Total Major Cardiovascular Events Research Articles

Total events and net clinical benefit of rivaroxaban and aspirin in patients with chronic coronary or peripheral artery disease: The COMPASS trial

Low dose rivaroxaban with aspirin reduced major cardiovascular events (MACE) compared to aspirin alone in patients with cardiovascular disease although effects on total events are unknown. The COMPASS clinical trial randomized 27,395 participants with chronic coronary and/or peripheral artery disease to rivaroxaban 2.5 mg twice daily plus aspirin 100 mg daily, rivaroxaban 5 mg twice daily alone, or aspirin 100 mg daily. We analyzed total (first and recurrent) MACE outcomes of cardiovascular death, stroke, or myocardial infarction, and the primary safety outcome of major bleeding. Exploratory analyses included on-treatment and net clinical benefit. Total MACE and safety events were modeled for each treatment. MACE events were lowest in rivaroxaban with aspirin (379 first MACE, 432 total MACE) compared with rivaroxaban (448 first, 508 total) or aspirin alone (496 first, 574 total). Rivaroxaban and aspirin reduced total MACE events compared with aspirin alone [HR 0.75, 95% CI 0.66-0.85, P < .0001, number needed to treat for 2 years (NNT2y) of 63]. Total major bleeding was higher for rivaroxaban with aspirin compared to aspirin, but severe bleeding was not increased. The net clinical benefit of rivaroxaban plus aspirin was 20% higher compared with aspirin alone [HR 0.80 (95% CI 16.3%-31.6%)]. Rivaroxaban alone had no benefit on MACE outcomes compared with aspirin alone. MACE outcomes were similar for those on and off randomized treatment. Low dose rivaroxaban with aspirin significantly reduces first and total cardiovascular events compared with aspirin alone with a NNT2y of 63 and a 20% net clinical benefit. NCT01776424. https://clinicaltrials.gov/ct2/show/NCT01776424.

IDF21-0652 Blood pressure-lowering for prevention of major cardiovascular diseases in persons with and without type 2 diabetes

Background: There is insufficient randomised evidence as to whether the effect of blood pressure (BP)-lowering treatment differs in people with type 2 diabetes versus those without this metabolic condition, particularly at a normal or high-normal BP level. Aim: To investigate the effects of BP-lowering treatment on the risk of major cardiovascular events in people with and without type 2 diabetes, and by baseline levels of systolic and diastolic BP. Method: We used the resource provided by the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC) to conduct a one-stage individual participant data meta-analysis of major randomised trials. The primary outcome was total major cardiovascular events, defined as the first occurrence of fatal or non-fatal stroke or cerebrovascular disease, fatal or non-fatal myocardial infarction, and heart failure causing death or requiring hospitalisation. The analysis was stratified for type 2 diabetes status at baseline, and baseline categories of systolic BP (in 10 mm Hg increments from <120 mm Hg to ≥170 mm Hg) and diastolic BP from <70 mm Hg to ≥110 mm Hg diastolic). Cox proportional hazard model stratified by the trial was used to estimate hazard ratio (HR). A Poisson regression model with an identity link was used to calculate the absolute risk reduction (ARR). Results: Data for 358,533 participants (58.4% men) from 51 randomised clinical trials were included in the analysis, in which 28.8% (n=103,325) of the participants had diagnosis of type 2 diabetes at baseline. Baseline mean systolic/diastolic BPs were 149/84 mm Hg in participants with type 2 diabetes (n=103,325) and 153/88 mm Hg in participants without type 2 diabetes (n=255,208). The incidence risks of primary events during the study follow-up time in participants with and without type 2 diabetes were 16.5% and 10.2%, respectively. Over 4.2 years of median follow-up, a fixed value of 5-mm Hg reduction in systolic BP was associated with a lower risk of major cardiovascular events both in participants with type 2 diabetes (HR 0.94 [95% CI 0.91 to 0.98]; ARR -0.015 [95% CI -0.020 to -0.010]) and in those without history of type 2 diabetes (HR 0.89 [95% CI 0.87 to 0.92]; ARR =-0.016 [95% CI -0.018 to -0.013]). In stratified analyses, we did not find reliable evidence for heterogeneity of treatment effects by baseline systolic or diastolic BP level in participants with or without type 2 diabetes (all P for interaction > 0.78). Discussion: The effect of BP reduction for primary and secondary prevention of major cardiovascular events was broadly comparable among people with and without type 2 diabetes, with no clinically important evidence that the level of systolic or diastolic BP at baseline is a determinant of treatment effect. Recommendations by guidelines on different BP reduction treatment in people with and without diabetes, or initiation of BP reduction therapy at a specific BP threshold, are not substantiated by these findings. This work will be presented on behalf of the Blood Pressure Lowering Treatment Trialists' Collaboration. Working group: Milad Nazarzadeh, Zeinab Bidel, Dexter Canoy, Emma Copland, Abbas Dehghan, Derrick A Bennett, George Davey Smith, Rury R. Holman, Mark Woodward, Ajay Gupta, Amanda Adler, Naveed Sattar, Richard J McManus, Koon Teo, Barry R Davis, John Chalmers, Carl J. Pepine, Kazem Rahimi.

Impact of active and stable cancer on survival in patients undergoing percutaneous coronary intervention

Abstract Background With advances in treatment of ischemic heart disease and cancer treatment, use of percutaneous coronary intervention (PCI) in cancer survivors and patients with active cancer (AC) is expanding. Objectives The purpose of this study was to determine the impact of cancer on survival and major cardiovascular events (MACE) in a long-term, single-center cohort of patients treated with PCI. Methods Patients treated with PCI between January 2010 and December 2017 were grouped as follows: controls (patients without cancer), stable cancer (SC), and AC. AC was included patients with cancer diagnosed within the past 6 months, patients who had cancer-related therapy within the past 6 months, active metastatic disease, or active recurrence of the cancer. The primary endpoints were 5-year survival and a secondary endpoint was 5-year MACE. Results A total of 6,743 patients (age 66±12 years, 68.4% men) treated with PCI were included: 6,404 (95.0%) controls, 245 (3.6%) SC, and 94 (1.4%) AC. Predominant malignancies were gastrointestinal (37.4%), lung (22.7%), and genitourinary cancer (14.7%). No differences were observed between patients with AC, SC and controls regarding 5-year MACE (total MACE, 33.2% vs. 28.1% vs. 17.5%, p=0.072; cardiac death, 13.6% vs. 9.1% vs. 6.7%, p=0.066; non-fatal myocardial infarction, 2.9% vs. 7.5% vs. 7.8%, p=0.820; revascularization, 17.9% vs. 17.6% vs. 11.6%, p=0.794, respectively). Patients with AC and SC had reduced 5-year survival compared with controls (62.0% vs. 81.5% vs. 89.8%, p&amp;lt;0.001) (Figure). AC was associated with a 1.76 (95% CI 1.22 to 2.54, p=0.002) fold increased risk of all-cause 5-year mortality in multivariable adjusted models. Conclusions Cumulative incidence of 5-year survival was discriminated by concurrent status of cancer following PCI. Individualized decision making is needed in the routine practice of PCI regarding concurrent cancer-specific treatment and prognosis. Funding Acknowledgement Type of funding sources: None.

Effects of renin-angiotensin system blockers on renal and cardiovascular outcomes in patients with diabetic nephropathy: a meta-analysis of randomized controlled trials.

This study aimed to evaluate the effect f angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) on renal or cardiovascular outcomes in patients with diabetic nephropathy (DN). PubMed, Embase, and Cochrane Library were searched for randomized controlled trials (RCTs) evaluating the treatment effects of ACEI and ARB on renal or cardiovascular outcomes in patients with DN until August 2017. The outcomes included end-stage renal disease (ESRD), doubling of serum creatinine levels, all-cause mortality, major cardiovascular events (MACEs), myocardial infarction (MI), stroke, and cardiac death. Relative risks (RR) with 95% confidence intervals (CIs) were used for calculating the summary results using a random-effects model. Twenty-four RCTs including 57,818 patients with DN and 891 events of ESRD, 1050 doubling of serum creatinine concentration, 4352 all-cause mortality, 6342 MACEs, 1073 MI, 2900 stroke, and 1674 cardiac deaths were reported. Overall, the summary results suggested that in patients with DN, receiving ACEI did not have a significant effect on ESRD, doubling of serum creatinine levels, all-cause mortality, MI, stroke, and cardiac death, while ACEI significantly reduced the risk of total MACEs. Furthermore, ARB therapy was associated with a low risk of ESRD and doubling of serum creatinine levels, while it did not differ significantly on all-cause mortality, MACEs, MI, stroke, and cardiac death in patients with DN. Patients with DN receiving ACEI had significantly reduced the risk of total MACEs, and ARB could reduce the incidence of ESRD and the doubling of serum creatinine levels.

Relationship Between Serum B7-H3 Levels and Prognosis of Congenital Heart Disease in Children.

The aim of this study was to investigate the role of B7-H3 in prognosis of congenital heart disease (CHD) children patients. A total of 65 CHD patients within age 3-12 years who went to our hospital were included during August 2011 to December 2012. Demographic data including age, sex, weight, clinical basic information such as New York Heart Association (NYHA) class, pathological type were collected. Blood samples were collected and serum levels of B7-H3, C-reactive protein (CRP), N-Terminal Pro-Brain Natriuretic Peptide (NT-pro-BNP), and High-sensitivity Troponin T (hsTnT) were determined by enzyme-linked immunosorbent assay (ELISA). Characteristics including age, gender, weight, pathological type, NYHA class, and serum levels of hsTnT and CRP showed no significant difference between deceased and survival patients. However, serum levels of B7-H3 and NT-pro-BNP were significantly higher in deceased patients compared survival patients. Patients with high expressed B7-H3 had higher risks for total major cardiovascular events (MACE) occurrence compared with the lower group. Among the MACE events, significant difference was observed in rates of death, new onset of arrhythmias, and surgical, but not in NYHA class worsening and percutaneous intervention. Patients with higher levels if B7-H3 had significantly higher risk for mortality in the 5-year follow-up compared with the lower group, logic analysis was also conducted and results showed that B7-H3 might be an independent risk factor for 5-year mortality for CHD patients. B7-H3 was up-regulated in dead CHD patients, and serum levels of B7-H3 were related to long-term MACE and 5-year mortality of CHD patients.

Rationale, design, and baseline characteristics of the Salt Substitute and Stroke Study (SSaSS)—A large-scale cluster randomized controlled trial

Lowering sodium intake with a reduced-sodium, added potassium salt substitute has been proved to lower blood pressure levels. Whether the same strategy will also reduce the risks of vascular outcomes is uncertain and controversial. The SSaSS has been designed to test whether sodium reduction achieved with a salt substitute can reduce the risk of vascular disease. The study is a large-scale, open, cluster-randomized controlled trial done in 600 villages across 5 provinces in China. Participants have either a history of stroke or an elevated risk of stroke based on age and blood pressure level at entry. Villages were randomized in a 1:1 ratio to intervention or continued usual care. Salt substitute is provided free of charge to participants in villages assigned to the intervention group. Follow-up is scheduled every 6months for 5years, and all potential endpoints are reviewed by a masked adjudication committee. The primary end point is fatal and nonfatal stroke, and the 2 secondary endpoints are total major cardiovascular events and total mortality. The study has been designed to provide 90% statistical power (with 2-sided α = .05) to detect a 13% or greater relative risk reduction for stroke. The power estimate assumes a primary outcome event rate of 3.5% per year and a systolic blood pressure difference of 3.0mm Hg between randomized groups. Recruitment is complete and there are 20,996 participants (about 35 per village) that have been enrolled. Mean age is 65years and 49% are female. There were 73% enrolled on the basis of a history of stroke. The trial is well placed to describe the effects of salt substitution on the risks of vascular disease and death and will provide important policy-relevant data.

Research in brief

Initiating type 2 diabetes glucose-lowering treatment with medications other than metformin could lead to an increased risk of treatment intensification, suggest the authors of a cohort study. With use of information from a US national health insurance database, researchers reviewed data for 15 516 individuals who received prescriptions for oral anti-hyperglycaemic drugs. 8964 (58%) of 15 516 individuals initiated glucose-lowering therapy with metformin. Sulfonylureas were the second most common drug class with which to initiate treatment, despite being associated with an increased risk of hypoglycaemia (hazard ratio 2·71, 95% CI 1·58–4·66) and congestive cardiac failure (1·19, 1·10–1·28). Compared with metformin, starting type 2 diabetes treatment with a sulfonylurea, thiazolidinedione, or DPP-4 inhibitor was more likely to lead to the addition of further medication (p<0·001). Whether the effect of lowering blood pressure on cardiovascular risk varies according to drug class in obese individuals is the topic of a recent meta-analysis. Individual patient data for 135 715 people included in 22 trials were analysed by researchers. The composite primary outcome of total major cardiovascular events (n=14 353) did not differ according to drug class between the normal weight, overweight, or obese groups. Using BMI as a continuous variable, angiotensin-converting enzyme inhibitors were associated with a lower risk of major cardiovascular events than diuretics (hazard ratio 0·93, 95% CI 0·89–0·98) or calcium channel antagonists (0·93, 95% CI 0·89–0·98) per 5 kg/m2 higher BMI. However, the authors note that “the data do not provide a strong case for a change in clinical practice, such that particular drug classes are directed specifically towards obese patients”. New research provides insight into the response of white adipose tissue in humans to seasonality and cold stimulus. With the use of subcutaneous adipose tissue samples from the thigh or abdomen of 71 generally healthy participants, gene expression was assessed by researchers. Compared with abdominal adipose tissue samples obtained in summer, samples obtained in winter had higher levels of UCP1 and PGC1 A mRNAs, and increased expression of other genes implicated in lipolysis and energy utilisation (p<0·05). The effect of seasonality on UCP1 mRNA was diminished in obese individuals. Subcutaneous adipose tissue samples obtained from the thighs of seven participants after acute exposure to cold stimulus in summer had 2·7-times higher levels of PGC1α mRNA compared with unexposed samples (p=0·015). The InterAct Consortium underlines the importance of smoking cessation for prevention of type 2 diabetes in their latest publication. With the use of data from the multicentre EPIC-InterAct study, the risk of diabetes attributed to smoking was calculated. 10 327 individuals with incident type 2 diabetes and 13 863 subcohort individuals (676 cases of incident diabetes) were included in the calculations. In analyses adjusted for age, education, and lifestyle, the risk of developing diabetes in men was higher in former (hazard ratio 1·40, 95% CI 1·26–1·55) and current smokers (1·43, 1.27–1·61) compared with non-smokers. Smoking imparted risks for diabetes in women as well, albeit at a lower level. Ornstrup and colleagues have investigated the effect of resveratrol on bone in a small placebo-controlled trial. In the 16-week single-centre study, 74 obese men with metabolic syndrome were randomly assigned to receive oral placebo, resveratrol 1 g daily, or resveratrol 150 mg daily. At week 16, the group receiving 1 g resveratrol daily had a higher percentage change in bone alkaline phosphatase from baseline compared with placebo (difference 15·2%, SD 3·7%, p<0·001). The effect of resveratrol on bone alkaline phosphatase was dose-dependent. Lumbar spine trabecular volumetric bone mineral density increased in the high dose resveratrol group compared with placebo (p=0·043). The authors propose that additional studies in people at risk of osteoporosis should be done. In a 24-week double-blind trial, Rosenstock and colleagues investigated a triple therapy strategy for treatment intensification in individuals with type 2 diabetes who had poor glycaemic control with metformin alone. Patients were randomly assigned to add-on therapy with saxagliptin (n=176), dapagliflozin (n=179), or both (n=179). The change in HbA1c from baseline in the triple therapy group was −1·5%, compared with −1·2% in the dapagliflozin group (treatment difference −0·27%, 95% CI −0·48% to −0·05%, p=0·0166) and −0·9% in the saxagliptin group (treatment difference −0·59%, −0·81% to −0·37%, p<0·0001). Longer-term studies are needed to adequately assess the sustainability of glycaemic control and safety of triple therapy.

Effects of blood pressure lowering on cardiovascular risk according to baseline body-mass index: a meta-analysis of randomised trials

The cardiovascular benefits of blood pressure lowering in obese people compared with people of normal weight might depend on choice of drug. We compared the effects of blood pressure-lowering regimens on cardiovascular risk in groups of patients categorised by baseline body-mass index (BMI). We used individual patient data from trials included in the Blood Pressure Lowering Treatment Trialists' Collaboration to compare the effects of different classes of blood pressure-lowering regimens for the primary outcome of total major cardiovascular events (stroke, coronary heart disease, heart failure, and cardiovascular death). We used meta-analyses and meta-regressions to assess interactions between treatment and BMI when fitted as either a categorical variable (<25 kg/m(2), 25 to <30 kg/m(2), and ≥30 kg/m(2)) or a continuous variable. Analyses were based on 135,715 individuals from 22 trials who had 14,353 major cardiovascular events. None of the six primary comparisons showed evidence that protection varied by drug class across the three BMI groups (all p for trend >0·20). When analysed as a continuous variable, angiotensin-converting-enzyme inhibitors gave slightly greater protection for each 5 kg/m(2) higher BMI than did calcium antagonists (hazard ratio 0·93, 95% CI 0·89-0·98; p=0·004) or diuretics (0·93, 0·89-0·98; p=0·002). The meta-regressions showed no relation between BMI category and the risk reduction for a given fall in systolic blood pressure. By contrast with a previous report, we noted no relation between BMI and the efficacy of calcium antagonists compared with diuretics. We found little evidence that selection of a particular class of blood pressure-lowering drug will lead to substantially different outcomes for individuals who are obese compared with those who are lean. None.

Blood pressure-lowering treatment based on cardiovascular risk: a meta-analysis of individual patient data

We aimed to investigate whether the benefits of blood pressure-lowering drugs are proportional to baseline cardiovascular risk, to establish whether absolute risk could be used to inform treatment decisions for blood pressure-lowering therapy, as is recommended for lipid-lowering therapy. This meta-analysis included individual participant data from trials that randomly assigned patients to either blood pressure-lowering drugs or placebo, or to more intensive or less intensive blood pressure-lowering regimens. The primary outcome was total major cardiovascular events, consisting of stroke, heart attack, heart failure, or cardiovascular death. Participants were separated into four categories of baseline 5-year major cardiovascular risk using a risk prediction equation developed from the placebo groups of the included trials (<11%, 11-15%, 15-21%, >21%). 11 trials and 26 randomised groups met the inclusion criteria, and included 67,475 individuals, of whom 51,917 had available data for the calculation of the risk equations. 4167 (8%) had a cardiovascular event during a median of 4·0 years (IQR 3·4-4·4) of follow-up. The mean estimated baseline levels of 5-year cardiovascular risk for each of the four risk groups were 6·0% (SD 2·0), 12·1% (1·5), 17·7% (1·7), and 26·8% (5·4). In each consecutive higher risk group, blood pressure-lowering treatment reduced the risk of cardiovascular events relatively by 18% (95% CI 7-27), 15% (4-25), 13% (2-22), and 15% (5-24), respectively (p=0·30 for trend). However, in absolute terms, treating 1000 patients in each group with blood pressure-lowering treatment for 5 years would prevent 14 (95% CI 8-21), 20 (8-31), 24 (8-40), and 38 (16-61) cardiovascular events, respectively (p=0·04 for trend). Lowering blood pressure provides similar relative protection at all levels of baseline cardiovascular risk, but progressively greater absolute risk reductions as baseline risk increases. These results support the use of predicted baseline cardiovascular disease risk equations to inform blood pressure-lowering treatment decisions. None.

Do men and women respond differently to blood pressure-lowering treatment? Results of prospectively designed overviews of randomized trials

Large-scale observational studies show that lower blood pressure is associated with lower cardiovascular risk in both men and women although some studies have suggested that different outcomes between the sexes may reflect different responses to blood pressure-lowering treatment. The aims of these overview analyses were to quantify the effects of blood pressure-lowering treatment in each sex and to determine if there are important differences in the proportional benefits of treatment between men and women. Thirty-one randomized trials that included 103,268 men and 87,349 women contributed to these analyses. For each outcome and each comparison summary estimates of effect and 95% confidence intervals were calculated for men and women using a random-effects model. The consistency of the effects of each treatment regimen across the sexes was examined using chi(2) tests of homogeneity. Achieved blood pressure reductions were comparable for men and women in every comparison made. For the primary outcome of total major cardiovascular events there was no evidence that men and women obtained different levels of protection from blood pressure lowering or that regimens based on angiotensin-converting-enzyme inhibitors, calcium antagonists, angiotensin receptor blockers, or diuretics/beta-blockers were more effective in one sex than the other (all P-homogeneity > 0.08). All of the blood pressure-lowering regimens studied here provided broadly similar protection against major cardiovascular events in men and women. Differences in cardiovascular risks between sexes are unlikely to reflect differences in response to blood pressure-lowering treatments.

Effects of different regimens to lower blood pressure on major cardiovascular events in older and younger adults: meta-analysis of randomised trials

Objective To quantify the relative risk reductions achieved with different regimens to lower blood pressure in younger and older adults.Design Meta-analyses and meta-regression analyses used to compare the effects on...

Revival of nifedipine, a dihydropyridine-based calcium blocker

A recent analysis by the Blood Pressure Lowering Treatment Trialists' Collaboration revealed that any commonly-used blood pressure (BP)-lowering regimen reduced the risk of total major cardiovascular events, and larger reductions in BP produced larger reductions in the risk. These observations suggest that most of the differences among treatment regimens in their effects on cardiovascular outcomes could be explained by the differences in achieved BP level. However, it may also be true that some treatment regimen is superior or inferior to others with regard to the risk reduction of cardiovascular events. Indeed, the data from dihydropyridine-based calcium antagonist (DHP) trails are consistent in that they could not protect against new-onset heart failure or progression of renal disease in patients with left-ventricular systolic dysfunction or overt proteinuria, respectively. However, a multicenter, randomized, placebo-controlled, double-blind ACTION trial, which compared the effect of long-acting nifedipine or placebo on mortality and cardiovascular morbidity in patients with stable angina, revealed that nifedipine reduced the risk for new-onset overt heart failure by 29%. Further, an open-label, randomized prospective J-MIND trial, which compared the effect of long-acting nifedipine or enalapril, an angiotensin-converting enzyme inhibitor on onset and progression of nephropathy in hypertensive patients with type 2 diabetes, showed that long-acting nifedipine had an equipotent reoprotective effect on diabetic nephropathy. In this paper, we would like to propose our hypothesis that nifedipine may be unique and superior in its effects on heart failure and proteinuria compared with various DHPs. For ensuring our hypothesis, the following clinical issues would be addressed. Does nifedipine treatment alone decrease the progression of renal disease with overt proteinuria? If these answers are yes, are these beneficial effects of nifedipine superior to that of other DHPs with equihypotensive properties? Does nifedipine treatment also reduce oxidative stress markers? Are these unique effects of nifedipine correlated with its anti-oxidative properties? These prospective studies will provide further valuable information whether nifedipine may be a preferred DHP to achieve BP goals in hypertensive patients with systolic dysfunction or overt proteinuria.

Antihypertensive therapy in patients with metabolic syndrome

It is amply recognized that the presence of metabolic syndrome is associated with subclinical cardiac, vascular and kidney damage, with an increased risk for cardiovascular and cerebrovascular disease and type 2 diabetes, and, as a consequence, with higher rates of cardiovascular mortality. Metabolic syndrome can be considered as a prediabetic state very frequently associated with arterial hypertension, requiring pharmacological therapy. All antihypertensive therapies have been shown to reduce the risk of total major cardiovascular events. Recently, the relevance of the type of hypertensive therapy used to treat hypertensive patients in facilitating the development of diabetes has been demonstrated in different trials. The recognition of the risk present in hypertensive patients with metabolic syndrome for developing diabetes reinforces the need to consider the ideal antihypertensive therapy, either mono or combination, in these patients. This brief review contains the available evidence showing that an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker is the most suitable therapy to be started in these patients, alone or in combination, due to their capacity to prevent or retard the development of diabetes, and the strong relationship between metabolic syndrome and arterial hypertension, focusing on the advantages and disadvantages of different antihypertensive drugs.

Effects of Different Blood Pressure–Lowering Regimens on Major Cardiovascular Events in Individuals With and Without Diabetes Mellitus

Blood pressure (BP) level is a major determinant of cardiovascular morbidity and mortality in individuals with diabetes mellitus. Several guidelines recommend lower BP goals and specific drug classes for these patients. The overviews reported herein were performed to formally compare the effects on cardiovascular events and death of different BP-lowering regimens in individuals with and without diabetes. Twenty-seven randomized trials (N = 158 709 participants) that included 33 395 individuals with diabetes and 125 314 without diabetes contributed to these analyses. For each outcome and each comparison summary, estimates of effect and 95% confidence intervals were calculated for patients with and without diabetes using a random-effects model. The constancy of the effects of each treatment regimen in participants with and without diabetes was examined using chi(2) tests of homogeneity. Total major cardiovascular events were reduced to a comparable extent in individuals with and without diabetes by regimens based on angiotensin-converting enzyme inhibitors, calcium antagonists, angiotensin receptor blockers, and diuretics/beta-blockers (P > .19 for all by chi(2) test of homogeneity). There was limited evidence that lower BP goals produced larger reductions in total major cardiovascular events in individuals with vs without diabetes (P = .03 by chi(2) test of homogeneity). These overviews showed that the short- to-medium-term effects on major cardiovascular events of the BP-lowering regimens studied were broadly comparable for patients with and without diabetes. Different effects of regimens on intermediate renal outcomes not evaluated in these overviews may still provide a rationale for using specific drug classes in patients with diabetes.

Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials

The benefits of reducing blood pressure on the risks of major cardiovascular disease are well established, but uncertainty remains about the comparative effects of different blood-pressure-lowering regimens. We aimed to estimate effects of strategies based on different drug classes (angiotensin-converting-enzyme [ACE] inhibitors, calcium antagonists, angiotensin-receptor blockers [ARBs], and diuretics or beta blockers) or those targeting different blood pressure goals, on the risks of major cardiovascular events and death. We did seven sets of prospectively-designed overviews with data from 29 randomised trials (n=162341). The trial eligibility criteria, primary outcomes, and main hypotheses were specified before the result of any contributing trial was known. In placebo-controlled trials the relative risks of total major cardiovascular events were reduced by regimens based on ACE inhibitors (22%; 95% CI 17-27) or calcium antagonists (18%; 5-29). Greater risk reductions were produced by regimens that targeted lower blood pressure goals (15%; 5-24). ARB-based regimens reduced the risks of total major cardiovascular events (10%; 4-17) compared with control regimens. There were no significant differences in total major cardiovascular events between regimens based on ACE inhibitors, calcium antagonists, or diuretics or beta blockers, although ACE-inhibitor-based regimens reduced blood pressure less. There was evidence of some differences between active regimens in their effects on cause-specific outcomes. For every outcome other than heart failure, the difference between randomised groups in achieved blood pressure reduction was directly related to the observed difference in risk. Treatment with any commonly-used regimen reduces the risk of total major cardiovascular events, and larger reductions in blood pressure produce larger reductions in risk.

The PROGRESS study

Patients with a history of cerebrovascular disease have a very high risk of stroke, and usual levels of both systolic and diastolic blood pressure are directly and continuously associated with this risk. Trials of blood pressure lowering in patients with transient ischaemic attacks or stroke have been too small to reliably detect the effects on stroke risk of the modest blood pressure reductions achieved. The primary objective of PROGRESS is to determine precisely the effects of blood pressure reduction with an angiotensin converting enzyme (ACE) inhibitor-based regimen on the stroke risk in patients with a history of transient ischaemic attacks or minor stroke. The study is a randomized, double-blind, placebo-controlled clinical trial. Before randomization, there is a 4-week run-in phase on open-label ACE inhibitor treatment. The scheduled duration of treatment and follow-up is 4-5 years. The study will be conducted in collaborating clinical centres in Australia, Belgium, the People's Republic of China, France, Italy, Japan, New Zealand, Sweden and the United Kingdom. The study will involve 6000 patients with a history of transient ischaemic attacks or stroke (ischaemic or haemorrhagic) in the past 5 years. To be eligible patients should have no definite indication for or contra-indication to treatment with an ACE inhibitor and no disability likely to prevent regular attendance at study clinics. Study treatment will comprise perindopril and indapamide or matching placebos for patients without an indication for or contra-indication to treatment with a diuretic, perindopril alone or matching placebo for all other patients. The primary study outcome is total strokes and secondary outcomes include fatal or disabling strokes, total major cardiovascular events, cardiovascular deaths, cognitive function and dementia, and disability and dependency.