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
Costas Thomopoulosa, Gianfranco Paratib,c, and Alberto Zanchettid,e
Background and objectives:Previous meta-analyses of our group have investigated the cardiovascular effects of more vs. less intense blood pressure (BP) treatment and the BP levels to be achieved by treatment. A few
additional trials have been completed recently, particularly the large SPRINT study. Updating of the previous meta- analyses has been done with the objective of further clarifying the practical question of BP targets of antihypertensive treatment.
Methods:Among randomized-controlled trials (RCTs) of BP lowering treatment between 1966 and 2015, 16 (52 235 patients) compared more vs. less intense treatment and fulfilled other preset criteria, and in 34 (138 127 patients) SBP in the active (vs. placebo) or the more (vs.
less) intense treatment was below (vs., respectively, above) three predetermined cutoffs. For their meta-analyses risk ratios (RR) and 95% confidence intervals, standardized to 10/5 mmHg SBP/DBP reduction, and absolute risk reductions of seven fatal and nonfatal outcomes were calculated.
Results:More intense BP lowering significantly reduced risk of stroke [RR 0.71 (0.60–0.84)], coronary events [0.80 (0.68–0.95)], major cardiovascular events [0.75 (0.68–
0.85)] and cardiovascular mortality [0.79 (0.63–0.97)], but not heart failure and all-cause death. When the 16 RCTs were stratified according to cardiovascular death risk, relative risk reduction did not differ between strata, but absolute risk reduction increased with cardiovascular risk, though the residual risk also increased. Stratification of the 34 RCTs according to the three different SBP cutoffs (150, 140 and 130 mmHg) showed that a SBP/DBP difference of 10/5 mmHg across each cutoff significantly reduced risk of all outcomes to the same proportion (relative risk reduction), but absolute risk reduction of most outcomes had a significant trend to decrease at lower cutoffs.
Conclusion:Updating of previous meta-analyses indicates that more vs. less intense BP lowering can reduce not only stroke and coronary events, but also cardiovascular mortality. Including data from recent RCTs also shows that all major outcomes can be reduced by lowering SBP a few
mmHg below vs. above 130 mmHg, but absolute risk reduction becomes smaller, suggesting patients at lower initial SBP were at a lower level of cardiovascular risk.
Keywords:antihypertensive treatment, hypertension, intense antihypertensive treatment, meta-analysis, randomized-controlled trials, target blood pressure Abbreviations:BP, blood pressure; CHD, coronary heart disease; CI, confidence interval; NNT, number needed to treat; RCT, randomized-controlled trial; RR, relative risk
INTRODUCTION
A
mong randomized-controlled trials (RCTs) of blood pressure (BP) lowering treatment we have recently identified as published between 1966 and 2013 [1], the overwhelming majority compared active BP lowering treatment with placebo (or no treatment) (54 RCTs on 203 531 patients) and only a minority (14 RCTs on 42 354 patients) compared more with less intense treatment [2–15].The latter type of RCTs, pioneered by the HOT [3] and the UKPDS-38 [4] studies, both published in 1998, could be designed and conducted only after a consistent number of placebo-controlled RCTs had shown that BP lowering could indeed reduce the risk of cardiovascular morbidity and mortality [16].
Journal of Hypertension 2016, 34:613–622
aDepartment of Cardiology, Helena Venizelou Hospital, Athens, Greece,bDepartment of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital, Istituto Aux- ologico Italiano IRCCS,cDepartment of Health Sciences, University of Milan Bicocca, Milan, Italy,dScientific Direction, Istituto Auxologico Italiano IRCCS andeCentro Interuniversitario di Fisiologia Clinica e Ipertensione, Universita` degli Studi di Milano, Milan, Italy.
Correspondence to Alberto Zanchetti, Direzione Scientifica, Istituto Auxologico Ital- iano, Via L. Ariosto, 13, I-20145 Milano, Italy. Tel: +39 02 619112237; fax: +39 02 619112901; e-mail: [email protected]
Received11 January 2016Accepted14 January 2016
J Hypertens 34:613–622 Copyrightß2016 Wolters Kluwer Health, Inc. All rights reserved.
DOI:10.1097/HJH.0000000000000881
The first five RCTs of more vs. less intense BP-lowering were meta-analyzed by the Blood Pressure Lowering Treatment Trialists’ Collaboration in 2003 [17], showing a significant risk reduction in stroke and the composite of major cardiovascular events, but not mortality, by more intense treatment. A subsequent meta-analysis was done by Lawet al.in 2009 [18], but, as previously remarked [1], Law et al.’s meta-analyses also included a number of RCTs in conditions different from hypertension (mostly, postmyocardial infarction and chronic heart failure), in which antihypertensive agents are likely to be beneficial independently of, and possibly despite, their BP-lowering properties.
Our 2014 meta-analysis [1] of 14 RCTs comparing more with less intense BP lowering [2–15] showed that more intense BP lowering significantly reduced the risk of stroke by 22% [95% confidence intervals (CI) 10–32%], coronary heart disease (CHD) events by 14% (1–24%), the composite of stroke and CHD by 16% (7–23%), but failed to signifi- cantly reduce the risk of heart failure, cardiovascular death and all-cause death [1]. Similar results have recently been published by Xieet al.[19], who have considered 19 RCTs (but only 14 providing cardiovascular outcomes). On the whole, 11 RCTs including 39 420 individuals are present in both meta-analyses, which explains the close similarities between their results.
The recent publication of the results of a large RCT focused on the cardiovascular effects of more vs. less intense BP lowering treatment, the SPRINT [20], suggests the oppor- tunity of updating the available meta-analyses in order to investigate whether, by the addition of a large number of recent data a significant risk reduction by more intense BP lowering can be demonstrated also for those outcomes (heart failure, cardiovascular death, all-cause death) for which previous meta-analyses [1,19] failed to show a significant effect.
There is another important reason for a new enlarged meta-analysis. Since the publication of the first RCTs on more vs. less intense BP lowering [3.4], their results were taken to support the concept ’the lower the better’, that is, the lower is the BP achieved the greater is the outcome reduction achieved by treatment, with the tacit implication the target BP should be as low as possible, or at least as close as possible to the 115/70 mmHg SBP/DBP values, that in observational studies on patients free from previous cardiovascular disease are associated with the lowest risk of stroke and CHD [21]. Obviously, this is not necessarily the case, as a number of RCTs have brought BP, and particularly SBP, values only to levels quite above 115/70 mmHg even in the group of patients more intensely treated. The correct way to investigate the optimal BP target by meta-analyses is to group RCTs according to mean SBP (or DBP) achieved in the most intensely treated arm. Meta-analyses of this kind should usefully include also RCTs comparing active treat- ment with placebo, when BP values achieved by active treatment are below the selected cutoff. In our 2014 set of meta-analyses we carried out such a type of analysis, showing that for SBP values below (vs. above) the 130 mmHg cutoff the risk reduction for stroke was still statistically significant, but this was not the case for other outcomes, such as CHD events, heart failure and
cardiovascular mortality [22]. Therefore, in the present updating we have also investigated whether significance for risk reduction of some of these outcomes could be attained by adding SPRINT data to the analyses.
METHODS
Trial eligibilityRCTs included in the present meta-analyses are those identified in our previous search of 2014 [1] with an additional extension to studies and meta-analyses pub- lished within 31 December 2015. Criteria for selection were:
RCTs enrolling hypertensive patients or cohorts with at least 40% hypertensive patients aged 18 years or above); exclu- sion of trials investigating patients with acute myocardial infarction, heart failure, acute stroke, renal dialysis and secondary hypertension; intention to treat with antihyper- tensive drugs one patient group more intensely than the control group; a between-group difference of at least 2 mmHg in either SBP or DBP; reporting at least one type of cardiovascular event or all-cause death; follow-up of at least 6 months; a minimum of five events during follow-up.
In one set of sensitivity analyses RCTs were considered including baseline untreated individuals with BP in the so- called prehypertension level, provided no exclusion criteria (see above) were present. In another set of analyses (inves- tigating BP treatment targets) RCTs in which SBP/DBP differences were obtained by comparing active treatment with placebo were also considered. Recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement [23] were adhered to.
Outcomes
Seven different outcomes were considered: stroke (fatal and nonfatal); CHD events (coronary death and nonfatal myocardial infarction); hospitalized heart failure; major cardiovascular events as composite of stroke and CHD events; major cardiovascular events as composite of stroke, CHD events and hospitalized heart failure; cardiovascular death; and all-cause death (see [1] for further details).
Statistical analyses
As in previous meta-analyses of this series [1], relative risk (RR) estimates (with 95% CI) for each selected outcome were combined using a random effects model, in which the log RR for every trial was weighted by the reciprocal of the variance of the log RR. The proportion of inconsistency across the studies not explained by chance was quantified with theI2statistics. Whenever no significant heterogeneity was detected by thex2Q statistics (P>0.1), a fixed-effect model was also implemented, and used whenever the significance of the RR estimate differed between the fixed and random effects models.
SBP/DBP differences between more and less intense treatments were the means of every individual trial values weighted by patients’ number and follow-up duration.
Whenever useful, RRs were standardized to a difference of 10/5 mmHg SBP/DBP after considering the effect of the inverse variance of individual trials. Five-year absolute risk reductions as well as the number of patients needed to treat (NNT) for five years to prevent an outcome were also
calculated, as previously detailed [1]. Stratification of RCTs according to the mean SBP (or DBP) achieved in the more intensely treated group was done as previously described [22]. A trend analysis investigated possible differences between the strata.
All statistical analyses were done by the Comprehensive Meta Analysis version 3 (Biostat, Englewood, New Jersey, USA). Statistical significance was defined as P value less than 0.05, but no correction was made for multiple comparisons.
RESULTS
Trials and patients
Of 23 RCTs comparing more with less intense BP lowering (identified by our updated search), 16 fulfilled all preset criteria [2–15,20,24] and two others were considered for a sensitivity analysis being on individuals with so-called pre- hypertension [25,26]. The following five RCTs did not fulfill all preset criteria and were excluded from meta-analyses: the Effect of Strict Blood Pressure Control and ACE Inhibitor on the Progression of CRF in Pediatric Patients (ESCAPE) trial [27] being in children and also reporting only one event; the trial on Autosomal-Dominant Polycystic Kidney Disease (ADPKD) [28] being in patients with a specific secondary type of hypertension, and also reporting only two events; the Hypertension Objective treatment Based on Measurement by Electrical Devices of Blood Pressure (HOMED-BP) trial [29] because SBP/DBP differences between randomized groups were both less than 2 mmHg; Totoet al.[30] because reporting an insufficient number of events (less than 5);
PAST-BP [31] because the published preliminary report does not indicate number of events.
The 16 RCTs for the primary analyses, and the two additional RCTs for the sensitivity analyses, are listed in Table 1. On the whole the primary analyses are based on 52 235 patients, followed for a mean of 3.7 years, 1158 strokes, 1131 CHD events, 528 heart failures, 908 cardio- vascular deaths and 2149 all-cause deaths.
Effect of more vs. less intense blood pressure lowering
As illustrated in Fig. 1, in the RCTs reporting stroke, CHD and cardiovascular or all-cause mortalities as outcome, the between treatment SBP/DBP differences were of about 8.1/3.4 mmHg. These BP differences were associated with statistically significant reductions in the risk of stroke, CHD events, the composites of stroke and CHD, and of stroke, CHD and heart failure. Also the risk of cardiovas- cular death was found significantly reduced by the use of the fixed-effect model (I2 34%, P¼0.11), whereas the reduction in risk of all-cause death (for which significant heterogeneity prevented the use of the fixed-effect model) only approached statistical significance. Also reduction of the risk of heart failure did not achieve statistical signifi- cance, but a smaller number of RCTs reported heart failure as an outcome. Calculation of absolute risk reduction indicates that 115 patients must be intensely treated for 5 years in order to prevent a stroke, 186 to prevent a CHD event, and only 56 to prevent a stroke or a CHD event or a heart failure episode; 213 patients must be treated for 5 years in order to prevent a cardiovascular death.
TABLE 1. Characteristics of the patients in the trials of more vs. less intense blood pressure lowering included in the meta-analysis Achieved (mmHg)
Follow-up
Difference
(mmHg) Patients (n)
Baseline
(mmHg) More Less
Trial acronym (years) SBP DBP More Less All SBP DBP SBP DBP SBP DBP
Patients with hypertension
BBB [2] 4.9 11 8 1063 1063 2126 154.9 94.5 141 83 152 91
HOT [3] 3.8 2.8 3.1 6262 12 528 18 790 170 105 139.7 81.1 142.5 84.2
UKPDS-38 [4] 8.4 10 5 758 390 1148 160 94 144 82 154 87
MDRD [5] 2.2 7.6 3.8 430 407 837 130.5 79.7 126.2 76.9 133.8 80.7
ABCD-H [6] 5 6 8 237 233 470 155 98 132 78 138 86
AASK [7] 4 13 7 540 554 1094 150.5 95.5 128 78 141 85
Fogari [8] 4 8.9 4.6 104 205 309 160.3 99.3 132.4 82.3 141.3 86.9
REIN-2 [9] 1.6 4.1 2.8 168 167 335 136.7 84.1 129.6 79.5 133.7 82.3
JATOS [10] 2 9.7 3.3 2212 2206 4418 171.6 89.1 135.9 74.8 145.6 78.1
SANDS [11] 3 12 6 252 247 499 130.5 75 117 67 129 73
Cardio-Sis [12] 2 3.8 1.5 558 553 1111 163.3 89.6 136 79.2 140 80.8
ACCORD [13] 4.7 14.2 6.4 2362 2371 4733 139.2 76 119.2 64.7 133.4 71.1
VALISH [14] 2.85 5.4 1.7 1627 1633 3260 169.6 81.4 136.6 74.8 142 76.5
SPS3 [15] 3.7 12.1 1501 1519 3020 143 78.5 125.8 137.9
Wei [24] 4 14 5.9 363 361 724 159.6 84.3 135.7 76.2 149.7 82.1
SPRINT [20] 3.3 13.1 0.8 4678 4683 9361 139.7 78.1 121.5 75.4 134.6 76.2
All hypertensive patients 3.88 8.08 3.35 52235 157.38 90.80 132.42 77.13 140.51 80.48
Patients with prehypertension
ABCD-N [25] 5.3 9 6 237 243 480 136.4 84.4 128 75 137 81
ABCD-2V [26] 1.9 6 5 66 63 129 126 84 118 75 124 80
Hypertensive and prehypertensive patients
3.66 8.09 3.38 52844 157.12 90.72 132.34 77.10 140.43 80.48
Column head ‘More’ indicates more intense and ‘Less’ indicates less intense blood pressure lowering treatment. In the Fogariet al.[8] trial, the more intense treatment group was that receiving combination therapy and the less intense one was the combination of the two groups receiving monotherapies; in the HOT [3] the more intense treatment group was that randomized to DBP less than 80 and the less intense one the combination of the two groups randomized to DBP less than 85 and less than 90 mmHg.
Addition of the two more vs. less intense treatment trials in patients with prehypertension [25,26] does not modify the results, the relative risk estimates adjusted to a 10/
5 mmHg SBP/DBP difference being as follows: stroke 0.67 (0.55–0.81); CHD 0.81 (0.70–0.96); cardiovascular death 0.77 (0.63–0.95).
As compared with our previous 2014 meta-analysis, addition of the Weiet al.[24] and the SPRINT [20] studies makes the reductions in the risk of cardiovascular death, previously reported nonsignificant, statistically significant.
We have also verified whether the risk reduction we have found with more intense BP lowering corresponded to what expected from the meta-regression analyses we have recently published [32] of the relationship of risk ratios (RR) with the extent of SBP reduction. Considering that less intense treatment had lowered SBP from the mean baseline level by a mean of 17 mmHg (Table 1), we have calculated from the meta-regression that this SBP reduction should have brought RRs for stroke, heart failure and cardiovascular death to values of 0.62, 0.60 and 0.74,
respectively. The effects of a further SBP reduction by 8 mmHg (25 mmHg below baseline values) by more intense treatment (Table 1), were obtained by multiplying the RRs calculated for less intense treatment by the RR of each outcome resulting from the meta-analyses of Fig. 1, and these RR values were compared with those expected for a similar SBP reduction (25 vs. 17 mmHg) from the meta- regression of our previous study [32]. It will be seen from the graphs of Fig. 2 that the RRs so calculated for stroke and cardiovascular death in the more intensely treated group (0.50 and 0.64, respectively) are practically superimposable on those expected from the meta-regression for a 25 mmHg SBP reduction from baseline, whereas the RR for heart failure was slightly higher than expected (0.51 instead of 0.44), a discrepancy justified by the much wider CIs for heart failure than for the two outcomes.
The relative risk reduction induced by more intense BP lowering was not influenced by the level of cardiovascular risk (Fig. 3). When the 16 RCTs were stratified in three groups according to the incidence of cardiovascular death
Outcome
Stroke CHD HF Stroke + CHD Stroke + CHD + HF CV death All-cause death
Trials (n)
13 14 10 13 9 15 16
Difference SBP/DBP (mmHg)
–8.2/–3.5 –8.1/–3.4 –7.9/–3.2 –8.2/–3.5 –8.0/–3.3 –8.2/–3.5 –8.1/–3.4
More intense
476/21959 514/22517 239/18222 986/21959 1012/17664 396/22557 963/23115
Less intense
682/27993 617/28546 289/24126 1297/27993 1326/23573 512/28567 1186/29120
Absolute risk reduction 1000 pts/5 years (95% CI) Events
(n/patients) Standardized RR (95% CI)
0.71 (0.60–0.84)*
0.80 (0.68–0.95)*
0.80 (0.49–1.31) 0.75 (0.68–0.85)*
0.75 (0.66–0.83)*
0.79 (0.63–0.97)*
0.83 (0.69–1.03)
Standardized RR (95% CI)
P-value (heterogen)
0.54 0.99 0.001 0.84 0.12 0.10 0.013
More intense better
Less intense better
0.3 0.6 1.0 1.5
–9 –5 –17
–14 –3 –5 –9
–30 –25 –20 –15 –10 –5 0 5
FIGURE 1Relative and absolute risk reduction of various outcomes in trials comparing more intense with less intense BP lowering. Standardized RR is to a SBP/DBP reduction of –10/–5 mmHg. Asterisks indicate that RR were calculated by a fixed effect model rather than a random effects model. The histograms of the column Absolute risk reduction represent the numbers (and 95% CI) of events prevented every 1000 patients more intensely treated for 5 years using the standardized RR. BP, blood pressure; CHD, coronary heart disease; CI, confidence interval; CV, cardiovascular; HF, heart failure; pts, patients; RR, Mantel–Haenszel risk ratio.
D-SBP (mmHg)
RR
0.1 1.0
0 –10 –20 –30 –40
0.7
0.4 P = 0.02
P < 0.001 P < 0.001 Stroke
HF CV death
FIGURE 2Effects of more vs. less intense BP-lowering on stroke, heart failure and cardiovascular death calculated as SBP reductions from baseline (17 mmHg for less and 25 mmHg for more intense lowering). The presumed RRs of less intense treatment vs. baseline have been calculated from previously conducted meta-regression analyses [32], the slopes of which are indicated by the dashed lines. The effects of more intense treatment vs. baseline have been calculated by multiplying the RRs of less intense treatment by the RRs of more vs. less intense treatment as in Fig. 1. The continuous lines between SBP differences of –17 and25 mmHg indicate the slope of the more vs. less intense treatment effects, to be compared with those of the meta-regression analysis (dashed lines). Green refers to stroke, red to heart failure, orange to cardiovascular death, CV, cardiovascular; D-SBP, difference in SBP; HF, heart failure; RR, risk ratio.
in the control (less intense treatment) arm (low to moderate risk:<5% in 10 years; high risk: 5% to<10% in 5 years; very high risk: 10% or higher) [33], eight RCTs (39 874 individuals) [2,3,8,10–12,14,20] were classified in the low-moderate risk group, five RCTs (9652 individuals) [6,7,9,15,20] in the high risk group and three RCTs (2709 individuals) [4,5,24] in the very high risk group. Because of the reduced statistical power of each group, only relative risk reduction of composite outcomes achieved the level of statistical significance, but trend analysis did not show any tendency of relative risk reduction to change according to the level of risk, except for heart failure (with very few events in the very high risk stratum, however). Absolute risk reduction of stroke, heart failure, and the composites of cardiovascular events signifi- cantly increased parallelly with the increase of cardiovascular risk, but the residual risk (that is the incidence of each event in the more actively treated group) also markedly and significantly increased from the low-moderate to the very high risk stratum.
Effects of achieving different blood pressure targets
More vs. less intense blood pressure-lowering trials For this type of analysis, the 16 RCTs of more vs. less intense BP lowering were stratified in three groups according to the mean SBP achieved in the more intensely treated arm: SBP
not less than 140 and below 150 mmHg: BBB [2] and UKPDS-38 [4], 3274 patients; SBP not less than 130 and below 140 mmHg: HOT [3], ABCD-H [6], Fogari et al. [8], JATOS [10], Cardio-Sis [12], VALISH [14] and Weiet al.[24], 29 082 patients; SBP below 130 mmHg: MDRD [5], AASK [7], REIN-2 [9], SANDS [11], ACCORD [13], SPS3 [15] and SPRINT [20], 19 879 patients.
Stratification of a relatively limited number of RCTs made it difficult to achieve statistical significance for most com- parisons, although reduction of the composite of stroke and CHD events attained statistical significance both when more intense treatment achieved SBP in the range 130 to less than 140 mmHg and in the range below 130 mmHg. In no case, however, trend analysis showed a tendency of the relative risk estimate to change with the lowering levels of achieved SBP (Fig. 4a). Addition of the two RCTs in patients with prehypertension (ABCD-N [25] to group 2 and ABCD-2 V [26] to group 3) did not modify the results.
Fifteen RCTs could also be stratified in two groups according to the mean DBP achieved in the more intensely treated arm: DBP at least 80 and below 90 mmHg: BBB [2], HOT [3], UKPDS-38 [4], and Fogariet al.[8], 22 373 patients;
DBP below 80 mmHg: MDRD [5], ABCD-H [6], AASK [7], REIN-2 [9], JATOS [10], SANDS [11], Cardio-Sis [12], ACCORD [13], VALISH [14], Wei et al. [16] and SPRINT [20], 26 842 patients. Except for the composite of stroke and CHD, no significant difference was found between risk reductions of all outcomes at the two different levels of
Outcome
Stroke
CHD
HF
Stroke + CHD
Stroke + CHD + HF
CV death
All-cause death
CV risk
L-M H VH L-M H VH L-M H VH L-M H VH L-M H VH L-M H VH L-M H VH
Trials (n)
7 4 2 8 4 2 5 3 2 7 4 2 4 3 2 7 5 3 8 5 3
Absolute risk reduction and residual risk
1000 pts/5 years (95% CI)
0.79 (0.57–1.08) 0.82 (0.70–0.96) 0.58 (0.42–0.79) 0.74 (0.54–1.06) 0.90 (0.78–1.03) 0.81 (0.63–1.05) 1.05 (0.24–4.88) 0.99 (0.82–1.19) 0.45 (0.28–0.71) 0.77 (0.62–0.96) 0.85 (0.77–0.94) 0.71 (0.58–0.85) 0.77 (0.61–0.98) 0.88 (0.80–0.97) 0.65 (0.55–0.77) 0.89 (0.45–1.77) 0.96 (0.79–1.16) 0.66 (0.51–0.87) 0.91 (0.60–1.41) 0.94 (0.80–1.12) 0.75 (0.58–0.97)
Standardized RR (95% CI) Standardized
RR (95% CI)
P-value for trend
0.13
0.43
0.03
0.22
0.17
0.11
0.25
More intense better
Less intense better
0.2 1.0 2.0 5.0
P-value for trend
0.001
<0.001
0.078
<0.001
0.004 0.088
0.031
<0.001
0.007
<0.001
0.28
<0.001
0.18
<0.001
0.5 –240 –180 –120 –60 0 60
–4 +12
–12 +42
–31 +66
–4 +9 –6 +44
–13 +94
<1 +7
< –1 +38
–22 +31
–9 +20 –18 +86
–40 +164
–11 +25
–17 +117
–62 +195
–2 +10
–1 +25 –26 +75
–4 +26
–5 +60
–32 +128
FIGURE 3Effects of more vs. less intense BP lowering in trials stratified by different levels of cardiovascular (CV) risk: low-moderate (L-M), high (H), very high (VH).
Standardized Mantel–Haenszel risk ratios (RR) are to a SBP/DBP difference of10/5 mmHg. The white histograms of the column absolute risk reduction and residual risk represent the absolute risk reductions as numbers (and 95% CI) of events prevented every 1000 patients more intensely treated for 5 years using the standardized RR;
the gray histograms represent the residual risk as numbers (and 95% CI) of residual events every 1000 patients more intensely treated for 5 years. The two columns headedPvalue for trend refer, the first, to the standardized RR, and the second to absolute risk reduction (value above) and residual risk (value below). CHD, coronary heart disease; HF, heart failure; pts, patients.
achieved DBP (Fig. 4b). Also in this case, addition of the two prehypertension RCTs [25,26] did not modify the results.
All blood pressure-lowering trials
Results of an updating of our 2014 meta-analyses in which BP-lowering RCTs were stratified in three groups compar- ing: achieved SBP from 140 to below 150 mmHg in the active or more active treatment arm with SBP at least 150 mmHg in the control group; achieved SBP from 130
to below 140 with SBP at least 140 mmHg; achieved SBP below 130 mmHg with SBP at least 130 mmHg are shown in Fig. 5. No RCT was added to group 1, which consisted of eight RCTs, including 13 841 patients [2,4,34–39]; the Wei et al.trial [24] was added to the 16 RCTs previously con- sidered in group 2 [3,8,10,12,14,40–50] for an updated total of 82 945 patients; and the SPRINT [20] and REIN-2 [9]
studies were added to the eight RCTs previously considered in group 3 [5,7,13,15,51–54] for an updated total of 41 666 patients.
Outcome
Stroke
CHD
HF
Stroke + CHD
Stroke + CHD + HF
CV death
All-cause death
Stroke
CHD
HF
Stroke + CHD Stroke + CHD + HF CV death
All-cause death
Achieved BP in more intense
(mmHg)
≥140, <150
≥130, <140
<130
≥140, <150
≥130, <140
<130
≥140, <150
≥130, <140
<130
≥140, <150
≥130, <140
<130
≥140, <150
≥130, <140
<130
≥140, <150
≥130, <140
<130
≥140, <150
≥130, <140
<130
≥80, <90
<80
≥80, <90
<80
≥80, <90
<80
≥80, <90
<80
≥80, <90
<80
≥80, <90
<80
≥80, <90
<80
Trials (n)
2 6 5 2 7 5 1 5 4 2 6 5 1 4 4 2 6 7 2 7 7 4 8 4 9 2 8 4 8 2 7 4 10 4 11
Standardized RR (95% CI)
0.59 (0.42–0.82) 0.67 (0.45–1.02) 0.79 (0.66–0.94) 0.87 (0.65–1.18) 0.66 (0.38–1.16) 0.84 (0.71–1.01)
- 0.90 (0.18–5.25) 0.81 (0.56–1.20) 0.78 (0.61–1.02) 0.67 (0.49–0.93) 0.81 (0.71–0.91)
- 0.72 (0.47–1.16) 0.78 (0.69–0.89) 1.14 (0.39–3.40) 0.69 (0.29–1.69) 0.80 (0.64–1.02) 1.20 (0.48–3.08) 0.67 (0.35–1.26) 0.88 (0.74–1.06) 0.47 (0.24–0.95) 0.73 (0.59–0.93) 0.65 (0.42–1.02) 0.84 (0.71–1.01) 1.00 (0.40–2.82) 0.77 (0.57–1.05) 0.58 (0.39–0.86) 0.79 (0.70–0.90) 0.56 (0.27–1.27) 0.82 (0.75–0.90) 0.89 (0.36–2.46) 0.73 (0.55–0.99) 0.98 (0.51–1.91) 0.78 (0.62–0.97)
Standardized RR (95% CI)
P-value
0.27
0.38
0.85
0.32
0.62
0.42
0.36
0.16
0.13
0.81
0.046
0.15
0.52
0.23
More intense better
Less intense better
0.2 0.5 1.0 2.0 5.0
SBP
DBP
(a)
(b)
FIGURE 4Effects of more intense treatment in trials of more vs. less intense BP lowering, stratified according to the level mean SBP (a) and mean DBP (b) attained in the more intensely treated group. Standardized RR is to a SBP/DBP difference of10/5 mmHg. For part (a), SBP,Pvalues were calculated for trend, whereas for part (b), DBP,Pvalues were calculated for differences between the two DBP ranges (Pfor heterogeneity). Mean SBP/DBP achieved on more vs. less intense treatment were for the three ranges of SBP (from above downward): 142.1/82.6 vs. 157.7/89.6; 138.3/79.2 vs. 142.9/82.3; 122.1/72.5 vs. 135.0/75.6 mmHg; for the two ranges of DBP: 139.9/
81.3 vs. 144.0/85.0; 126.9/73.6 vs. 137.9/76.7. BP, blood pressure; CHD, coronary heart disease; CI, confidence interval; CV, cardiovascular; HF, heart failure; RR, Mantel–
Haenszel risk ratios.
The updated meta-analyses of Fig. 5 shows that for all types of outcomes (stroke, CHD events, the composite of stroke and CHD, the composite of stroke, CHD and heart failure, cardiovascular mortality and all-cause mortality), with the only exception of heart failure, statistically signifi- cant risk reductions could be found at all three levels of mean achieved SBP (mean group values 142 vs. 158; 138 vs.
143; 122 vs. 135 mmHg).
For the same standard difference in SBP/DBP (10/5 mmHg) no significant trend toward a higher or lower relative risk reduction was found at progressively lower levels of achieved SBP. The standardized SBP/DBP reduction was, however, associated with absolute reductions in the risk of stroke, major cardiovascular events, cardiovascular and all-cause mortalities progressively lower the lower was the SBP value attained, suggesting patients at lower initial SBP were at a lower level of cardiovascular risk. Consequently, NNT values increased from 19 to 45 patients to be treated for 5 years to prevent a major cardiovascular event (stroke, CHD or heart failure), from 49 to 119 to prevent a stroke, from 61 to 182 to prevent a cardiovascular death.
Updating of our 2014 meta-analyses stratifying all BP- lowering RCTs with mean achieved DBP values in the active or more active treatment and in the placebo or less active treatment across the two predeterminate cutoffs of 90 and 80 mmHg, by the addition of the Weiet al.study [24] to the
group across the 80 mmHg cutoff only minimally changed the relative risk estimates, confirming our previous report that all tested cardiovascular outcomes, with the exclusion of heart failure, were significantly reduced by a standard SBP/DBP difference of 10/5 mmHg, also when this difference was across the DBP 80 mmHg cutoff, with no significant difference with the risk reductions observed when the DBP cutoff between treatments was 90 mmHg.
DISCUSSION
The present meta-analyses update our 2014 meta-analyses [1,22] and a subsequent one by another group [19] of more vs. less intense BP-lowering trials, mostly by adding the recent results of the large SPRINT study [20]. Although both previous meta-analyses concordantly showed that more intense BP lowering significantly reduced the risk of stroke, CHD events and the composite of major cardi- ovascular events but not the risk of heart failure and mortality (both cardiovascular and all-cause death), addition of SPRINT data [20] for the first time indicates that also the risk of cardiovascular death is significantly reduced, and risk of all-cause death tends to a reduction with borderline significance. We have also verified that the extent of risk reductions for a more intense treatment producing a 10/5 mmHg SBP/DBP difference corre- sponds to what was expected from meta-regression
–10 –10 –16
–5 –8 –16 –22
–22 –52
–16 –22 –25
–6 –4 –21
–8 –8 –6 –8 –16 –20
–80 –60 –40 –20 0 20
Outcome
Stroke
CHD
HF
Stroke + CHD
Stroke + CHD + HF
CV death
All-cause death
Achieved SBP cutoff
(mmHg)
140–149 vs ≥150 130–139 vs ≥140
<130 vs ≥130 140–149 vs ≥150 130–139 vs ≥140
<130 vs ≥130 140–149 vs ≥150 130–139 vs ≥140
<130 vs ≥130 140–149 vs ≥150 130–139 vs ≥140
<130 vs ≥130 140–149 vs ≥150 130–139 vs ≥140
<130 vs ≥130 140–149 vs ≥150 130–139 vs ≥140
<130 vs ≥130 140–149 vs ≥150 130–139 vs ≥140
<130 vs ≥130 Trials
(n)
8 15
7 8 16
8 7 10
5 8 16
7 7 10
5 8 16
9 8 16
9
Absolute risk reduction 1000 pts/5 years
(95% CI) Standardized
RR (95% CI)
0.68 (0.60–0.79) 0.62 (0.51–0.76) 0.71 (0.61–0.84) 0.81 (0.68–0.95) 0.77 (0.70–0.86) 0.86 (0.76–0.97) 0.52 (0.41–0.65) 0.75 (0.35–1.59) 0.81 (0.51–1.30) 0.73 (0.67–0.82) 0.71 (0.63–0.78) 0.81 (0.72–0.89) 0.69 (0.63–0.76) 0.72 (0.60–0.85) 0.76 (0.64–0.89) 0.79 (0.71–0.89) 0.77 (0.63–0.93) 0.80 (0.67–0.97) 0.89 (0.82–0.96) 0.83 (0.72–0.96) 0.84 (0.73–0.95)
Standardized RR (95% CI)
P-value for trend
0.44
0.18
0.24
0.11
0.24
0.73
0.52
P-value for trend
<0.001
0.35
0.11
0.002
0.021
0.001
0.008
Lower SBP better
Higher SBP better
0.3 0.6 1.0 1.5
FIGURE 5Effects of BP lowering in trials of active treatment vs. placebo and more vs. less intense treatment (considered together), stratified in three strata with mean SBP achieved by active or more intense treatment vs. mean SBP achieved in the placebo or less intense treatment: 140–149 vs. at least 150 mmHg; 130–139 vs. at least 140 mmHg; less than 130 vs. at least 130 mmHg. Standardized RR is to a SBP/DBP difference of10/5 mmHg. The histograms of the column Absolute risk reduction represent the numbers (and 95% CI) of events prevented every 1000 patients actively or more intensely treated for 5 years using the standardized RR. The two columns headedPvalue for trend refer, the first, to the standardized RR, and the second to absolute risk reduction. Mean SBP/DBP achieved in the three strata of achieved SBP were (from above downward): 143.3/76.4 vs. 157.1/82.1; 137.2/81.0 vs. 144.3/84.8; 125.8/76.3 vs. 134.9/79.4. BP, blood pressure; CHD, coronary heart disease; CI, confidence interval; CV, cardiovascular; HF, heart failure; pts, patients; RR, Mantel–Haenszel risk ratio.
analyses we have recently calculated by a large body of BP-lowering RCTs [32].
Also in RCTs comparing more with less intense BP lowering relative risk reduction does not appear to depend on the level of risk, as trend analysis did not show signifi- cant differences between relative risk reductions of any outcome when the RCTs were stratified according to risk of cardiovascular death in the control group with less intense treatment. Furthermore, significant reductions of composite outcomes (stroke and CHD; stroke, CHD and heart failure) could also be found in the stratum of RCTs in patients classified as low to moderate cardiovascular risk (admit- tedly, risk defined in the control group under usual treat- ment). As previously shown by our group [33] and another one [55] in larger numbers of BP-lowering trials, similar relative risk reductions in patients at different overall risks mean the higher the overall risk, the higher are the absolute risk reductions. However, we have shown that also in the stratum of low to moderate cardiovascular risk a greater SBP/DBP reduction of 10/5 mmHg could induce an important absolute reduction of 11 major cardiovascular events every 1000 patients more intensely treated for 5 years, with a NNT of 91 patients.
Residual risk [33] remains reasonably low in low- moderate risk patients more intensely treated (25 major cardiovascular events every 1000 patients despite more intense treatment for 5 years), and significantly lower than in high and very high risk patients with the same SBP/DBP reduction (117 and 195, respectively; odds ratios 2.5 and 8.0) (Fig. 3).
The demonstration of significant benefits of more intense BP-lowering treatment cannot obviously be trans- lated into the message that the lower the achieved BP the better is the benefit for the patient [56]. The issue of the optimal BP, and particularly SBP, level to be achieved by treatment has been widely debated in the last few years [57], and the point taken by the most recent guidelines [58–60]
has been that sufficient trial-based evidence was available to recommend a SBP target of less than 140 mmHg, whereas such an evidence was not available for a SBP target lower than 130 mmHg. Guidelines were clear to point out that lack of evidence does not mean evidence against, and indeed some of them [58] recommended to further investigate the problem of the optimal BP target. In response to this invitation, we published in 2014 a meta-analysis of BP- lowering trials stratified according to different levels of SBP (and DBP) achieved by treatment and found that achieving SBP a few mmHg below the cutoff of 130 mmHg (127 vs.
137 mmHg) was associated with a significant reduction of stroke and a marginally significant reduction of all-cause death, but reductions in CHD, heart failure and cardiovas- cular death did not attain statistical significance [22].
The present updating of this meta-analysis, particularly thanks to the addition of the recent data from SPRINT [20], has further extended the previous evidence by showing that: stratification of RCTs of more vs. less intense BP lowering according to three levels of achieved SBP (and two levels of DBP) did not result into different relative risk reductions, and stratification of all RCTs of BP lowering (both active vs. placebo treatment and more intense vs. less intense) now shows most outcomes considered (stroke,
CHD, composites of major specific events, cardiovascular and all-cause mortalities) are significantly reduced by BP lowering, and to a similar proportion when a 10 mmHg SBP difference occurs across the 150, 140 and 130 mmHg cutoffs (for the last cutoff 125 vs. 135 mmHg). The same is the case for a 5 mmHg DBP difference across the cutoffs of 90 and 80 mmHg (for the latter 78 vs. 83 mmHg).
Of course, analyzing SBP and DBP separately is artificial as all BP-lowering treatments reduce both types of BP. None- theless, in the achieved SBP stratum across the 130 mmHg cutoff mean achieved DBP were 72.3 vs. 79.4 mmHg, and therefore our meta-analysis can be taken to show that there are significant reductions in all major outcomes when SBP/
DBP are lowered a few mmHg below (as compared with above) 130/80 mmHg. For the same BP reduction, however, the absolute risk reduction is smaller at lower BP targets (across the 130 mmHg cutoff approximately a half of that observed across the 150 mmHg cutoff). This smaller benefit should be considered when deciding the BP target to achieve in the individual patient, especially in front of a possible increase in adverse effects and a consequent decrease in the patient’s adherence to the treatment.
We are aware that meta-analyses are not a real substitute of large and good RCTs [61], but believe the evidence we so provide is at least more valuable and solid than simple opinion experts of recent guidelines had to use for their recommendations on target BP. Unfortunately, the only three large RCTs that specifically aimed at investigating the possible benefits of lowering SBP quite below 130 mmHg [13,15,20] have given some contrasting results both on primary endpoints (ACCORD [13] and SPS3 [15]
failing to find a significant reduction, and SPRINT [20]
succeeding) and specific events (ACCORD [13] showing a significant reduction of stroke, SPS3 [15] only of hemor- rhagic stroke, SPRINT [20] no significant stroke risk reduction; ACCORD [13] failing to reduce significantly heart failure and SPRINT [20] showing benefits of more intense SBP lowering particularly on heart failure). All these trials had important limitations: SPS3 was numerically under- powered, ACCORD was underpowered because of a lower than expected incidence of cardiovascular events;
interpretation of SPRINT is also being debated, particularly because in this trial the benefits of more intense BP low- ering were dominated by a reduced incidence of heart failure, which is responsive not only to BP lowering but to the drugs being used (diuretics, blockers of the renin–
angiotensin system) [62]. An additional large RCT on the best SBP target to prevent recurrent stroke in poststroke patients, the ESH-CHL-SHOT trial [62,63], is under way.
In the meta-analyses here presented we have purposely refrained from stratifying the RCTs according to baseline BP in order to investigate the level of BP that deserves initiation of BP-lowering treatment. Indeed, of the 16 RCTs of more vs. less intense BP lowering we could include in our meta- analyses, 12 were in patients already under antihyperten- sive treatment, which was not withdrawn or was directly switched to randomized therapy, so that untreated BP values, i.e., those on the base of which treatment is decided, are unknown. Therefore, although in a few of these RCTs BP values at randomization were within the so-called high – normal BP range, their data cannot be taken to indicate
treatment benefits for untreated individuals with high–
normal BP or prehypertension.
In a previous set of meta-analyses, however, we were able to identify 32 BP-lowering RCTs, mostly of active treatment vs. placebo, in which baseline values were not polluted by current treatment, and could show that signifi- cant reductions of the risk of most outcomes can be obtained by BP reduction at all grades of hypertension, including grade 1 (SBP 140–159, DBP 90–99 mmHg) at low-moderate risk [22]. No evidence is available yet about benefits of BP-lowering treatment in individuals with high–
normal BP or prehypertension: the two RCTs [25,26] we have considered in sensitivity analyses in the present study were too small and associated with too few outcomes to provide significant evidence, and, when added to the other RCTs on hypertensive patients, failed to modify the results of the meta-analyses. Larger trials are desirable.
ACKNOWLEDGEMENTS
The corresponding author (A.Z.) is responsible for the design of the study and preparation of the first draft of the manu- script, A.Z. and C.T. have done the systematic review of the literature and extracted data, C.T. has conducted the meta- analyses, but all three authors (C.T., G.P., A.Z.) have sub- stantially contributed to interpretation of data, critical revi- sion of the manuscript for important intellectual content, and given final approval of the version to be published. The corresponding author (A.Z.) and C.T. take responsibility for the integrity of the analyses. The overview and meta-analyses were designed and conducted with funds made available to Istituto Auxologico Italiano by current research grants of the Ministry of Health of Italy, and in the context of contract EC 278249 (EU-MASCARA). C.T. was visiting investigator at the Istituto Auxologico Italiano, Milan under a fellowship granted by the Hellenic Society of Cardiology. The valuable help of Mrs Donatella Mihalich for literature searching and that of Mrs Paulina Wijnmaalen for preparation of manuscript and illustrations are gratefully acknowledged.
Conflicts of interest
The authors declare no conflict of interest regarding the overview and meta-analyses, but C.T. declares consultancy fees from Astra Zeneca and lecture honoraria from Sanofi;
G.P. declares lecture honoraria from Bayer, Daiichi Sankyo, Guidotti and Boehringer Ingelheim; and A.Z. declares lecture honoraria from Menarini International, Recordati SpA and CVRx.
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