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Thomopoulos C.,Helena Venizelou Hospital | Parati G.,Neural and Metabolic science | Parati G.,University of Milan Bicocca | Zanchetti A.,Scientific Direction | Zanchetti A.,University of Milan
Journal of Hypertension | Year: 2014

Background: Randomized controlled trials (RCTs) of blood pressure (BP) lowering lend themselves to be meta-analyzed to help providing evidence-based recommendations for hypertension treatment. Objectives: To investigate whether relative or absolute risk reductions increase at increasing levels of baseline cardiovascular risk and whether BP-lowering treatment should be addressed to patients in risk categories promising larger absolute treatment benefits. Methods: Sixty-eight RCTs of intentional and nonintentional BP lowering were classified in four strata of increasing average 10-year incidence of cardiovascular death in the placebo or less active treatment group: lowto- moderate risk (<5%; 23 RCTs, 81 675 individuals), high risk (5% to <10%; 11 RCTs, 46 162 individuals), very high risk (10% to <20%; 19 RCTs, 91 152 individuals), and very very high risk (≥20%; 16 RCTs, 26 881 individuals). Risk ratios and 95% confidence intervals (CIs; random-effects model) standardized to 10/5mmHg SBP/DBP reduction, absolute risk reduction, and residual risk of seven major fatal/nonfatal outcomes were calculated. Relative and absolute risk reductions in the cardiovascular risk strata were compared by the trend analysis, residual risk by calculating odds ratio (OR) relative to low-to-moderate risk. Results: Relative reductions of all outcomes did not differ in the risk strata, but absolute reductions significantly increased with increasing cardiovascular risk (P for trend <0.001 except for CHD): a 10/5mmHg SBP/DBP reduction reduced the incidence of major cardiovascular events by 7 (95% CI 3-10), 30 (9-50), 56 (35-76), and 87 (62-112) events every 1000 patients treated 5 years, with increasing cardiovascular risk. However, also residual risk significantly (P < 0.001) increased with increasing cardiovascular risk [up to an OR 9.43 (8.60-10.35) for cardiovascular death]. The increase in residual risk with increasing level of cardiovascular risk persisted when RCTs with average initial age at least 65 years were excluded, and mean ages at the different cardiovascular risk levels were comparable. Conclusion: BP-lowering treatment induces greater absolute risk reductions the higher the cardiovascular risk level, but a higher risk level is also associated with higher absolute residual risk, independent of age. Whereas reserving antihypertensive treatment to high-risk hypertensive patients maximizes the cost-benefit ratio, only treatment of low-to-moderate risk hypertensive patients may prevent the increasing number of treatment failures when treatment is initiated at higher risk. Copyright © Lippincott Williams & Wilkins. Source


Thomopoulos C.,Helena Venizelou Hospital | Parati G.,Neural and Metabolic science | Parati G.,University of Milan Bicocca | Zanchetti A.,Scientific Direction | Zanchetti A.,University of Milan
Journal of Hypertension | Year: 2014

Background: Relevant clinical questions not approached by randomized controlled trials (RCTs) of blood pressure (BP)-lowering treatment can be explored by meta-analyses stratified by clinical criteria. Objectives: Investigating whether all grades of hypertension benefit from BP-lowering treatment and which are the target BP levels to maximize outcome reduction. Methods: Of the 68 RCTs of intentional and nonintentional BP-lowering, those without baseline antihypertensive drugs were stratified by the average baseline SBP and DBP (hypertension grades 1, 2, and 3). RCTs with or without baseline treatment were considered for investigating the effects of mean achieved SBP/DBP across three SBP cutoffs and two DBP cutoffs. Risk ratios (RR) and 95% confidence interval (CI) (random-effects model), standardized to 10/5mmHg SBP/DBP reduction, and absolute risk reductions of seven fatal and nonfatal outcomes were calculated. Differences between relative and absolute risk reductions in the different strata of baseline or achieved SBP/DBP were evaluated by trend or heterogeneity analyses. Results: In 32 RCTs (104 359 individuals), significant outcome reductions were found independently of the hypertension grade, with no trend toward risk ratio changes with increasing baseline BP. A secondary analysis limited to RCTs on grade 1 hypertension at low-to-moderate risk showed significant outcome reductions [risk ratio: stroke 0.33 (0.11-0.98), coronary events 0.68 (0.48-0.95), and death 0.53 (0.35-0.80)]. In 32 RCTs (128 232 individuals), relative and absolute outcome reductions were significant for the SBP differences across 150 and 140mmHg cutoffs. Below 130 mmHg, only stroke and all-cause death were significantly reduced. Absolute outcome reduction showed a significant trend to decrease, the lower the SBP cutoff considered. In 29 RCTs (107 665 individuals), outcomes were significantly reduced across DBP cutoffs of 90 and 80 mmHg. After excluding RCTs with baseline DBP less than 90 mmHg, only stroke reduction was significant at achieved DBP less than 80 mmHg. Conclusion: Meta-analyses favor BP-lowering treatment even in grade 1 hypertension at low-to-moderate risk, and lowering SBP/DBP to less than 140/90 mmHg. Achieving less than 130/80mmHg appears safe, but only adds further reduction in stroke. Copyright © Lippincott Williams & Wilkins. Source


Thomopoulos C.,Helena Venizelou Hospital | Parati G.,Neural and Metabolic science | Parati G.,University of Milan Bicocca | Zanchetti A.,Scientific Direction | Zanchetti A.,University of Milan
Journal of Hypertension | Year: 2014

Background: Antihypertensive treatment is based on randomized controlled trials (RCTs) started since 1966. Meta-analyses comprehensive of all RCTs but limited to RCTs investigating blood pressure (BP) lowering in hypertensive patients are lacking. Objectives: Two clinical questions were investigated: the extent of different outcome reductions by BP lowering in hypertensive patients, and the proportionality of outcome reductions to SBP, DBP, and pulse pressure (PP) reductions. Methods: PubMed between 1966 and December 2013 (any language), Cochrane Collaboration Library and previous overviews were used as data sources for identifying and selecting all RCTs comparing the antihypertensive drugs with placebo or less intense BP lowering (intentional BP-lowering RCTs); comparing BP-lowering drugs with placebo without BP-lowering intention, but with BP difference (nonintentional BPlowering RCTs); and enrolling at least 40% hypertensive patients. RCTs on acute myocardial infarction, heart failure, acute stroke, and dialysis were excluded. RCT quality was assessed by scoring. Risk ratios and 95% confidence interval (CI), standardized to 10/5mmHg SBP/DBP reduction, of seven fatal and nonfatal outcomes were calculated (random-effects model). The relationships of different outcome reductions to SBP, DBP, and PP reductions were investigated by meta-regressions. Results: A total of 68 RCTs (245 885 individuals) were eligible, of which 47 (153 825 individuals) were 'intentional' RCTs. All outcomes were reduced (P < 0.001) by BP lowering, stroke [-36% (-29, -42)], and heart failure [-43% (-28, -54)] to a greater extent, with smaller reductions for coronary events [coronary heart disease (CHD): -16% (-10, -21)], cardiovascular [-18% (-11, -24)], and all-cause mortality [-11% (-5, -16)]. Absolute risk reductions were 17 (14, 20) strokes, 28 (19, 35) cardiovascular events, and 8 (4, 12) deaths prevented every 1000 patients treated for 5 years. Logarithmic risk ratios were related to SBP, DBP, and PP reductions (P = 0.001-0.003) for stroke and composite cardiovascular events, but not for CHD. Conclusion: Meta-analyses of all BP-lowering RCTs involving hypertensive patients provide precise estimates of benefits (larger for stroke and heart failure, but also significant for CHD and mortality). Absolute risk reductions are substantial. Relationships of logarithmic risk ratios with BP reductions imply risk reduction increases progressively to a smaller extent the larger the BP reduction. Copyright © Lippincott Williams & Wilkins. Source


Thomopoulos C.,Helena Venizelou Hospital | Parati G.,Neural and Metabolic science | Parati G.,University of Milan Bicocca | Zanchetti A.,University of Milan
Journal of Hypertension | Year: 2016

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 (52235 patients) compared more vs. less intense treatment and fulfilled other preset criteria, and in 34 (138127 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/-5mmHg 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 130mmHg) showed that a SBP/DBP difference of -10/-5mmHg 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 130mmHg, but absolute risk reduction becomes smaller, suggesting patients at lower initial SBP were at a lower level of cardiovascular risk. © 2016 Wolters Kluwer Health, Inc. Source


Thomopoulos C.,Helena Venizelou Hospital | Parati G.,Neural and Metabolic science | Parati G.,University of Milan Bicocca | Zanchetti A.,Scientific Direction | Zanchetti A.,University of Milan
Journal of Hypertension | Year: 2016

Background and objectives: Relative effectiveness of blood pressure (BP)-lowering treatment on various outcomes was evaluated by meta-analyses restricted to randomized controlled trials (RCTs) measuring all major outcomes, and the question whether BP lowering and each class of antihypertensive agents prevent new-onset heart failure by meta-analyses limited to RCTs excluding baseline heart failure from randomization. Methods: Source of these meta-analyses are our databases of BP-lowering RCTs vs placebo or less-active treatment, and head-to-head comparisons of different antihypertensive classes. Risk ratios (RRs) and 95% confidence intervals of seven outcomes were calculated by a random-effects model. The relationships of outcome reductions to BP differences were investigated by meta-regressions. Results: First, 35 BP-lowering RCTs measured all outcomes, and heart failure [RR 0.63 (0.52-0.75)] and stroke [RR 0.58 (0.49-0.68)] were the outcomes most effectively prevented. Second, heart failure and stroke reductions were significantly related to SBP, DBP and pulse pressure reductions. Third, in 18 BP-lowering RCTs excluding baseline heart failure from recruitment, heart failure reduction ('new-onset' heart failure) [RR 0.58 (0.44-0.75)] was very similar to that in the entire set of RCTs. Fourth, in meta-analyses of head-to-head comparisons of different antihypertensive classes, calcium antagonists were inferior in preventing 'new-onset' heart failure [RR 1.16 (1.01-1.33)]. However, this inferiority disappeared when meta-analysis was limited to RCTs allowing concomitant use of diuretics, β-blockers or renin-angiotensin system blockers also in the calcium antagonist group [RR 0.96 (0.81-1.12)]. Conclusion: BP-lowering treatment effectively prevents 'new onset' heart failure. It is suggested that BP lowering by calcium antagonists is effective as BP lowering by other drugs in preventing 'new-onset' heart failure, unless the trial design creates an unbalance against calcium antagonists. © Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved. Source

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