Costas Thomopoulos

Effects of blood pressure lowering on outcome incidence in hypertension. 1. Overview, meta-analyses, and meta-regression analyses of randomized trials.

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 BP-lowering 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 10/5 mmHg 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.

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.

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.

Effects of blood pressure lowering on outcome incidence in hypertension: 2. Effects at different baseline and achieved blood pressure levels--overview and meta-analyses of randomized trials.

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 10/5 mmHg 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 140 mmHg 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 130/80 mmHg appears safe, but only adds further reduction in stroke.

Effects of blood pressure lowering on outcome incidence in hypertension: 4. Effects of various classes of antihypertensive drugs--overview and meta-analyses.

Background and objectives: In 68 randomized controlled trials (RCTs), blood pressure (BP) lowering was obtained by using drugs of different classes. We have investigated whether BP lowering by any of the major drug classes is effective in reducing the cardiovascular outcomes. Methods: A total of 55 RCTs (195 267 individuals) were suitable for drug-class meta-analyses. Risk ratios and their 95% confidence intervals of seven fatal and nonfatal outcomes were estimated by a random-effects model. Results: Twelve RCTs (48 898 patients) compared a diuretic with no treatment. SBP/DBP differences of about −12/–5 mmHg were accompanied by significant reductions of all outcomes, including mortality. The same results were obtained by limiting analyses to eight RCTs using low-dose diuretics. Separate analyses for thiazides, chlorthalidone and indapamide (all low dose) showed each subclass was associated with significant reduction of some major outcome. Five RCTs (18 724 patients; SBP/DBP difference –10.5/–7 mmHg) showed beta-blockers significantly reduced stroke, heart failure and major cardiovascular events. In RCTs comparing calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) with placebo smaller SBP/DBP differences were achieved, mostly because in the majority of these later RCTs the antihypertensive drug and placebo were added on a background treatment with other antihypertensive agents. Nonetheless, significant reductions of stroke, major cardiovascular events, cardiovascular and all-cause death were obtained with calcium antagonists (10 RCTs, 30 359 patients); stroke, coronary heart disease, heart failure and major cardiovascular events by ACE inhibitors (12 RCTs, 35 707 patients); and stroke, heart failure and major cardiovascular events by ARBs (13 RCTs, 65 256 patients). Conclusion: BP lowering by all classes of antihypertensive drugs is accompanied by significant reductions of stroke and major cardiovascular events. This supports the concept that reduction of these events is because of BP lowering per se rather than specific drug properties. However, evidence of risk reduction of other events and particularly mortality was obtained so far with some drug classes only. As a result of marked differences in the trial design, total cardiovascular risk, SBP/DBP differences and statistical power, comparisons of meta-analyses of different drug-specific placebo-controlled RCTs appear unwarranted.

Effects of blood pressure lowering on outcome incidence in hypertension: 3. Effects in patients at different levels of cardiovascular risk - overview and meta-analyses of randomized trials

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: low-to-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 10/5 mmHg 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 10/5 mmHg 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.

Periodontitis and blood pressure: The concept of dental hypertension

Chronic periodontitis is a common inflammatory disorder that is being contemplated as a risk factor for atherosclerotic complications. Current epidemiological evidence also supports its potential association with increases in blood pressure levels and hypertension prevalence. Furthermore, data from cross-sectional studies suggest that in hypertensive subjects periodontitis may enhance the risk and degree of target organ damage. A possible pathogenetic background of an effect of periodontitis on blood pressure should include the systemic generalization of the local oral inflammation, the role of the host immune response, the direct microbial effect on the vascular system and alterations in endothelial function. Inversely, the concept of hypertension unfavorably affecting periodontal tissues cannot be excluded. The two conditions share multiple common risk factors that should be readily controlled for when assessing a possible association. Thoroughly designed prospective and interventional trials are needed in order to determine the impact of periodontitis on blood pressure regulation and incident hypertension and its integration in the clinical approach of both dental and hypertensive patients.

Left ventricular hypertrophy versus chronic kidney disease as predictors of cardiovascular events in hypertension : a Greek 6-year-follow-up study

Objectives We assessed the comparative prognostic role of left ventricular hypertrophy (LVH) and chronic kidney disease (CKD) for major cardiovascular events in a prospective observational study in Greek essential hypertensive patients. Methods We followed up 1652 hypertensive patients (mean age 54.3 years, 696 male patients, office blood pressure 147/93 mmHg) free of cardiovascular disease for a mean period of 6 years. CKD and echocardiographically detected LVH were evaluated at baseline along with five major traditional risk factors [age > 65 years, sex, current smoking, diabetes mellitus and dyslipidemia (low density lipoprotein > 160 mg/dl)]. End points of interest were the incidence of coronary artery disease, stroke, all-cause mortality and their composite. Results At the end of follow-up, coronary artery disease was the most prevalent (5.2%), followed by stroke (5%) and total mortality (3.1%). The presence of both LVH and CKD is associated with a 2.5-fold increase in coronary artery disease (P = 0.034), four-fold in stroke (P = 0.002) and 3.2-fold in the composite (P < 0.001), whereas the presence of LVH alone was associated with a 2.5-fold higher risk for stroke (P = 0.009) and 1.7-fold for the composite (P = 0.018). By multivariate Cox regression analysis, LVH (hazard ratio = 1.53, P = 0.036) and CKD (hazard ratio = 1.66, P = 0.039) turned out to be independent prognosticators of the composite end point, whereas age more than 65 years (hazard ratio = 4.59, P < 0.001) and the presence of LVH (hazard ratio = 2.01, P = 0.043) were the only predictors of stroke. Conclusions In hypertensive patients free of cardiovascular disease, CKD and LVH are both independent prognosticators of the composite end point of all-cause death and cardiovascular morbidity, whereas LVH but not CKD is a major predictor for stroke.

Randomized Controlled Trials of Blood Pressure Lowering in Hypertension A Critical Reappraisal

Sixty-eight blood pressure (BP)-lowering randomized controlled trials (defined as randomized controlled trials comparing active treatment with placebo, or less active treatment, achieving a BP difference, performed between 1966 and end 2013 in cohorts with ≥ 40% hypertensive patients, and exclusive of trials in acute myocardial infarction, heart failure, acute stroke, and dialysis) were identified and meta-analyzed grouping the randomized controlled trials on the basis of clinically relevant questions: (1) does BP lowering reduce all types of cardiovascular outcome? (2) Is prevention of all outcomes proportional to the extent of systolic, diastolic, and pulse BP? (3) Have all classes of BP-lowering drugs been shown capable of reducing all types of cardiovascular outcome? (4) Is BP lowering beneficial when intervention is initiated at any grade (or stage) of hypertension? (5) Do BP-lowering randomized controlled trials provide evidence about systolic BP and diastolic BP targets of treatment? (6) Should BP-lowering treatment be preferentially addressed to patients in higher risk categories promising larger absolute treatment benefits? The results of these meta-analyses provide further support to current hypertension treatment guidelines by showing that BP lowering can significantly reduce major cardiovascular outcomes largely independent of the agents used, significant risk reduction is found at all hypertension grades (stages), and when systolic BP is lowered below a cut off of 140 mm Hg with some further reduction limited to stroke at systolic BP values just <130 mm Hg. Absolute risk reduction progressively increases higher is total cardiovascular risk, but this greater benefit is associated with a progressively higher residual risk, ie, higher treatment failures.

ADMA, C-Reactive Protein, and Albuminuria in Untreated Essential Hypertension: A Cross-sectional Study

BACKGROUND Asymmetric dimethylarginine (ADMA) and subclinical inflammation are associated with atherosclerosis progression, whereas microalbuminuria is an established index of hypertensive organ damage. STUDY DESIGN Cross-sectional. SETTING & PARTICIPANTS In an outpatient hypertensive unit, 296 nondiabetic and untreated participants with hypertension were studied. Participants with atherosclerotic cardiovascular disease, severe valvulopathy, congestive heart failure, presence of neoplastic or other concurrent systemic disease, atrial fibrillation, serum creatinine level > 1.5 mg/dL in men and > 1.4 mg/dL in women, and urinary albumin excretion > 300 mg/24 h were excluded. PREDICTORS ADMA and high-sensitivity C-reactive protein (hs-CRP) levels. OUTCOME VARIABLE Albuminuria assessed using albumin-creatinine ratio (ACR). MEASUREMENTS Participants underwent ambulatory blood pressure monitoring, echocardiography, routine assessment of metabolic profile, ADMA, and hs-CRP, whereas ACR was determined as the mean of 3 values in nonconsecutive morning spot urine samples. RESULTS 64 participants had an ACR of 30-300 mg/g. Stratification based on ADMA level showed that participants with hypertension in quartile [Q] 4 compared with those in Q3, Q2, and Q1 showed the highest ACRs (53.2 vs 31.2 vs 30.4 vs 16.7 mg/g; P < 0.008 for all). Moreover, stratification based on hs-CRP level showed that participants with hypertension in Q4 (69.8% had microalbuminuria) showed the highest ACRs (72.2 vs 25.6, 16.2, and 19.2 mg/g for Q3, Q2, and Q1, respectively; P < 0.008 for all). Stepwise regression analysis showed that age, 24-hour systolic blood pressure, hs-CRP level, ADMA level, and the interaction of hs-CRP with ADMA were independent predictors of ACR (R(2) = 0.674; P < 0.001). LIMITATIONS Cross-sectional study. CONCLUSIONS In patients with untreated essential hypertension, increased hs-CRP and ADMA levels are associated with microalbuminuria, suggesting the involvement of inflammation and endothelial dysfunction in vascular and kidney damage.

Association of obstructive sleep apnea with urinary albumin excretion in essential hypertension: a cross-sectional study.

BACKGROUND Microalbuminuria reflects a state of widespread vascular dysfunction, whereas obstructive sleep apnea (OSA) further promotes atherosclerotic damage in hypertension. STUDY DESIGN Cross-sectional. SETTING & PARTICIPANTS In an outpatient hypertensive unit, 62 untreated hypertensive patients (aged 48 +/- 7 years; office blood pressure [BP], 151 +/- 8/97 +/- 7 mm Hg) with OSA and 70 hypertensive patients without OSA (apnea hypopnea index [AHI] < or = 5) matched for age, sex, smoking status, body mass index, and 24-hour pulse pressure were studied. PREDICTOR VARIABLE Hypertension and OSA compared with hypertension without OSA. OSA defined as AHI greater than 5, documented by polysomnography. OUTCOME VARIABLE Albuminuria assessed by urinary albumin-creatinine ratio (ACR). MEASUREMENTS Participants underwent polysomnography, ambulatory BP monitoring, echocardiography, routine metabolic profile assessment, and glomerular filtration rate estimation, whereas ACR was measured from 2 nonconsecutive morning spot urine samples. RESULTS Hypertensive patients with OSA compared with those without OSA showed increased 24-hour diastolic BP (87 +/- 7 versus 85 +/- 7 mm Hg; P = 0.03) and nighttime pulse pressure (50 +/- 10 versus 45 +/- 10 mm Hg; P = 0.008), but did not differ regarding metabolic profile and estimated glomerular filtration rate. Albuminuria was greater by 57% in patients with OSA compared with those without OSA: log(10)ACR, 1.1 +/- 0.2 versus 0.7 +/- 0.4 mg/g; P < 0.001). In the entire study population, log10(ACR) correlated with log10(AHI) (r = 0.35; P < 0.001), minimum oxygen saturation during sleep (r = -0.33; P < 0.001), 24-hour pulse pressure (r = 0.38; P < 0.001), and nighttime pulse pressure (r = 0.21; P =0 .01). In a multivariable linear regression model, independent predictors of ACR were AHI (beta = 0.36; P < 0.001) and 24-hour pulse pressure (beta = 0.25; P = 0.01). LIMITATIONS Cross-sectional study. CONCLUSIONS Albuminuria increases within the normal range in hypertensive individuals with OSA compared with those without OSA proportionally to OSA severity independently of confounders. The association of upper-airway dysfunction with albuminuria and pulsatile hemodynamic load may provide an explanatory mechanism for the OSA-related risk in hypertension.