study, we used a cumulative TSA of BP-lowering intervention trials to determine whether the evidence progres-sively accrued on specific outcomes is reliable and conclu-sive. Several arguments suggest a higher level of skepticism in interpreting a meta-analysis than a single randomized and rigorously conducted controlled trial.9 On the other hand, however, several major strategy trials were underpowered to test the hypothesis of superiority of a more intensive versus less intensive BP control, thereof justifying meta-analyses and further controlled trials.42 The question of whether a meta-analysis is definitive and no further studies are needed, can be addressed by using the same logic of early stopping rules for a randomized intervention trial. Our TSA suggests conclusive evidence of a 20% reduction in the risk of stroke, and 15%
reduction in the risk of MI as a result of a more intensive ver-sus a less intensive strategy of BP reduction. Conversely, the cumulative Z curves for the hypotheses of a 25% reduction in HF and 18% reduction in cardiovascular death, although crossing the conventional Z=1.96 (P<0.05) boundary, did not cross the monitoring boundaries, whereas the curve test-ing the hypothesis of a 11% reduction of all-cause death did not cross either the conventional or the sequential monitoring boundaries. Hence, if the data included in our meta-analysis were from a single randomized controlled trial at an interim analysis, insufficient evidence of benefit would have accrued to justify stopping the trial for HF, cardiovascular death, or all-cause death.
Our results support the decision to continue the ongoing SHOT (Stroke in Hypertension Optimal Treatment), a trial jointly promoted by the European Society of Hypertension and the Chinese Hypertension League.43 The SHOT trial is being conducted in hypertensive patients with a history of stroke or transient ischemic attach 1 to 6 months before entry. These patients are being randomized to 3 systolic BP targets: <135 to 145, <125 to 135, and <125 mm Hg. Although the primary study outcome is a composite of fatal and nonfatal stroke, for which conclusive evidence of benefit is suggested by the present review, several major cardiovascular events and death have been included as secondary outcomes.43
In the present study we did not address safety issues. Xie et al40 found an increase in hypotension episodes in patients allocated to the more intensive compared to the less
Figure 3. Effect of more intensive versus less intensive blood pressure reduction on the risk of cardiovascular death and all-cause death. Weights are from random-effect analysis and diamonds represent the 95% confidence interval (CI) for pooled estimate of effect.AASK indicates African-American Study of Kidney Disease and Hypertension; ABCD, Appropriate Blood Pressure Control in Diabetes; ACCORD-BP, Action to Control Cardiovascular Risk in Diabetes Blood Pressure; BP, blood pressure; Cardio-Sis, Italian Study on the Cardiovascular Effects of Systolic Blood Pressure Control; DBP, diastolic blood pressure; HOMED-BP, Hypertension Objective Treatment Based on Measurement by Electrical Devices of Blood Pressure; HOT, Hypertension Optimal Treatment; JATOS, Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients; MAP, mean blood pressure; MDRD, Modification of Diet in Renal Disease; OR, odds ratio; REIN-2, Renoprotection in Patients with Non-diabetic chronic renal disease; RRR, relative risk reduction; SBP, systolic blood pressure; SPRINT, Systolic Blood Pressure Intervention Trial; SPS3, Secondary Prevention of Small Subcortical Strokes; UKPDS, UK Prospective Diabetes Study; and VALISH, Valsartan in Elderly Isolated Systolic Hypertension.
by guest on June 30, 2018http://hyper.ahajournals.org/
Verdecchia et al Intensive Blood Pressure Reduction and Outcome 7
51946HOT
UKPDSABCD (H)
ABCD (N)
JATOSCardio-Sis
ACCORD
VALISH SPS3SPRINT
AASK
HOMED-BP
Wei et al
Conventional 0.05Boundary
Conventional 0.05Boundary
Number ofpatients
Diversity adjusted sample size = 5623420% RRR, alpha=0.05 power 80%
Pooled Effect (OR): 0.80 (C.I: 0.68 to 0.95); p-value=0.011Heterogeneity p-value : 0.069Inconsistency (I²) : 40%; Diversity (D²) : 52%
Favo
rs M
ore
Inte
nsiv
eFa
vors
Les
s In
tens
ive
Cum
ulat
ive
Z-va
lue
8
7
6
5
3
2
1
-1
-2
-3
-4
-5
-6
-7
-8
4
Efficacy
Futility
51946
SPRINT
Favo
rs M
ore
Inte
nsiv
eFa
vors
Les
s In
tens
ive
Cum
ulat
ive
Z-va
lue
8
7
6
5
3
2
1
-1
-2
-3
-4
-5
-6
-7
-8
4
Diversity adjusted sample size = 5575615% RRR, alpha=0.05 power 80%
Conventional 0.05Boundary
Conventional 0.05Boundary
Number ofpatients
Efficacy
Futility
Pooled Effect (OR): 0.85 (C.I: 0.76 to 0.96); p-value=0.007Heterogeneity p-value : 0.994Inconsistency (I²) : 0%; Diversity (D²) : 0%
Myocardial Infarction
Stroke
Wei et alSPS3
HOT
UKPDS
ABCD (H)ABCD (N)
JATOSCardio-Sis
ACCORD
VALISHAASK
HOMED-BP
Figure 4. Cumulative trial sequential analysis of the effect of more intensive versus less intensive blood pressure reduction on the risk of stroke and myocardial infarction. The red lines denote the sequential monitoring boundaries. The gray area denotes the futility zone. AASK indicates African-American Study of Kidney Disease and Hypertension; ABCD, Appropriate Blood Pressure Control in Diabetes; ACCORD-BP, Action to Control Cardiovascular Risk in Diabetes Blood Pressure; BP, blood pressure; Cardio-Sis, Italian Study on the Cardiovascular Effects of Systolic Blood Pressure Control; DBP, diastolic blood pressure; HOMED-BP, Hypertension Objective Treatment Based on Measurement by Electrical Devices of Blood Pressure; HOT, Hypertension Optimal Treatment; JATOS, Japanese (Continued )
by guest on June 30, 2018http://hyper.ahajournals.org/
intensive BP-lowering arm. In the SPRINT study, patients allocated to the intensive treatment arm showed, compared to those allocated to standard treatment, a significantly higher incidence of serious adverse events including hypotension (2.4% versus 1.4%), syncope (2.3% versus 1.7%), electro-lyte abnormalities (3.1% versus 2.3%), and acute kidney injury or renal failure (4.1% versus 2.5%).21 In a recent post hoc analysis of the SPS3 (Secondary Prevention of Small Subcortical Strokes) trial, conducted in patients with previ-ous lacunar stroke and relatively preserved kidney function, a more intensive BP-lowering strategy was associated with a more rapid decline in kidney function during the first year of follow-up, but not during the subsequent years of follow-up.44 Overall, controlled studies suggest that the benefits of a more intensive BP-lowering strategy in terms of prevention of major CV morbid events seem to outweigh the risk of adverse events.
Although the studies examined in this review targeted dif-ferent systolic and diastolic BP levels, the achieved BP was by 7.6/4.5 mm Hg lower in the more intensive than in the less intensive BP-lowering arm, in keeping with the 6.8/3.5 mm Hg found by Xie et al.40 Notably, at least 7 of these stud-ies targeted a systolic BP level <130 mm Hg,3,23,24,27,28,30,32 and 7 studies targeted a diastolic BP target <80 mmHg17,18,20,23–25,30 in the more intensive treatment arm. These data support the suggestion that hypertension guidelines should reconsider the BP targets, possibly moving toward lower values.4,40,45–50 In the present overview, average BP was 148/86 mm Hg at baseline, whereas achieved BP was 129.4/75.9 mm Hg in the more intensive arm and 137.9/80.8 mm Hg in the less inten-sive arm. Our findings are consistent with the results of the HOPE (Heart Outcomes Prevention Evaluation)-3 study, in which the participants with baseline systolic BP in the upper third (>143.5 mm Hg; mean 154.1 mm Hg) showed a
23539
Conventional 0.05Boundary
Conventional 0.05Boundary
Number ofpatients
Diversity adjusted sample size = 3772425% RRR, alpha=0.05 power 80%
Pooled Effect (OR): 0.75 (C.I: 0.57 to 0.99); p-value=0.044Heterogeneity p-value : 0.082Inconsistency (I²) : 43%; Diversity (D²) : 58%
Favo
rs M
ore
Inte
nsiv
eFa
vors
Les
s In
tens
ive
Cum
ulat
ive
Z-va
lue
8
7
6
5
3
2
1
-1
-2
-3
-4
-5
-6
-7
-8
4
Efficacy
Futility
Heart Failure
UKPDS
SPRINT
ABCD (H)
ABCD (N)JATOS
Cardio-SisACCORD
AASK
Wei et al
Figure 5. Cumulative trial sequential analysis of the effect of more intensive versus less intensive blood pressure reduction on the risk of congestive heart failure. The red lines denote the sequential monitoring boundaries. The gray area denotes the futility zone. AASK indicates African-American Study of Kidney Disease and Hypertension; ABCD, Appropriate Blood Pressure Control in Diabetes; ACCORD-BP, Action to Control Cardiovascular Risk in Diabetes Blood Pressure; BP, blood pressure; Cardio-Sis, Italian Study on the Cardiovascular Effects of Systolic Blood Pressure Control; DBP, diastolic blood pressure; HOMED-BP, Hypertension Objective Treatment Based on Measurement by Electrical Devices of Blood Pressure; HOT, Hypertension Optimal Treatment; JATOS, Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients; MAP, mean blood pressure; MDRD, Modification of Diet in Renal Disease; OR, odds ratio; REIN-2, Renoprotection in Patients with Non-diabetic chronic renal disease; RRR, relative risk reduction; SBP, systolic blood pressure; SPRINT, Systolic Blood Pressure Intervention Trial; SPS3, Secondary Prevention of Small Subcortical Strokes; UKPDS, UK Prospective Diabetes Study; and VALISH, Valsartan in Elderly Isolated Systolic Hypertension.
Figure 4. Continued Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients; MAP, mean blood pressure; MDRD, Modification of Diet in Renal Disease; OR, odds ratio; REIN-2, Renoprotection in Patients with Non-diabetic chronic renal disease; RRR, relative risk reduction; SBP, systolic blood pressure; SPRINT, Systolic Blood Pressure Intervention Trial; SPS3, Secondary Prevention of Small Subcortical Strokes; UKPDS, UK Prospective Diabetes Study; and VALISH, Valsartan in Elderly Isolated Systolic Hypertension.
by guest on June 30, 2018http://hyper.ahajournals.org/
Verdecchia et al Intensive Blood Pressure Reduction and Outcome 9
52359
53405
Conventional 0.05Boundary
Conventional 0.05Boundary
Number ofpatients
Diversity adjusted sample size = 8374918% RRR, alpha=0.05 power 80%
Pooled Effect (OR): 0.82 (C.I: 0.67 to 0.99); p-value=0.037Heterogeneity p-value : 0.112Inconsistency (I²) : 32%; Diversity (D²) : 49%
Favo
rs M
ore
Inte
nsiv
eFa
vors
Les
s In
tens
ive
Cum
ulat
ive
Z-va
lue
8
7
6
5
3
2
1
-1
-2
-3
-4
-5
-6
-7
-8
4
Efficacy
Futility
Cardiovascular Death
Favo
rs M
ore
Inte
nsiv
eFa
vors
Les
s In
tens
ive
Cum
ulat
ive
Z-va
lue
8
7
6
5
3
2
1
-1
-2
-3
-4
-5
-6
-7
-8
4
Diversity adjusted sample size = 10924511% RRR, alpha=0.05 power 80%
Conventional 0.05Boundary
Conventional 0.05Boundary
Number ofpatients
Efficacy
Futility
Pooled Effect (OR): 0.89 (C.I: 0.77 to 1.02); p-value=0.094Heterogeneity p-value : 0.037Inconsistency (I²) : 41%; Diversity (D²) : 59%
All-cause Death
SPRINT
SPRINT
MDRD
Toto et al.HOT
UKPDSABCD (H)
AASKABCD (N
)
Schrie
r et a
l.
Wei et al.
HO
MED
-BP
VALI
SH
SPS3ACCORD
Cardio-Sis
JATOS
REIN-2
ABCD-2V
HOT
UKPDS
ABCD (H)
AASKABCD (N)
Schrier et al.
Wei et al.
HOM
ED-BP
VALISH
SPS3
ACCORD
Cardio-SisJATO
S
REIN
-2
Figure 6. Cumulative trial sequential analysis of the effect of more intensive versus less intensive blood pressure reduction on the risk of cardiovascular death and all-cause death. The red lines denote the sequential monitoring boundaries. The gray area denotes the futility zone. AASK indicates African-American Study of Kidney Disease and Hypertension; ABCD, Appropriate Blood Pressure Control in Diabetes; ACCORD-BP, Action to Control Cardiovascular Risk in Diabetes Blood Pressure; BP, blood pressure; Cardio-Sis, (Continued )
by guest on June 30, 2018http://hyper.ahajournals.org/
significant trend toward a lower risk of events with cande-sartan plus hydrochlorothiazide, whereas less or no benefit was observed in those with lower baseline BP.51 There is concern that an excessive BP reduction may be detrimental (the so-called J curve phenomenon), particularly in patients with coronary artery disease.52–54 Several data, however, sug-gest that the benefits of an intensive BP control outweigh its adverse effects in most patients. We conducted a post hoc analysis of the ONTARGET (Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial) study in 19 102 patients with coronary artery disease at base-line. After adjustment for several potential determinants of reverse causality including cancer and HF, which entered the analysis as time-varying covariables, a reduction in BP from baseline by 34/21 mm Hg, corresponding to an achieved BP of only 118/68 mm Hg, was associated with a markedly reduced risk of stroke, without any significant increase in the risk of MI.55 A post hoc analysis of the VALUE (Valsartan Antihypertensive Long-Term Use Evaluation) trial did not show any evidence of a J curve in the treatment of high-risk hypertensive patients.56 Overall, these data sound reassuring as to the safety of BP reduction even for achieved BP values <130/80 mm Hg. The J curve phenomenon seems thus largely attributable to reverse causality induced by diseases associ-ated with low BP and poor outcome (ie, cancer, HF, etc), not to the impact of BP lowering by itself.40
LimitationsA limitation of our meta-analysis, shared by other system-atic reviews, regards the absence of individual patient data, which would have allowed a better precision of estimates. Furthermore, the exact definition of some outcome events may have not exactly the same in all studies. Although our litera-ture search procedures were extensive and included a broad range of information sources, we recognize that publication bias may still exist despite our best efforts to conduct a com-prehensive search and despite the lack of statistical evidence for the existence of bias. Another limitation shared by system-atic reviews is the methodological quality of the original stud-ies. We used the Cochrane Collaboration’s tool for assessing risk of bias and found no evidence of heterogeneity between higher and lower quality trials.
PerspectivesThe take-home message of our systematic review and TSA is that a more intensive BP-lowering strategy is definitely supe-rior to a less intensive strategy for prevention of stroke and MI. Conversely, evidence is suggestive, but not yet conclu-sive, that cardiovascular death, HF, and all-cause death are reduced by a more intensive BP-lowering strategy. On a side, these considerations provide argument to continue trials com-paring different BP targets.43 On the other side, hypertension
guidelines should recommend lower BP targets in the treat-ment of hypertension, with the goal of reducing the burden of major and often devastating complications including stroke and MI. The safety of more aggressive strategies targeting lower BP values should be carefully checked in the individual patients.
Sources of FundingThis study has been funded, in part, by the no-profit Fondazione Umbra Cuore e Ipertensione—ONLUS, Perugia, Italy.
DisclosuresNone.
References 1. Mancia G, Fagard R, Narkiewicz K, et al; Task Force Members. 2013
ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013;31:1281–1357. doi: 10.1097/01.hjh.0000431740.32696.cc.
2. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311:507–520. doi: 10.1001/jama.2013.284427.
3. The SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373:2103–2116.
4. Ettehad D, Emdin CA, Kiran A, Anderson SG, Callender T, Emberson J, Chalmers J, Rodgers A, Rahimi K. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analy-sis. Lancet. 2016;387:957–967. doi: 10.1016/S0140-6736(15)01225-8.
5. Staessen JA, Wang JG, Thijs L. Cardiovascular protection and blood pressure reduction: a meta-analysis. Lancet. 2001;358:1305–1315. doi: 10.1016/S0140-6736(01)06411-X.
6. Turnbull F; Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovas-cular events: results of prospectively-designed overviews of randomised trials. Lancet. 2003;362:1527–1535.
7. Lau J, Antman EM, Jimenez-Silva J, Kupelnick B, Mosteller F, Chalmers TC. Cumulative meta-analysis of therapeutic trials for myo-cardial infarction. N Engl J Med. 1992;327:248–254. doi: 10.1056/NEJM199207233270406.
8. Lau J, Schmid CH, Chalmers TC. Cumulative meta-analysis of clini-cal trials builds evidence for exemplary medical care. J Clin Epidemiol. 1995;48:45–57; discussion 59.
9. Pogue JM, Yusuf S. Cumulating evidence from randomized trials: uti-lizing sequential monitoring boundaries for cumulative meta-analysis. Control Clin Trials. 1997;18:580–93; discussion 661.
10. Wetterslev J, Thorlund K, Brok J, Gluud C. Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. J Clin Epidemiol. 2008;61:64–75. doi: 10.1016/j.jclinepi.2007.03.013.
11. Whitehead A. Meta-Analysis of Controlled Clinical Trials. Chichester, New York: John Wiley & Sons; 2002.
12. Haynes RB, Wilczynski N, McKibbon KA, Walker CJ, Sinclair JC. Developing optimal search strategies for detecting clinically sound stud-ies in MEDLINE. J Am Med Inform Assoc. 1994;1:447–458.
13. Grégoire G, Derderian F, Le Lorier J. Selecting the language of the publi-cations included in a meta-analysis: is there a Tower of Babel bias? J Clin Epidemiol. 1995;48:159–163.
14. McAuley L, Pham B, Tugwell P, Moher D. Does the inclusion of grey litera-ture influence estimates of intervention effectiveness reported in meta-anal-yses? Lancet. 2000;356:1228–1231. doi: 10.1016/S0140-6736(00)02786-0.
Figure 6. Continued Italian Study on the Cardiovascular Effects of Systolic Blood Pressure Control; DBP, diastolic blood pressure; HOMED-BP, Hypertension Objective Treatment Based on Measurement by Electrical Devices of Blood Pressure; HOT, Hypertension Optimal Treatment; JATOS, Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients; MAP, mean blood pressure; MDRD, Modification of Diet in Renal Disease; OR, odds ratio; REIN-2, Renoprotection in Patients with Non-diabetic chronic renal disease; RRR, relative risk reduction; SBP, systolic blood pressure; SPRINT, Systolic Blood Pressure Intervention Trial; SPS3, Secondary Prevention of Small Subcortical Strokes; UKPDS, UK Prospective Diabetes Study; and VALISH, Valsartan in Elderly Isolated Systolic Hypertension.
by guest on June 30, 2018http://hyper.ahajournals.org/
Verdecchia et al Intensive Blood Pressure Reduction and Outcome 11
15. Peterson JC, Adler S, Burkart JM, Greene T, Hebert LA, Hunsicker LG, King AJ, Klahr S, Massry SG, Seifter JL. Blood pressure control, pro-teinuria, and the progression of renal disease. The Modification of Diet in Renal Disease Study. Ann Intern Med. 1995;123:754–762.
16. Lazarus JM, Bourgoignie JJ, Buckalew VM, Greene T, Levey AS, Milas NC, Paranandi L, Peterson JC, Porush JG, Rauch S, Soucie JM, Stollar C. Achievement and safety of a low blood pressure goal in chronic renal disease. The Modification of Diet in Renal Disease Study Group. Hypertension. 1997;29:641–650.
17. Toto RD, Mitchell HC, Smith RD, Lee HC, McIntire D, Pettinger WA. “Strict” blood pressure control and progression of renal disease in hyper-tensive nephrosclerosis. Kidney Int. 1995;48:851–859.
18. Hansson L, Zanchetti A, Carruthers SG, Dahlöf B, Elmfeldt D, Julius S, Ménard J, Rahn KH, Wedel H, Westerling S. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) ran-domised trial. HOT Study Group. Lancet. 1998;351:1755–1762.
19. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998;317:703–713.
20. Estacio RO, Jeffers BW, Gifford N, Schrier RW. Effect of blood pressure control on diabetic microvascular complications in patients with hyperten-sion and type 2 diabetes. Diabetes Care. 2000;23 Suppl 2:B54–B64.
21. Wright JT Jr, Bakris G, Greene T, et al; African American Study of Kidney Disease and Hypertension Study Group. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA. 2002;288:2421–2431.
22. Schrier R, McFann K, Johnson A, Chapman A, Edelstein C, Brosnahan G, Ecder T, Tison L. 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. J Am Soc Nephrol. 2002;13:1733–1739.
23. Schrier RW, Estacio RO, Esler A, Mehler P. Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albumin-uria, retinopathy and strokes. Kidney Int. 2002;61:1086–1097. doi: 10.1046/j.1523-1755.2002.00213.x.
24. Ruggenenti P, Perna A, Loriga G, et al; REIN-2 Study Group. Blood-pressure control for renoprotection in patients with non-diabetic chronic renal disease (REIN-2): multicentre, randomised controlled trial. Lancet. 2005;365:939–946. doi: 10.1016/S0140-6736(05)71082-5.
25. Estacio RO, Coll JR, Tran ZV, Schrier RW. Effect of intensive blood pres-sure control with valsartan on urinary albumin excretion in normotensive patients with type 2 diabetes. Am J Hypertens. 2006;19:1241–1248. doi: 10.1016/j.amjhyper.2006.05.011.
26. JATOS Study Group. Principal results of the Japanese trial to assess opti-mal systolic blood pressure in elderly hypertensive patients (JATOS). Hypertens Res. 2008;31:2115–2127. doi: 10.1291/hypres.31.2115.
27. Verdecchia P, Staessen JA, Angeli F, de Simone G, Achilli A, Ganau A, Mureddu G, Pede S, Maggioni AP, Lucci D, Reboldi G; Cardio-Sis Investigators. Usual versus tight control of systolic blood pressure in non-diabetic patients with hypertension (Cardio-Sis): an open-label randomised trial. Lancet. 2009;374:525–533. doi: 10.1016/S0140- 6736(09)61340-4.
28. The ACCORD Study Group, Cushman WC, Evans GW, Byington RP. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362:1575–1585. doi: 10.1056/NEJMoa1001286.
29. Ogihara T, Saruta T, Rakugi H, Matsuoka H, Shimamoto K, Shimada K, Imai Y, Kikuchi K, Ito S, Eto T, Kimura G, Imaizumi T, Takishita S, Ueshima H; Valsartan in Elderly Isolated Systolic Hypertension Study Group. Target blood pressure for treatment of isolated systolic hyperten-sion in the elderly: valsartan in elderly isolated systolic hypertension study. Hypertension. 2010;56:196–202. doi: 10.1161/HYPERTENSIONAHA. 109.146035.
30. Asayama K, Ohkubo T, Metoki H, Obara T, Inoue R, Kikuya M, Thijs L, Staessen JA, Imai Y; Hypertension Objective Treatment Based on Measurement by Electrical Devices of Blood Pressure (HOMED-BP). Cardiovascular outcomes in the first trial of antihypertensive ther-apy guided by self-measured home blood pressure. Hypertens Res. 2012;35:1102–1110. doi: 10.1038/hr.2012.125.
31. Wei Y, Jin Z, Shen G, Zhao X, Yang W, Zhong Y, Wang J. Effects of inten-sive antihypertensive treatment on Chinese hypertensive patients older than 70 years. J Clin Hypertens (Greenwich). 2013;15:420–427. doi: 10.1111/jch.12094.
targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet. 2013;382:507–515. doi: 10.1016/S0140-6736(13)60852-1.
33. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151:264–9, W64.
34. Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions. Oxford: Wiley-Blackwell; 2008.
35. Sutton A, Abrams K, Jones D, Sheldon T, Song F. Methods for Meta-Analysis in Medical Research. John Wiley & Sons, Inc, 2000.
36. Sterne JA, Sutton AJ, Ioannidis JP, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ. 2011;343:d4002.
37. Whitehead A. A prospectively planned cumulative meta-analysis applied to a series of concurrent clinical trials. Stat Med. 1997;16:2901–2913.
38. Wetterslev J, Thorlund K, Brok J, Gluud C. Estimating required informa-tion size by quantifying diversity in random-effects model meta-analyses. BMC Med Res Methodol. 2009;9:86. doi: 10.1186/1471-2288-9-86.
39. Thorlund K, Devereaux PJ, Wetterslev J, Guyatt G, Ioannidis JP, Thabane L, Gluud LL, Als-Nielsen B, Gluud C. Can trial sequential monitor-ing boundaries reduce spurious inferences from meta-analyses? Int J Epidemiol. 2009;38:276–286. doi: 10.1093/ije/dyn179.
40. Xie X, Atkins E, Lv J, et al. Effects of intensive blood pressure low-ering on cardiovascular and renal outcomes: updated systematic review and meta-analysis. Lancet. 2016;387:435–443. doi: 10.1016/S0140-6736(15)00805-3.
41. 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. Lancet. 2002;360:1903–1913.
42. Kjeldsen SE, Lund-Johansen P, Nilsson PM, 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. Hypertension. 2016; doi: 10.1161/HYPERTENSIONAHA.116.07257.
43. Zanchetti A, Liu L, Mancia G, et al; ESH-CHL-SHOT Trial Investigators. Continuation of the ESH-CHL-SHOT trial after publication of the SPRINT: rationale for further study on blood pressure targets of antihy-pertensive treatment after stroke. J Hypertens. 2016;34:393–396. doi: 10.1097/HJH.0000000000000853.
44. Peralta CA, McClure LA, Scherzer R, Odden MC, White CL, Shlipak M, Benavente O, Pergola P. 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. Circulation. 2016;133:584–591. doi: 10.1161/CIRCULATIONAHA.115.019657.
45. Touyz RM, Dominiczak AF. Hypertension guidelines: is it time to reap-praise blood pressure thresholds and targets? Hypertension. 2016;67:688–689. doi: 10.1161/HYPERTENSIONAHA.116.07090.
46. Esler M. SPRINT, or false start, toward a lower universal treated blood pressure target in hypertension. Hypertension. 2016;67:266–267. doi: 10.1161/HYPERTENSIONAHA.115.06735.
47. Kjeldsen SE, Oparil S, Narkiewicz K, Hedner T. The J-curve phe-nomenon revisited again: SPRINT outcomes favor target systolic blood pressure below 120 mmHg. Blood Press. 2016;25:1–3. doi: 10.3109/08037051.2016.1096564.
48. Perkovic V, Rodgers A. redefining blood-pressure targets–SPRINT starts the marathon. N Engl J Med. 2015;373:2175–2178. doi: 10.1056/NEJMe1513301.
49. Chobanian AV. Time to reassess blood-pressure goals. N Engl J Med. 2015;373:2093–2095. doi: 10.1056/NEJMp1513290.
50. Jones DW, Weatherly L, Hall JE. SPRINT: what remains unanswered and where do we go from here? Hypertension. 2016;67:261–262. doi: 10.1161/HYPERTENSIONAHA.115.06723.
51. Lonn EM, Bosch J, Lopez-Jaramillo P, et al, Hope-3 Investigators. Blood-pressure lowering in intermediate-risk persons without cardiovascular dis-ease. N Engl J Med. 2016; doi: 10.1056/NEJMoa1600175.
52. Chalmers J. Is a blood pressure target of <130/80 mm Hg still appropriate for high-risk patients? Circulation. 2011;124:1700–1702. doi: 10.1161/CIRCULATIONAHA.111.057091.
53. Messerli FH, Mancia G, Conti CR, Hewkin AC, Kupfer S, Champion A, Kolloch R, Benetos A, Pepine CJ. Dogma disputed: can aggressively low-ering blood pressure in hypertensive patients with coronary artery disease be dangerous? Ann Intern Med. 2006;144:884–893.
54. Cruickshank JM, Thorp JM, Zacharias FJ. Benefits and potential harm of lowering high blood pressure. Lancet. 1987;1:581–584.
by guest on June 30, 2018http://hyper.ahajournals.org/
What Is New?•The recent SPRINT trial added consistent evidence to the view that BP
goals should be stricter than those suggested by current guidelines. However, it is not know to what extent the SPRINT trial influenced the evidence accrued so far from studies comparing a more intensive with a less intensive BP–lowering strategy.
What Is Relevant?•Solely after the SPRINT study, the cumulative Z curve crossed the effica-
cy monitoring boundary for stroke and myocardial infarction, thus provid-ing firm evidence of superiority of a more intensive over a less intensive BP-lowering strategy. Surprisingly, none of these 2 key outcomes was significantly reduced in the intensive treatment arm of the SPRINT study.
•After SPRINT, the cumulative Z curve crossed the conventional signifi-cance boundary, but not the sequential monitoring boundary, for car-diovascular death and heart failure. Hence, the hypothesis that a more
intensive BP-lowering strategy reduces cardiovascular death and heart failure is not yet conclusive.
• For all-cause death, the SPRINT trial pushed the cumulative Z curve away from the futility area, without reaching, however, the conventional significance boundary.
Summary
A more intensive BP reduction is definitely superior to a less in-tensive reduction for prevention of stroke and myocardial infarc-tion. Conversely, evidence is not yet conclusive that cardiovascular death, heart failure, and all-cause death are reduced by a more intensive BP-lowering strategy
Novelty and Significance
55. Verdecchia P, Reboldi G, Angeli F, Trimarco B, Mancia G, Pogue J, Gao P, Sleight P, Teo K, Yusuf S. Systolic and diastolic blood pressure changes in relation with myocardial infarction and stroke in patients with coronary artery disease. Hypertension. 2015;65:108–114. doi: 10.1161/HYPERTENSIONAHA.114.04310.
56. Kjeldsen SE, Berge E, Bangalore S, Messerli FH, Mancia G, Holzhauer B, Hua TA, Zappe D, Zanchetti A, Weber MA, Julius S. No evidence for a J-shaped curve in treated hypertensive patients with increased car-diovascular risk: The VALUE trial. Blood Press. 2016;25:83–92. doi: 10.3109/08037051.2015.1106750.
by guest on June 30, 2018http://hyper.ahajournals.org/
is online at: Hypertension Information about subscribing to Subscriptions:
http://www.lww.com/reprints Information about reprints can be found online at: Reprints:
document. Permissions and Rights Question and Answer this process is available in the
click Request Permissions in the middle column of the Web page under Services. Further information aboutOffice. Once the online version of the published article for which permission is being requested is located,
can be obtained via RightsLink, a service of the Copyright Clearance Center, not the EditorialHypertensionin Requests for permissions to reproduce figures, tables, or portions of articles originally publishedPermissions:
by guest on June 30, 2018http://hyper.ahajournals.org/
60 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48 or 49 or 50 or 51 or 52 or 53 or 54 or 55 or 56 or 57 or 58 or 59
72 ("intensive versus standard" adj blood pressure).ti,ab,hw. 6
73 ("tight versus standard" adj blood pressure).ti,ab,hw. 1
74 ("tight versus usual" adj blood pressure).ti,ab,hw. 2
75 blood pressure goal$.ti,ab,hw. 469
76 blood pressure target$.ti,ab,hw. 446
77 optimal blood pressure$.ti,ab,hw. 347
78 (different adj "blood press$" adj "target$").mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]
7
79 (different adj "blood press$" adj "goal$").mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary
4
concept word, unique identifier]
80 61 or 62 or 63 or 64 or 65 or 66 or 67 or 68 or 69 or 70 or 71 or 72 or 73 or 74 or 75 or 76 or 77 or 78 or 79
11940
81 Randomized Controlled Trial/ 409627
82 Controlled Clinical Trial/ 90286
83 random$.ti,ab,hw. 920514
84 Clinical Trial/ 497622
85 (open adj label*).ti,ab,hw. 26649
86 Double-Blind Method/ 133858
87 Single-Blind Method/ 21500
88 ((singl* or doubl* or tripl* or trebl*) adj (blind* or mask*)).tw. 130966
89 81 or 82 or 83 or 84 or 85 or 86 or 87 or 88 1227279
90 60 and 80 and 89 2417
91 Limit 90 to yr=”1950-2015” 2416
EMBASE OVID
Searches Results
1 antihypertensive agent/ 75243
2 angiotensin II antagonist/ or angiotensin 1 receptor antagonist/ or angiotensin receptor/
13297
3 losartan/ or losartan potassium/ 21048
4 valsartan/ 9653
5 irbesartan/ 6385
6 candesartan/ or candesartan hexetil/ 9058
7 telmisartan/ 6135
8 eprosartan/ 1507
9 olmesartan/ 3580
10 tasosartan/ 99
11 angiotensin converting enzyme inhibitors.mp. or dipeptidyl carboxypeptidase inhibitor/
60 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48 or 49 or 50 or 51 or 52 or 53 or 54 or 55 or 56 or 57 or 58 or 59
543463
61 randomized controlled trial/ 397891
62 controlled clinical trial/ 392577
63 randomized controlled trial/ 397891
64 randomization/ 69641
65 random allocation.mp. 1661
66 double blind procedure/ 129398
67 single blind procedure/ 21712
68 placebo/ 284760
69 (random*or sham or placebo*).ti,ab,hw. 370478
70 (((singl* or doubl*) adj blind*) or dumm* or mask*).ti,ab,hw.
323821
71 (((tripl* or trebl*) adj blind*) or dumm* or mask*).ti,ab,hw.
97514
72 61 or 62 or 63 or 64 or 65 or 66 or 67 or 68 or 69 or 70 or 71
969946
73 blood pressure regulation/ 34711
74 60 and 72 and 73 4550
75 limit 74 to yr="1966 - 2015" 4527
Cochrane Central Register of Controlled Trials (CENTRAL)
Searches Results
1 Hypertension/ 13755
2 Antihypertensive Agents/ 6695
3 Angiotensin Receptor Antagonists/ 575
4 Losartan/ 912
5 valsartan.mp. 1196
6 irbesartan.mp. 556
7 candesartan.mp. 768
8 candesartan cilexetil.mp. 208
9 telmisartan.mp. 656
10 eprosartan.mp. 112
11 olmesartan.mp. 420
12 tasosartan.mp. 10
13 Angiotensin-Converting Enzyme Inhibitors/ 3570
14 Captopril/ 1213
15 Ramipril/ 470
16 Fosinopril/ 133
17 Lisinopril/ 523
18 Cilazapril/ 165
19 Perindopril/ 419
20 zofenopril.mp. 64
21 benazepril.mp. 347
22 quinapril.mp. 305
23 spirapril.mp. 59
24 temocapril.mp. 35
25 imidapril.mp. 77
26 moexipril.mp. 34
27 Adrenergic beta-Antagonists/ 3975
28 Atenolol/ 1702
29 carvedilol.mp. 832
30 Metoprolol/ 1396
31 Propranolol/ 2555
32 Oxprenolol/ 200
33 Pindolol/ 511
34 Nadolol/ 167
35 Alprenolol/ 80
36 Calcium Channel Blockers/ 2618
37 Amlodipine/ 1113
38 Felodipine/ 384
39 lacidipine.mp. 133
40 Nicardipine/ 327
41 Nifedipine/ 1953
42 Nisoldipine/ 151
43 Nitrendipine/ 348
44 Nimodipine/ 211
45 Diuretics/ 2019
46 Hydrochlorothiazide/ 1701
47 Chlorothiazide/ 58
48 Bendroflumethiazide/ 201
49 Methyclothiazide/ 11
50 Chlorthalidone/ 342
51 Amiloride/ 256
52 Triamterene/ 142
53 Indapamide/ 246
54 Furosemide/ 911
55 Bumetanide/ 90
56 Adrenergic alpha-Antagonists/ 918
57 Prazosin/ 495
58 terazosin.mp. 208
59 Labetalol/ 349
60 Minoxidil/ 120
61 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48 or 49 or 50 or 51 or 52 or 53 or 54 or 55 or 56 or 57 or 58 or 59 or 60
30336
62 blood pressure control.ti,ab,hw. 1780
63 blood pressure lower$.ti,ab,hw. 1478
64 (strict adj blood pressure).ti,ab,hw. 27
65 blood pressure goal$.ti,ab,hw. 118
66 (intensive adj blood pressure).ti,ab,hw. 118
67 (tight adj blood pressure).ti,ab,hw. 20
68 (standard adj blood pressure).ti,ab,hw. 24
69 (rigorous adj blood pressure).ti,ab,hw. 5
70 optimal blood pressure$.ti,ab,hw. 54
71 optimal systolic blood pressure$.ti,ab,hw. 9
72 optimal diastolic blood pressure$.ti,ab,hw. 5
73 (aggressive adj blood pressure).ti,ab,hw. 17
74 (usual adj blood pressure).ti,ab,hw. 18
75 (conventional adj blood pressure).ti,ab,hw. 21
76 blood pressure target$.ti,ab,hw. 131
77 ("intensive versus standard" adj blood pressure).ti,ab,hw. 3
78 ("tight versus standard" adj blood pressure).ti,ab,hw. 1
79 62 or 63 or 64 or 65 or 66 or 67 or 68 or 69 or 70 or 71 or 72 or 73 or 74 or 75 or 76 or 77 or 78
3466
80 61 and 79 2035
81 limit 78 to yr="1898 - 2015" 2034
Supplementary Table - S2. Methodological quality of the trials included in the systematic review and meta-analysis
Study Publication
Year
Adequate
sequence
generation
Allocation
concealment
Blinding Incomplete
outcome
data
addressed
Free of
selective
reporting
Free of
other bias
Overall
risk of
bias
MDRD 1995 Yes Yes No Unclear Yes Unclear Unclear
Toto et al. 1995 Unclear Unclear No Unclear Unclear Unclear Unclear
HOT 1998 Yes Yes Yes Unclear No No High
UKPDS-38 1998 Yes Yes Yes Unclear No No High
ABCD (H) 2000 Yes Yes No Unclear Unclear Unclear Unclear
AASK 2002 Yes Yes Yes Yes Yes Yes Low
Schrier et al. 2002 Yes Unclear No Yes Yes No High
ABCD (N) 2002 Yes Yes No Unclear Unclear Unclear Unclear
REIN-2 2005 Yes Yes No Yes Yes Yes Low
ABCD-2V 2006 Yes Yes No Unclear Unclear No Unclear
Title 1 Identify the report as a systematic review, meta-analysis, or both. 1
ABSTRACT
Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.
2
INTRODUCTION
Rationale 3 Describe the rationale for the review in the context of what is already known. 3
Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).
3
METHODS
Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.
N/A
Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years
considered, language, publication status) used as criteria for eligibility, giving rationale.
4
Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.
4
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.
S1-18
Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).
Figure 1
Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.
4, 5
Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.
4
Risk of bias in individual studies
12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.
5
Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). 5
Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I2) for each meta-analysis.
5,6
Risk of bias across studies
15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).
5
Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.
5,6
RESULTS
Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.
7, Figure 1
Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.
Table 1
Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). S19
Results of individual studies
20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.
8, Figures 2-3
Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. Figures 2-3
Risk of bias across studies
22 Present results of any assessment of risk of bias across studies (see Item 15). 7-8
Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]).
8, Figures 4-6
DISCUSSION
Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).
9-13
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).
13
Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research.
13
FUNDING
Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.
14
Supplementary Figure – S1.
Funnel plot for publication bias. Each study is plotted by its effect size on the horizontal axis and its
