Effects of off-pump and on-pump coronary-artery bypass grafting at 1 year.

BACKGROUND: Previously, we reported that there was no significant difference at 30 days in the rate of a primary composite outcome of death, myocardial infarction, stroke, or new renal failure requiring dialysis between patients who underwent coronary-artery bypass grafting (CABG) performed with a beating-heart technique (off-pump) and those who underwent CABG performed with cardiopulmonary bypass (on-pump). We now report results on quality of life and cognitive function and on clinical outcomes at 1 year. METHODS: We enrolled 4752 patients with coronary artery disease who were scheduled to undergo CABG and randomly assigned them to undergo the procedure off-pump or on-pump. Patients were enrolled at 79 centers in 19 countries. We assessed quality of life and cognitive function at discharge, at 30 days, and at 1 year and clinical outcomes at 1 year. RESULTS: At 1 year, there was no significant difference in the rate of the primary composite outcome between off-pump and on-pump CABG (12.1% and 13.3%, respectively; hazard ratio with off-pump CABG, 0.91; 95% confidence interval [CI], 0.77 to 1.07; P=0.24). The rate of the primary outcome was also similar in the two groups in the period between 31 days and 1 year (hazard ratio, 0.79; 95% CI, 0.55 to 1.13; P=0.19). The rate of repeat coronary revascularization at 1 year was 1.4% in the off-pump group and 0.8% in the on-pump group (hazard ratio, 1.66; 95% CI, 0.95 to 2.89; P=0.07). There were no significant differences between the two groups at 1 year in measures of quality of life or neurocognitive function. CONCLUSIONS: At 1 year after CABG, there was no significant difference between off-pump and on-pump CABG with respect to the primary composite outcome, the rate of repeat coronary revascularization, quality of life, or neurocognitive function. (Funded by the Canadian Institutes of Health Research; CORONARY ClinicalTrials.gov number, NCT00463294.).

Vorapaxar in the secondary prevention of atherothrombotic events.

BACKGROUND: Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1. METHODS: We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage. RESULTS: At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P=0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001). CONCLUSIONS: Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.).

Off-pump or on-pump coronary-artery bypass grafting at 30 days.

BACKGROUND: The relative benefits and risks of performing coronary-artery bypass grafting (CABG) with a beating-heart technique (off-pump CABG), as compared with cardiopulmonary bypass (on-pump CABG), are not clearly established. METHODS: At 79 centers in 19 countries, we randomly assigned 4752 patients in whom CABG was planned to undergo the procedure off-pump or on-pump. The first coprimary outcome was a composite of death, nonfatal stroke, nonfatal myocardial infarction, or new renal failure requiring dialysis at 30 days after randomization. RESULTS: There was no significant difference in the rate of the primary composite outcome between off-pump and on-pump CABG (9.8% vs. 10.3%; hazard ratio for the off-pump group, 0.95; 95% confidence interval [CI], 0.79 to 1.14; P=0.59) or in any of its individual components. The use of off-pump CABG, as compared with on-pump CABG, significantly reduced the rates of blood-product transfusion (50.7% vs. 63.3%; relative risk, 0.80; 95% CI, 0.75 to 0.85; P<0.001), reoperation for perioperative bleeding (1.4% vs. 2.4%; relative risk, 0.61; 95% CI, 0.40 to 0.93; P=0.02), acute kidney injury (28.0% vs. 32.1%; relative risk, 0.87; 95% CI, 0.80 to 0.96; P=0.01), and respiratory complications (5.9% vs. 7.5%; relative risk, 0.79; 95% CI, 0.63 to 0.98; P=0.03) but increased the rate of early repeat revascularizations (0.7% vs. 0.2%; hazard ratio, 4.01; 95% CI, 1.34 to 12.0; P=0.01). CONCLUSIONS: There was no significant difference between off-pump and on-pump CABG with respect to the 30-day rate of death, myocardial infarction, stroke, or renal failure requiring dialysis. The use of off-pump CABG resulted in reduced rates of transfusion, reoperation for perioperative bleeding, respiratory complications, and acute kidney injury but also resulted in an increased risk of early revascularization. (Funded by the Canadian Institutes of Health Research; CORONARY ClinicalTrials.gov number, NCT00463294.).

Dronedarone in high-risk permanent atrial fibrillation.

BACKGROUND: Dronedarone restores sinus rhythm and reduces hospitalization or death in intermittent atrial fibrillation. It also lowers heart rate and blood pressure and has antiadrenergic and potential ventricular antiarrhythmic effects. We hypothesized that dronedarone would reduce major vascular events in high-risk permanent atrial fibrillation. METHODS: We assigned patients who were at least 65 years of age with at least a 6-month history of permanent atrial fibrillation and risk factors for major vascular events to receive dronedarone or placebo. The first coprimary outcome was stroke, myocardial infarction, systemic embolism, or death from cardiovascular causes. The second coprimary outcome was unplanned hospitalization for a cardiovascular cause or death. RESULTS: After the enrollment of 3236 patients, the study was stopped for safety reasons. The first coprimary outcome occurred in 43 patients receiving dronedarone and 19 receiving placebo (hazard ratio, 2.29; 95% confidence interval [CI], 1.34 to 3.94; P=0.002). There were 21 deaths from cardiovascular causes in the dronedarone group and 10 in the placebo group (hazard ratio, 2.11; 95% CI, 1.00 to 4.49; P=0.046), including death from arrhythmia in 13 patients and 4 patients, respectively (hazard ratio, 3.26; 95% CI, 1.06 to 10.00; P=0.03). Stroke occurred in 23 patients in the dronedarone group and 10 in the placebo group (hazard ratio, 2.32; 95% CI, 1.11 to 4.88; P=0.02). Hospitalization for heart failure occurred in 43 patients in the dronedarone group and 24 in the placebo group (hazard ratio, 1.81; 95% CI, 1.10 to 2.99; P=0.02). CONCLUSIONS: Dronedarone increased rates of heart failure, stroke, and death from cardiovascular causes in patients with permanent atrial fibrillation who were at risk for major vascular events. Our data show that this drug should not be used in such patients. (Funded by Sanofi-Aventis; PALLAS ClinicalTrials.gov number, NCT01151137.).

Rationale and design of the coronary artery bypass grafting surgery off or on pump revascularization study: a large international randomized trial in cardiac surgery.

BACKGROUND: Uncertainty remains regarding the benefits and risks of the technique of operating on a beating heart (off pump) for coronary artery bypass grafting (CABG) surgery versus on-pump CABG. Prior trials had few events and relatively short follow-up. There is a need for a large randomized, controlled trial with long-term follow-up to inform both the short- and long-term impact of the 2 approaches to CABG. METHODS: We plan to randomize 4,700 patients in whom CABG is planned to undergo the procedure on pump or off pump. The coprimary outcomes are a composite of total mortality, myocardial infarction (MI), stroke, and renal failure at 30 days and a composite of total mortality, MI, stroke, renal failure, and repeat revascularization at 5 years. We will also undertake a cost-effectiveness analysis at 30 days and 5 years after CABG surgery. Other outcomes include neurocognitive dysfunction, recurrence of angina, cardiovascular mortality, blood transfusions, and quality of life. RESULTS: As of May 3, 2011, CORONARY has recruited >3,884 patients from 79 centers in 19 countries. Currently, patient's mean age is 67.6 years, 80.7% are men, 47.0% have a history of diabetes, 51.4% have a history of smoking, and 34.4% had a previous MI. In addition, 20.9% of patients have a left main disease, and 96.6% have double or triple vessel disease. CONCLUSIONS: CORONARY is the largest trial yet conducted comparing off-pump CABG to on-pump CABG. Its results will lead to a better understanding of the safety and efficacy of off-pump CABG.

Stroke risk and efficacy of apixaban in atrial fibrillation patients with moderate chronic kidney disease.

BACKGROUND: Apixaban is superior to aspirin for the prevention of stroke in patients with atrial fibrillation. Apixaban is partially renally excreted and may accumulate in patients with renal impairment. METHODS: We evaluated the efficacy and safety of apixaban 5 mg twice daily (2.5 mg twice daily in selected patients) compared with aspirin 81 to 324 mg daily in 1697 patients with stage III chronic kidney disease (CKD) enrolled in the Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial. Primary outcome was all stroke and non-central nervous system emboli. RESULTS: Compared with patients with estimated glomerular filtration rates (eGFRs) ≥60 mL/min per 1.73 m2, stage III CKD patients (n = 1697; 30% of the cohort; mean eGFR 49 mL/min per 1.73 m2) were older (mean age 75 v 68 years) with more frequent hypertension, diabetes, heart failure, and previous stroke (all P < .01). Stage III CKD was an independent predictor of primary events (hazard ratio [HR] 1.6; P = .01) and major hemorrhage (HR 2.2; P = .02). Apixaban significantly reduced primary events by 68% (5.6% per year on aspirin v 1.8% per year on apixaban; HR 0.32; 95% confidence interval [CI] 0.18-0.55; P < .001) for stage III CKD participants and by 43% (2.8% per year on aspirin v 1.6% per year on apixaban; HR 0.57; 95% CI 0.37-0.87; P = .009) for patients with eGFRs ≥60 mL/min per 1.73 m2 (P for interaction = .10). There was no significant difference in major hemorrhage in stage III CKD patients by treatment: 2.2% per year with aspirin versus 2.5% per year with apixaban (HR 1.2; 95% CI 0.65-2.1). CONCLUSIONS: Stage III CKD was an independent predictor of stroke in atrial fibrillation patients taking aspirin. Among stage III CKD patients, apixaban significantly reduced stroke relative to aspirin without a significant increase in major hemorrhage.

Culprit-only or multivessel percutaneous coronary stenting in patients with non-ST-segment elevation acute coronary syndromes: one-year follow-up.

OBJECTIVE: To investigate the major cardiac events at 1-year follow-up of multivessel versus culprit-vessel stenting in patients presenting with non-ST elevation acute coronary syndrome (NSTE-ACS) and multivessel disease (MVD). INTRODUCTION: Percutaneous coronary intervention is a standard revascularization strategy for patients with NSTE-ACS. However, when these patients have MVD it is not clear whether multivessel (MVR) is superior to culprit-vessel revascularization (CVR). METHODS: We screened 1,100 consecutive patients with NSTE-ACS from an institutional database. Comparisons of 1-year outcomes between multivessel and culprit-vessel revascularized patients were made. The primary outcome was the composite (MACE) of death, myocardial infarction (MI), or any revascularization. Secondary end-points were the components of the composite end-point. Regression analysis was performed to detect predictors of MACE. RESULTS: A total of 609 patients were considered for this analysis: 204 (33.5%) and 405 (66.5%) had MVR and CVR treatment, respectively. The strategy adopted was based on a clinical decision. The incidence of MACE was lower in MVR (9.45% vs. 16.34%, P = 0.02) with lower revascularization rate (7.46% vs. 13.86%, P = 0.04) than in CVR. There was no difference in death (1.99% vs. 1.98%, P = 0.8) nor death/MI (2.49% vs. 3.22%, P = 0.8) between MVR and CVR, respectively. Multivariate analysis showed CVR as the only independent predictor of improved MACE (OR 0.66, CI95% 1.12-3.47, P = 0.01). CONCLUSION: Multivessel stenting in patients with NSTE-ACS and multivessel disease using a clinical decision of treatment is associated with lower rate of MACE driven by lower repeat revascularization, compared with culprit-vessel stenting, without difference in rates of death or MI.

Effect of glucose-insulin-potassium infusion on mortality in patients with acute ST-segment elevation myocardial infarction: the CREATE-ECLA randomized controlled trial.

CONTEXT: Glucose-insulin-potassium (GIK) infusion is a widely applicable, low-cost therapy that has been postulated to improve mortality in patients with acute ST-segment elevation myocardial infarction (STEMI). Given the potential global importance of GIK infusion, a large, adequately powered randomized trial is required to determine the effect of GIK on mortality in patients with STEMI. OBJECTIVE: To determine the effect of high-dose GIK infusion on mortality in patients with STEMI. DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial conducted in 470 centers worldwide among 20,201 patients with STEMI who presented within 12 hours of symptom onset. The mean age of patients was 58.6 years, and evidence-based therapies were commonly used. INTERVENTION: Patients were randomly assigned to receive GIK intravenous infusion for 24 hours plus usual care (n = 10,091) or to receive usual care alone (controls; n = 10,110). MAIN OUTCOME MEASURES: Mortality, cardiac arrest, cardiogenic shock, and reinfarction at 30 days after randomization. RESULTS: At 30 days, 976 control patients (9.7%) and 1004 GIK infusion patients (10.0%) died (hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.95-1.13; P = .45). There were no significant differences in the rates of cardiac arrest (1.5% [151/10 107] in control and 1.4% [139/10,088] in GIK infusion; HR, 0.93; 95% CI, 0.74-1.17; P = .51), cardiogenic shock (6.3% [640/10 107] vs 6.6% [667/10 088]; HR, 1.05; 95% CI, 0.94-1.17; P = .38), or reinfarction (2.4% [246/10,107] vs 2.3% [236/10,088]; HR, 0.98; 95% CI, 0.82-1.17; P = .81). The rates of heart failure at 7 days after randomization were also similar between the groups (16.9% [1711/10,107] vs 17.1% [1721/10,088]; HR, 1.01; 95% CI, 0.95-1.08; P = .72). The lack of benefit of GIK infusion on mortality was consistent in prespecified subgroups, including in those with and without diabetes, in those presenting with and without heart failure, in those presenting early and later after symptom onset, and in those receiving and not receiving reperfusion therapy (thrombolysis or primary percutaneous coronary intervention). CONCLUSION: In this large, international randomized trial, high-dose GIK infusion had a neutral effect on mortality, cardiac arrest, and cardiogenic shock in patients with acute STEMI.

Challenges in the conduct of large simple trials of important generic questions in resource-poor settings: the CREATE and ECLA trial program evaluating GIK (glucose, insulin and potassium) and low-molecular-weight heparin in acute myocardial infarction.

BACKGROUND: Approximately 15.5 million deaths from cardiovascular diseases occur every year. About half are due to acute myocardial infarction (AMI), and 80% occur in low- and middle-income countries. Therefore, low-cost therapies would be invaluable. Although glucose-insulin-potassium (GIK) infusion and low-molecular-weight heparin (LMWH) appear to be promising in AMI, the available trials are inconclusive and these treatments require rigorous evaluation. METHODS: The Clinical Trial of Reviparin and Metabolic Modulation in Acute Myocardial Infarction Treatment and Evaluation-Estudios Clinicos Latino America (CREATE-ECLA) study is a randomized controlled trial in ST-elevation AMI patients evaluating a 24-hour infusion of Glucose-Insulin-Potassium (GIK) intravenous vs usual care (control) on 30-day mortality in 20,000 patients from 21 countries. Patients from India and China (n = 15,000) are also randomized using a factorial design to receive low-molecular-weight heparin (Reviparin) or placebo injection twice daily for 7 days to assess the impact on the composite outcomes of death, reinfarction or stroke (first co-primary outcome) or the composite + refractory ischemia (second co-primary outcome). RESULTS: Twenty thousand two hundred and one (20,201) GIK/control patients and 15,570 Reviparin/placebo patients have been included, with results expected in November 2004. CONCLUSIONS: The CREATE-ECLA trial will provide definitive answers to the role of 2 practical, promising and low-cost therapies, LMWH and GIK, in AMI patients. If effective, these therapies could be used in small medical centers in low- and middle- income countries. The experiences in this trial indicate that large trials of important questions can be successfully conducted in resource-poor settings, by academic groups without industry involvement.

Current and new oral antithrombotics in non-valvular atrial fibrillation: a network meta-analysis of 79 808 patients.

BACKGROUND: Antithrombotic therapy reduces stroke, embolism and mortality in patients with atrial fibrillation (AF); however, meta-analyses have focused on pairwise comparisons of treatments. OBJECTIVE: To synthesise the evidence from trials using a multiple treatment comparison methods thereby permitting a broader comparison across multiple therapies. DESIGN, SETTING, PATIENTS: Randomised controlled trials in patients with AF of antithrombotics were identified from MEDLINE, Embase, and Cochrane Central Register of Controlled Trials through May 2012. We performed a random-effects model within a Bayesian framework using Markov Chain Monte Carlo simulation to calculate pooled OR and 95% credibility intervals (CrI). We also ranked therapies by their likelihood of leading to the best results for the outcomes. MAIN OUTCOME MEASURE: Multiple endpoints including stroke, embolism, death and bleeding. RESULTS: We identified 20 studies with 79 808 patients allocated to 8 treatments: ASA, ASA plus clopidogrel, vitamin K antagonists (VKAs), dabigatran 110 mg, dabigatran 150 mg, rivaroxaban, apixaban or placebo/control. Compared with placebo/control, dabigatran 150 mg was associated with the lowest risk of stroke (OR=0.25, 0.15-0.43), the composite of ischaemic stroke or systemic embolism (OR=0.26, 0.12-0.54) and mortality (OR=0.53, 0.28-0.88). ASA plus clopidogrel was associated with the highest risk of major bleeding (OR=3.65, 1.22-13.56). In simulated comparisons, the novel oral anticoagulants ranked better than VKA or antiplatelet therapies for prevention of stroke, ischaemic stroke or systemic embolism and mortality. CONCLUSIONS: In this network meta-analysis, novel oral anticoagulants were the most promising treatments to reduce stroke, stroke or systemic embolism, and all-cause mortality in patients with AF.

Novel oral anticoagulants in atrial fibrillation: a meta-analysis of large, randomized, controlled trials vs warfarin.

BACKGROUND: Warfarin reduces ischemic stroke in atrial fibrillation, but has numerous limitations. Novel oral anticoagulants provide more predictable anticoagulation with fewer shortcomings. HYPOTHESIS: Novel oral anticoagulants are superior to warfarin to prevent stroke or systemic embolism. METHODS: Phase III randomized warfarin-controlled trials enrolling >3000 patients that reported clinical efficacy and safety of novel oral anticoagulants in patients with atrial fibrillation were identified from MEDLINE, Embase, and Cochrane Central Register of Controlled Trials through October 2012. Two reviewers extracted data; differences were resolved by consensus. The end points analyzed were stroke or systemic embolism (primary efficacy composite); all-cause mortality, ischemic stroke, systemic embolism (individually, secondary efficacy); and hemorrhagic stroke, major bleeding (individually, safety). The Mantel-Haenszel method was used to calculate pooled relative risk (RR) and 95% confidence intervals (CI) from fixed-effects (if homogenous) or random-effects models (if heterogeneous). RESULTS: In 5 studies of 51895 patients, the composite of stroke or systemic embolism (RR: 0.82; 95% CI: 0.69-0.98; P = 0.03) and all-cause mortality (RR: 0.91; 95% CI: 0.85-0.96; P = 0.0026, respectively) were reduced with the novel agents. Factor Xa inhibitors significantly reduced the primary composite (RR: 0.84; 95% CI: 0.74-0.94; P = 0.004) and all-cause mortality (RR: 0.91; 95% CI: 0.84 - 0.98; P = 0.01). Direct thrombin inhibitor achieved results similar to the overall meta-analysis (drug class-outcome interactions P = 0.47 for primary outcome, P = 1.00 for mortality). Compared with warfarin, novel anticoagulants markedly reduced hemorrhagic stroke (RR: 0.51; 95% CI: 0.41-0.64; P < 0.0001). CONCLUSIONS: Novel oral anticoagulants may be superior to warfarin in patients with atrial fibrillation, reducing the composite of stroke or systemic embolism and lowering all-cause mortality. The benefit is largely due to fewer hemorrhagic strokes.

Effects of telmisartan on glucose levels in people at high risk for cardiovascular disease but free from diabetes: the TRANSCEND study.

OBJECTIVE: Several large clinical trials suggest that ACE inhibitors may reduce the incidence of diabetes. Less is known about the effects of angiotensin receptor blockers (ARBs) on reducing incident diabetes or leading to regression of impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) to normoglycemia. RESEARCH DESIGN AND METHODS: Participants were 3,488 adults at high risk for cardiovascular disease but free from diabetes (mean age 67 years; 61% male) in the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND) study. The participants were randomized to the ARB telmisartan 80 mg (n = 1,726) or placebo (n = 1,762) in addition to usual care. RESULTS: During a median 56 months, 21.8% of participants treated with telmisartan and 22.4% of those on placebo developed diabetes (relative ratio 0.95 [95% CI 0.83-1.10]; P = 0.51). Participants originally diagnosed with IFG and/or IGT were equally likely to regress to normoglycemia (26.9 vs. 24.5%) or to progress to incident diabetes (20.1 vs. 21.1%; P = 0.59) on telmisartan or placebo. CONCLUSIONS: There was no evidence that addition of the ARB telmisartan to usual care prevents incident diabetes or leads to regression of IFG or IGT in people at high risk for cardiovascular disease but free from diabetes.

Renin-angiotensin system blockade and cognitive function in patients at high risk of cardiovascular disease: analysis of data from the ONTARGET and TRANSCEND studies.

BACKGROUND: cardiovascular risk factors are associated with dementia and cognitive decline. We investigated the effects of renin-angiotensin system blockade on cognitive function in patients aged 55 years and older with established atherosclerotic cardiovascular disease or diabetes with end-organ damage in two clinical trials. METHODS: in the main study, ONTARGET, a double-blind, double-dummy, randomised controlled trial, the effects on cardiovascular outcomes of standard doses of an angiotensin-converting enzyme (ACE) inhibitor (ramipril), an angiotensin-receptor blocker (telmisartan), and a combination of the drugs were evaluated in 25 620 participants. In the parallel TRANSCEND trial, the effects of telmisartan were compared with those of placebo in 5926 participants intolerant to ACE inhibitors. Secondary outcomes included cognitive impairment (defined by investigator-reported diagnosis of dementia or significant cognitive dysfunction, or a score of ≤ 23 on the Mini-Mental State Examination [MMSE]) and cognitive decline (a decrease of ≤ 3 points on the MMSE from baseline during follow-up). Analyses were by intention to treat. We pooled data from these studies to identify baseline predictors of cognitive impairment and its frequency according to mean systolic blood pressure during follow-up. These studies were registered with ClinicalTrials.gov, number NCT00153101. FINDINGS: During a median duration of 56 months (IQR 51-64) of follow-up in ONTARGET, cognitive impairment occurred in 652 (8%) of 7865 patients allocated ramipril, 584 (7%) of 7797 allocated telmisartan, and 618 (8%) of 7807 allocated combination treatment (combination vs ramipril, odds ratio [OR] 0·95, 95% CI 0·85-1·07, p= 0·39; telmisartan vs ramipril, OR 0·90, 0·80-1·01, p = 0·06). Corresponding figures for cognitive decline were 1314 (17%), 1279 (17%), and 1240 (17%) in each of the groups, respectively (telmisartan vs ramipril, OR 0·97, 0·89-1·06, p= 0·53; combination vs ramipril, OR 0·95, 0·88-1·04, p=0·28). In TRANSCEND, cognitive impairment occurred in 239 (9%) of 2694 participants allocated telmisartan compared with 245 (9%) of 2689 allocated placebo (OR 0·97, 0·81-1·17, p= 0·76). The corresponding figures for cognitive decline were 454 (17%) and 412 (16%; OR 1·10, 0·95-1·27, p= 0·22). INTERPRETATION: In patients with cardiovascular disease or diabetes, different approaches to blocking of the renin-angiotensin system had no clear effects on cognitive outcomes. Although patients with the lowest systolic blood pressure had the greatest preservation of cognitive function, meta-regression analyses did not show any benefits of blood-pressure lowering on cognition over several years of treatment.

Outcomes of patients in clinical trials with ST-segment elevation myocardial infarction among countries with different gross national incomes.

AIMS: To evaluate whether there is an association between 30-day mortality in patients with ST-segment elevation myocardial infarction (STEMI) included in clinical trials and country gross national income (GNI). METHODS AND RESULTS: A retrospective analysis of the databases of five randomized trials including 50 310 patients with STEMI (COBALT 7169, GIK-2 2931, HERO-2 17,089, ASSENT-2 17,005, and ASSENT-3 6116 patients) from 53 countries was performed. Countries were divided into three groups according to their GNI based on the World Bank data: low (less than 2900 US dollars), medium (between 2900 US dollars and 9000 US dollars), and high GNI (more than 9000 US dollars per capita). Baseline characteristics, in-hospital management variables, and 30-day outcomes were evaluated. A previously defined logistic regression model was used to adjust for differences in baseline characteristics and to predict mortality. The observed mortality was higher than the predicted mortality in the low (12.1 vs. 11.8%) and in the medium income groups (9.4 vs. 7.9%), whereas it was lower in the high income group (4.9 vs. 5.6%). CONCLUSION: An inverse relationship between mortality and GNI was observed in STEMI clinical trials. Most of the variability in mortality can be explained by differences in baseline characteristics; however, after adjustment, lower income countries have higher mortality than the expected.