Effects of blood pressure lowering drugs in heart failure:a systematic review and meta-analysis of randomised controlled trials

We aimed to combine evidence from all heart failure trials that have investigated the effects of drugs with blood pressure (BP)-lowering properties to assess the extent to which such drugs reduce BP in heart failure, the association between the net change in BP between treatment arms and cause-specific outcomes and whether treatment effects (efficacy and safety) vary according to baseline BP. We conducted a systematic review and metaanalysis including randomized clinical trials of drugs with BP-lowering properties in patients with chronic heart failure with at least 300 patient-years follow-up. We included a total of 37 trials (91 950 patients) and showed that treatment with drugs with BP-lowering properties resulted in a small but significant decrease in SBP in patients with heart failure with no evidence that the efficacy and safety of those drugs varied according to baseline BP

Genetic susceptibility, elevated blood pressure and risk of atrial fibrillation:A Mendelian randomization study

Background: Whether elevated blood pressure (BP) is a modifiable risk factor for atrial fibrillation (AF) is not established. We tested (1) whether the association between BP and risk of AF is causal, (2) whether it varies according to individual’s genetic susceptibility for AF, and (3) the extent to which specific BP-lowering drugs are expected to reduce this risk. Methods: First, causality of association was assessed through two-sample Mendelian randomization, using data from two independent genome-wide association studies that included a total of one million European population. Second, the UK Biobank data of 329,237 participants at baseline was used to study the effect of BP on AF according to genetic susceptibility of developing AF. Third, a possible treatment effect with major BP-lowering drug classes on AF risk was predicted through genetic variants in genes encode the therapeutic targets of each drug class. Estimated drug effects were compared with effects on incident coronary heart disease, for which direct trial evidence exists. Results: The two-sample Mendelian randomization analysis indicated that, on average, exposure to a higher systolic BP increased the risk of AF by 19% (odds ratio per each 10-mm Hg [OR]: 1.19 [1.12 to 1.27]). This association was replicated in the UK biobank using individual participant data. However, in a further genetic risk-stratified analysis, there was evidence for a linear gradient in the relative effects of systolic BP on AF; while there was no conclusive evidence of an effect in those with low genetic risk, a strong effect was observed among those with high genetic susceptibility for AF. The comparison of predicted treatment effects using genetic proxies for three main drug classes (angiotensin-converting enzyme inhibitors, beta-blockers and calcium channel blockers) suggested similar average effects for the prevention of atrial fibrillation and coronary heart disease. Conclusions: The effect of elevated BP on the risk of AF is likely to be causal, suggesting that BP-lowering treatment may be effective in AF prevention. However, average effects masked clinically important variations, with a more pronounced effect in individuals with high genetic susceptibility risk for AF

Blood pressure lowering and risk of new-onset type 2 diabetes:an individual participant data meta-analysis

Background Blood pressure lowering is an established strategy for preventing microvascular and macrovascular complications of diabetes, but its role in the prevention of diabetes itself is unclear. We aimed to examine this question using individual participant data from major randomised controlled trials. Methods We performed a one-stage individual participant data meta-analysis, in which data were pooled to investigate the effect of blood pressure lowering per se on the risk of new-onset type 2 diabetes. An individual participant data network meta-analysis was used to investigate the differential effects of five major classes of antihypertensive drugs on the risk of new-onset type 2 diabetes. Overall, data from 22 studies conducted between 1973 and 2008, were obtained by the Blood Pressure Lowering Treatment Trialists' Collaboration (Oxford University, Oxford, UK). We included all primary and secondary prevention trials that used a specific class or classes of antihypertensive drugs versus placebo or other classes of blood pressure lowering medications that had at least 1000 persons-years of followup in each randomly allocated arm. Participants with a known diagnosis of diabetes at baseline and trials conducted in patients with prevalent diabetes were excluded. For the one-stage individual participant data meta-analysis we used stratified Cox proportional hazards model and for the individual participant data network meta-analysis we used logistic regression models to calculate the relative risk (RR) for drug class comparisons. Findings 145 939 participants (88 500 [60.6%] men and 57 429 [39.4%] women) from 19 randomised controlled trials were included in the one-stage individual participant data meta-analysis. 22 trials were included in the individual participant data network meta-analysis. After a median follow-up of 4.5 years (IQR 2.0), 9883 participants were diagnosed with new-onset type 2 diabetes. Systolic blood pressure reduction by 5 mm Hg reduced the risk of type 2 diabetes across all trials by 11% (hazard ratio 0.89 [95% CI 0.84-0.95]). Investigation of the effects of five major classes of antihypertensive drugs showed that in comparison to placebo, angiotensin-converting enzyme inhibitors (RR 0.84 [95% 0.76-0.93]) and angiotensin II receptor blockers (RR 0.84 [0.76-0.92]) reduced the risk of new-onset type 2 diabetes; however, the use of beta blockers (RR 1.48 [1.27-1.72]) and thiazide diuretics (RR 1.20 [1.07-1.35]) increased this risk, and no material effect was found for calcium channel blockers (RR 1.02 [0.92-1.13]). Interpretation Blood pressure lowering is an effective strategy for the prevention of new-onset type 2 diabetes. Established pharmacological interventions, however, have qualitatively and quantitively different effects on diabetes, likely due to their differing off-target effects, with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers having the most favourable outcomes. This evidence supports the indication for selected classes of antihypertensive drugs for the prevention of diabetes, which could further refine the selection of drug choice according to an individual's clinical risk of diabetes

Prevalence of Cannabis Lifetime Use in Iranian High School and College Students: A Systematic Review, Meta-Analyses,and Meta-Regression

Cannabis is the most widely used substance in the world. This study aimed to estimate the prevalence of cannabis lifetime use (CLU) in high school and college students of Iran and also to determine factors related to changes in prevalence. A systematic review of literature on cannabis use in Iran was conducted according to MOOSE guideline. Domestic scientific databases, PubMed/Medline, ISI Web of Knowledge, and Google Scholar, relevant reference lists, and relevant journals were searched up to April, 2014. Prevalences were calculated using the variance stabilizing double arcsine transformation and confidence intervals (CIs) estimated using the Wilson method. Heterogeneity was assessed by Cochran's Q statistic and I-2 index and causes of heterogeneity were evaluated using meta-regression model. In electronic database search, 4,000 citations were retrieved, producing a total of 33 studies. CLU was reported with a random effects pooled prevalence of 4.0 (95 CI = 3.0 to 5.0). In subgroups of high school and college students, prevalences were 5.0 (95 CI = 3.0 to -7.0) and 2.0 (95 CI = 2.0 to -3.0), respectively. Meta-regression model indicated that prevalence is higher in college students (beta = 0.089, p < .001), male gender (beta = 0.017, p < .001), and is lower in studies with sampling versus census studies (beta = -0.096, p < .001). This study reported that prevalence of CLU in Iranian students are lower than industrialized countries. In addition, gender, level of education, and methods of sampling are highly associated with changes in the prevalence of CLU across provinces

Fatal Suicide and Modelling its Risk Factors in a Prevalent Area of Iran

Background and objectives: This paper aimed to study the epidemiology of suicide and causes related to fatal suicide in Ilam province, west of Iran. Methods: All data related to attempted suicide and fatal suicide during 2011-2012 were extracted from the suicide registry of authorized directorates in Ilam Province, Iran. Risk factors for fatal suicide were evaluated using logistic regression modeling and discrimination of model assessed using ROC curve. Results: A total of 1537 registered cases were analyzed, among which 130 were recorded as fatal suicides (1227 attempted suicides). Overall, 805 (52.4) cases were female, 9.2 had a history of suicide, 59.3 were married and 63.3 of cases were aged under 24 years. The most common suicide method was overdose of medications (75.5). In multivariable analysis, male gender (OR: 0.50; CI 95 0.25 to 0.99) and higher education (OR: 0.36; CI 95 0.20 to 0.65) were protective factors and application of physical methods (OR: 11.61; 95 CI 5.40 to 24.95) was a risk factor for fatal suicide. Conclusions: Female gender, low education level and use of physical methods of suicide were revealed as risk factors of fatal suicide. We suggest population based case-control studies based on the suicide registry data for further assessing the risk factors of suicide in Ilam

Antihypertensive treatment and risk of cancer: individual participant data meta-analysis of randomized clinical trials

Background: Some studies have suggested a link between antihypertensive medication and cancer, but the evidence is so far inconclusive. Thus, we aimed to investigate this association in a large individual patient data meta-analysis of randomised clinical trials. Methods: We searched PubMed, MEDLINE, The Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from Jan 1, 1966, to Sept 1, 2019, to identify potentially eligible randomised controlled trials. Eligible studies were randomised controlled trials comparing one blood pressure lowering drug class with a placebo, inactive control, or other blood pressure lowering drug. We also required that trials had at least 1000 participant years of follow-up in each treatment group. Trials without cancer event information were excluded. We requested individual participant data from the authors of eligible trials. We pooled individual participant-level data from eligible trials and assessed the effects of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), β blockers, calcium channel blockers, and thiazide diuretics on cancer risk in one-stage individual participant data and network meta-analyses. Cause-specific fixed-effects Cox regression models, stratified by trial, were used to calculate hazard ratios (HRs). The primary outcome was any cancer event, defined as the first occurrence of any cancer diagnosed after randomisation. This study is registered with PROSPERO (CRD42018099283). Findings: 33 trials met the inclusion criteria, and included 260 447 participants with 15 012 cancer events. Median follow-up of included participants was 4·2 years (IQR 3·0–5·0). In the individual participant data meta-analysis comparing each drug class with all other comparators, no associations were identified between any antihypertensive drug class and risk of any cancer (HR 0·99 [95% CI 0·95–1·04] for ACEIs; 0·96 [0·92–1·01] for ARBs; 0·98 [0·89–1·07] for β blockers; 1·01 [0·95–1·07] for thiazides), with the exception of calcium channel blockers (1·06 [1·01–1·11]). In the network meta-analysis comparing drug classes against placebo, we found no excess cancer risk with any drug class (HR 1·00 [95% CI 0·93–1·09] for ACEIs; 0·99 [0·92–1·06] for ARBs; 0·99 [0·89–1·11] for β blockers; 1·04 [0·96–1·13] for calcium channel blockers; 1·00 [0·90–1·10] for thiazides). Interpretation: We found no consistent evidence that antihypertensive medication use had any effect on cancer risk. Although such findings are reassuring, evidence for some comparisons was insufficient to entirely rule out excess risk, in particular for calcium channel blockers. Funding: British Heart Foundation, National Institute for Health Research, Oxford Martin School

Blood pressure lowering and risk of new-onset type 2 diabetes: an individual participant data meta-analysis

Background Blood pressure lowering is an established strategy for preventing microvascular and macrovascular complications of diabetes, but its role in the prevention of diabetes itself is unclear. We aimed to examine this question using individual participant data from major randomised controlled trials. Methods We performed a one-stage individual participant data meta-analysis, in which data were pooled to investigate the effect of blood pressure lowering per se on the risk of new-onset type 2 diabetes. An individual participant data network meta-analysis was used to investigate the differential effects of five major classes of antihypertensive drugs on the risk of new-onset type 2 diabetes. Overall, data from 22 studies conducted between 1973 and 2008, were obtained by the Blood Pressure Lowering Treatment Trialists’ Collaboration (Oxford University, Oxford, UK). We included all primary and secondary prevention trials that used a specific class or classes of antihypertensive drugs versus placebo or other classes of blood pressure lowering medications that had at least 1000 persons-years of follow-up in each randomly allocated arm. Participants with a known diagnosis of diabetes at baseline and trials conducted in patients with prevalent diabetes were excluded. For the one-stage individual participant data meta-analysis we used stratified Cox proportional hazards model and for the individual participant data network meta-analysis we used logistic regression models to calculate the relative risk (RR) for drug class comparisons. Findings 145 939 participants (88 500 [60·6%] men and 57 429 [39·4%] women) from 19 randomised controlled trials were included in the one-stage individual participant data meta-analysis. 22 trials were included in the individual participant data network meta-analysis. After a median follow-up of 4·5 years (IQR 2·0), 9883 participants were diagnosed with new-onset type 2 diabetes. Systolic blood pressure reduction by 5 mm Hg reduced the risk of type 2 diabetes across all trials by 11% (hazard ratio 0·89 [95% CI 0·84–0·95]). Investigation of the effects of five major classes of antihypertensive drugs showed that in comparison to placebo, angiotensin-converting enzyme inhibitors (RR 0·84 [95% 0·76–0·93]) and angiotensin II receptor blockers (RR 0·84 [0·76–0·92]) reduced the risk of new-onset type 2 diabetes; however, the use of β blockers (RR 1·48 [1·27–1·72]) and thiazide diuretics (RR 1·20 [1·07–1·35]) increased this risk, and no material effect was found for calcium channel blockers (RR 1·02 [0·92–1·13]). Interpretation Blood pressure lowering is an effective strategy for the prevention of new-onset type 2 diabetes. Established pharmacological interventions, however, have qualitatively and quantitively different effects on diabetes, likely due to their differing off-target effects, with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers having the most favourable outcomes. This evidence supports the indication for selected classes of antihypertensive drugs for the prevention of diabetes, which could further refine the selection of drug choice according to an individual's clinical risk of diabetes

Blood pressure and risk of venous thromboembolism: a cohort analysis of 5.5 million UK adults and Mendelian randomization studies

AIM: Evidence for the effect of elevated blood pressure on the risk of venous thromboembolism (VTE) has been conflicting. We sought to assess the association between systolic blood pressure and the risk of VTE. METHODS AND RESULTS: Three complementary studies comprising an observational cohort analysis, a one-sample and two-sample Mendelian randomization were conducted using data from 5,588,280 patients registered in the Clinical Practice Research Datalink (CPRD) dataset and 432,173 UK Biobank participants with valid genetic data. Summary statistics of International Network on Venous Thrombosis (INVENT) genome-wide association meta-analysis was used for two-sample Mendelian randomization. The primary outcome was the first occurrence of VTE event, identified from hospital discharge reports, death registers, and/or primary care records. In the CPRD cohort, 104,017 (1.9%) patients had a first diagnosis of VTE during the 9.6-year follow-up. Each 20 mmHg increase in systolic blood pressure was associated with a 7% lower risk of VTE (hazard ratio 0.93, 95% CI [0.92 to 0.94]). Statistically significant interactions were found for sex and body mass index, but not for age and subtype of VTE (pulmonary embolism and deep venous thrombosis). Mendelian randomization studies provided strong evidence for the association between systolic blood pressure and VTE, both in the one-sample (odds ratio [OR]: 0.69 [95% CI 0.57 to 0.83] and two-sample analyses (OR 0.80, 95% CI [0.70 to 0.92]). CONCLUSIONS: We found an increased risk of VTE with lower blood pressure and this association was independently confirmed in two Mendelian randomization analyses. The benefits of blood pressure reduction are likely to outweigh the harms in most patient groups, but in people with predisposing factors for VTE, further blood pressure reduction should be made cautiously. TRANSLATIONAL PERSPECTIVE: In a large-scale population cohort, with over 100,000 first episodes of VTE and a median follow-up of about 10 years, we found a 7% higher risk of VTE for each 20 mmHg lower systolic blood pressure. The association was comparable when we examined pulmonary embolism and deep venous thrombosis separately, and persisted after taking into account age and other factors, including anticoagulant treatment during follow-up. These results were confirmed using two independent Mendelian randomization studies. Although the beneficial effects of blood pressure-lowering are likely to outweigh any harms in most patient groups, clinicians should be aware of the potential risk of VTE from antihypertensive therapy, in particular in people who have predisposing factors for VTE