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Aims The International Polycap Study 3 (TIPS-3) trial demonstrated that a polypill containing cholesterol- and multiple blood-pressure-lowering drugs reduces cardiovascular events by 20% compared with placebo in people without cardiovascular disease. The polypill plus aspirin led to a 31% relative risk reduction in cardiovascular disease events compared with double placebo. We report regional variations in costs and affordability of a polypill based on the TIPS-3 trial. Methods and results Countries were categorized using World Bank economic groups: lower-middle-income, upper-middle-income, and high-income countries. Country-specific costs were obtained for hospitalization events, procedures, and non-study medications (2019 US dollars). Polypill price was based on the cheapest equivalent substitute (CES) for each component. For the polypill vs. placebo, the difference in cost over the 4.6 years of the trial was $291 [95% confidence interval (CI): $243–339] per participant in lower-middle-income countries, $1068 (95% CI: $992–1144) in upper-middle-income countries, and $48 (95% CI: −$271 to $367) in high-income countries. Results were similar for the polypill plus aspirin vs. a double placebo. In both cases, the polypill was affordable in all groups using monthly household capacity to pay or a threshold of 4% of the gross national income per capita. Conclusion The use of a polypill (CES) in TIPS-3 increases costs in lower-middle-income countries and upper-middle-income countries but is affordable in countries at various economic levels and is cost neutral (dominant) in high-income countries.

BackgroundCardiovascular disease (CVD) is a leading cause of death globally. Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB), compared in the ONTARGET trial, each prevent CVD. However, trial populations may not be representative of the general population.MethodsUsing trial replication methods within routine-care data, we explored replicability of the ONTARGET trial. For people prescribed an ACEi and/or an ARB in the UK Clinical Practice Research Datalink CPRD GOLD from 1/1/2001-31/7/2019, we applied trial criteria and propensity-score methods to create an ONTARGET trial-eligible cohort. Comparing ARB to ACEi, using Cox-proportional hazards models, we estimated hazard ratios for the primary composite trial outcome (cardiovascular death, myocardial infarction, stroke, or hospitalisation for heart failure), as well as secondary outcomes. As the pre-specified criteria were met confirming trial replicability, we then explored treatment effect heterogeneity of ACEi and ARB among three trial-underrepresented subgroups: females, those aged ≥75 years and those with chronic kidney disease.FindingsIn the trial-eligible population (n=137,155), results for the primary outcome met pre-specified criteria for similarity to the ONTARGET trial and demonstrated similar effects of ARB and ACEi, (HR 0.97 [95% CI: 0.93, 1.01]). When extending to trial-underrepresented groups, similar treatment effects of ARB and ACEi were observed by sex (P=0.09), age (P=0.70) and chronic kidney disease status (P=0.10).InterpretationWe were able to replicate the results of the ONTARGET trial using routinely-collected healthcare data. Results suggest that trial findings were generalisable to population subgroups underrepresented in the trial.FundingGlaxoSmithKlineResearch in ContextEvidence before this studyTrial replication is an important methodology increasingly used to validate findings from observational studies against target trials. Unlike many naïve observational comparisons, a previous study demonstrated replicability of the ONTARGET trial using United States insurance claims data. However, it is unknown whether trial replicability can be extended to UK routinely-collected healthcare data. In addition, little work has been done to extend findings of comparative effectiveness among trial-underrepresented subgroups such as women, the elderly and those with chronic kidney disease despite high rates of prescribing of ACE Inhibitors and angiotensin receptor blockers among these groups in routine-care.Added value of this studyWith access to the individual patient data from the ONTARGET study and using propensity-score methods to address confounding, we demonstrated trial replicability using routinely-collected primary care data, representative of a large proportion of the UK population. We were then able to leverage the large sample size of the trial-eligible cohort to extend findings to trial-underrepresented groups and demonstrated similar comparative effectiveness for subgroups of patients treated with ARB and ACEi among women, those aged ≥75 years and those with chronic kidney disease.Implications of all the available evidenceOur findings support similar effectiveness for cardiovascular and renal outcomes for patients receiving an ARB compared to an ACEi in a trial-eligible cohort and subgroups for which there is currently a lack of evidence of treatment effectiveness. Trial-replication methodology can be used to provide evidence for populations underrepresented in clinical trials.

Digital, Background and Purpose: The HOPE-3 trial (Heart Outcomes Prevention Evaluation–3) found that antihypertensive therapy combined with a statin reduced first stroke among people at intermediate cardiovascular risk. We report secondary analyses of stroke outcomes by stroke subtype, predictors, treatment effects in key subgroups. Methods: Using a 2-by-2 factorial design, 12 705 participants from 21 countries with vascular risk factors but without overt cardiovascular disease were randomized to candesartan 16 mg plus hydrochlorothiazide 12.5 mg daily or placebo and to rosuvastatin 10 mg daily or placebo. The effect of the interventions on stroke subtypes was assessed. Results: Participants were 66 years old and 46% were women. Baseline blood pressure (138/82 mm Hg) was reduced by 6.0/3.0 mm Hg and LDL-C (low-density lipoprotein cholesterol; 3.3 mmol/L) was reduced by 0.90 mmol/L on active treatment. During 5.6 years of follow-up, 169 strokes occurred (117 ischemic, 29 hemorrhagic, 23 undetermined). Blood pressure lowering did not significantly reduce stroke (hazard ratio [HR], 0.80 [95% CI, 0.59–1.08]), ischemic stroke (HR, 0.80 [95% CI, 0.55–1.15]), hemorrhagic stroke (HR, 0.71 [95% CI, 0.34–1.48]), or strokes of undetermined origin (HR, 0.92 [95% CI, 0.41–2.08]). Rosuvastatin significantly reduced strokes (HR, 0.70 [95% CI, 0.52–0.95]), with reductions mainly in ischemic stroke (HR, 0.53 [95% CI, 0.37–0.78]) but did not significantly affect hemorrhagic (HR, 1.22 [95% CI, 0.59–2.54]) or strokes of undetermined origin (HR, 1.29 [95% CI, 0.57–2.95]). The combination of both interventions compared with double placebo substantially and significantly reduced strokes (HR, 0.56 [95% CI, 0.36–0.87]) and ischemic strokes (HR, 0.41 [95% CI, 0.23–0.72]). Conclusions: Among people at intermediate cardiovascular risk but without overt cardiovascular disease, rosuvastatin 10 mg daily significantly reduced first stroke. Blood pressure lowering combined with rosuvastatin reduced ischemic stroke by 59%. Both therapies are safe and generally well tolerated., Correction to: Antihypertensives and Statin Therapy for Primary Stroke Prevention: A Secondary Analysis of the HOPE-3 Trial, Ciencias Médicas y de la Salud

ObjectiveTo evaluate the effects of fixed dose combination (FDC) medications on cardiovascular outcomes in different age groups in an individual participant meta-analysis of three primary prevention randomised trials.MethodsParticipants at intermediate risk (17.7% mean 10-year Framingham Cardiovascular Risk Score), randomised to FDC of two or more antihypertensives and a statin with or without aspirin, or to their respective control, were followed up for 5 years. Age groups were ResultsThe primary outcome risk was reduced by 37% (3.3% in FDC vs 5.2% in control (HR 0.63; 95% CI 0.54 to 0.74)) in the total population of 18 162 participants with larger benefits in older groups (HR 0.58; 95% CI 0.42 to 0.78, 60 to 65 years) and (HR 0.57; 95% CI 0.47 to 0.70, ≥65 years), as were their numbers needed to treat to avoid one primary outcome: 53 and 33, respectively. The primary outcome risk was reduced in the two oldest groups with FDC with aspirin (n=8951) by 54% and 54%, and without aspirin (n=12 061) by 34% and 38%. Dizziness, the most frequent FDC adverse effects, was higher in participants aged ConclusionsIn participants with intermediate cardiovascular risk, FDCs produce larger cardiovascular benefits in older individuals, which appear greater with aspirin.Trial registration numberHOPE-3,NCT00468923; TIPS-3,NCT016464137; PolyIran,NCT01271985.

Patients with chronic kidney disease (CKD) carry a high cardiovascular (CV) risk. Since whether this risk is reduced by aspirin is unclear, we examined if the effect of aspirin on cardiovascular outcomes varied by baseline kidney function in a primary cardiovascular disease prevention trial. The International Polycap Study-3 (TIPS-3) trial had randomized people without previous cardiovascular disease to aspirin (75 mg daily) or placebo. We now examined aspirin versus placebo on cardiovascular events in participants grouped by estimated glomerular filtration rate (eGFR), using a threshold of 60 ml/min/1.73 m

BACKGROUND AND AIMS Subjects with CKD carry a high (CV) risk. Whether this risk is blunted by aspirin is controversial. We examined CV outcomes of CKD participants of the TIPS3 trial. METHOD The International Polycap Study3 (TIPS3) randomized people (N = 5713) with and without CKD, but without previous CV disease, to aspirin, aspirin plus polypill, polypill or respective placebo in a factorial design. In 983 participants that were randomized to aspirin or placebo, eGFR was below 60 mL/min/1.73 m2 at baseline (CKD). The primary outcome for this comparison was non-fatal myocardial infarction (MI), non-fatal stroke or CV death. The mean follow-up was 4.6 years. RESULTS In all participants, there were 250 primary MACE outcomes, 116 on aspirin and 134 on placebo (HR 0.86; 95% CI 0.67–1.10). In those with CKD, there were 65 primary MACE outcomes, 26 in the 502 participants on aspirin, 39 in the 481 participants on placebo, HR 0.57 (95% CI 0.34–0.94). Directionally similar results were found for aspirin versus placebo for the secondary outcome all-cause death with 312 events in all participants (HR 0.87; 0.70–1.07) and 82 events in CKD patients (HR 0.64; 0.41–0.99). There was no significant interaction of eGFR When aspirin was combined with a polypill (containing atenolol, ramipril, hydrochlorothiazide and simvastatin) and compared to double placebo, in all participants the HR for the MACE outcome was 0.69, 0.50–0.97 and for all-cause death 0.80, 0.59–1.08; in CKD patients the HR was 0.37, 0.18–0.75 for MACE and HR 0.49, 0.29–0.97 for death. CONCLUSION Results suggest that the CV risk in people with CKD may be substantially alleviated with aspirin alone and in combination with a polypill.

Background: Accuracy and feature sets of continuous glucose monitoring (CGM) systems may influence device utilization and outcomes. We compared clinical trial accuracy and real-world utilization and effectiveness of two different CGM systems. Materials and Methods: Separately conducted accuracy studies of a fifth-generation and a sixth-generation CGM system involved 50 and 159 adults, respectively. For between-system performance comparisons, propensity score methods were utilized to balance cohort characteristics. Real-world outcomes were assessed in 10,000 anonymized patients who had switched from the fifth-generation to the sixth-generation system and had used connected mobile devices to upload data from both systems, allowing pairwise comparisons of device utilization and glucose concentration distributions. Results: Propensity score-adjusted mean absolute relative differences for the fifth- and sixth-generation systems were 9.0% and 9.9%, and the percentages of values within ±20%/20 mg/dL were 93.1% and 92.5%, respectively. The sixth-generation system, but not the fifth-generation system, met accuracy criteria for interoperable CGM systems. Both systems had high real-world utilization rates (93.8% and 95.3% in the fifth- and sixth-generation systems, respectively). Use of the sixth-generation system was associated with fewer glucose values

Background: Between-system differences for continuous glucose monitoring (CGM) devices have important clinical consequences. Purpose: Here we review attributes of Dexcom’s fifth-, sixth-, and seventh-generation (G5, G6, and G7) CGM systems. Methods: Accuracy metrics were derived from preapproval trials of the three systems and compared after propensity score adjustments were used to balance baseline demographic characteristics. Metrics included mean absolute relative differences (MARD) between CGM and YSI values and the proportion of CGM values within 20% or 20 mg/dL of the YSI values (“%20/20”). Ease-of-use was evaluated by formal task analysis. Conclusions: Adjusted MARD and %20/20 agreement rates were 9.0%/93.1% (abdomen-placed G5), 9.9%/92.3% (abdomen-placed G6), 9.1%/93.2% (abdomen-placed G7), and 8.2%/95.3% (arm-placed G7). Task analysis favored G7 over earlier systems. Favorable clinical outcomes such as hemoglobin A1c reduction and hypoglycemia avoidance seen with G5 and G6 are anticipated with G7 use.

ObjectiveApproximately 10% of patients with myocardial infarction (MI) have no obstructive coronary artery disease. The prognosis and role of intensified antiplatelet therapy in those patients were evaluated.MethodsWe analysed data from the Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events–Seventh Organisation to Assess Strategies in Ischaemic Symptoms trial randomising patients with ACS referred for early intervention to receive either double-dose (600 mg, day 1; 150 mg, days 2–7; then 75 mg/day) or standard-dose (300 mg, day 1; then 75 mg/day) clopidogrel. Outcomes in patients with myocardial infarction with non-obstructive coronary arteries (MINOCA) versus those with obstructive coronary artery disease (CAD) and their relation to standard-dose versus double-dose clopidogrel were evaluated. The primary outcome was cardiovascular (CV) death, MI or stroke at 30 days.ResultsWe included 23 783 patients with MI and 1599 (6.7%) with MINOCA. Patients with MINOCA were younger, presented more frequently with non-ST-segment elevation MI and had fewer comorbidities. All-cause mortality (0.6% vs 2.3%, p=0.005), CV mortality (0.6% vs 2.2%, p=0.006), repeat MI (0.5% vs 2.3%, p=0.001) and major bleeding (0.6% vs 2.4%, pConclusionsPatients with MINOCA are at lower risk of recurrent CV events compared with patients with MI with obstructive CAD. Compared with a standard clopidogrel-based dual antiplatelet therapy (DAPT) regimen, an intensified dosing strategy appears to offer no additional benefit with a signal of possible harm. Further randomised trials evaluating the effects of potent DAPT in patients with MINOCA are warranted.Trial registration numberNCT00335452.

Background Routine thrombus aspiration in patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) does not improve clinical outcomes. However, there is remaining uncertainty about the potential benefit in those patients with high thrombus burden, where there is a biological rationale for greater benefit. Objectives The purpose of this study was to evaluate the benefit of thrombus aspiration among STEMI patients with high thrombus burden. Methods TOTAL (ThrOmbecTomy with PCI vs. PCI ALone in patients with STEMI) was a randomized trial of routine manual thrombectomy versus PCI alone in patients with STEMI (n = 10,732). High thrombus burden (Thrombolysis In Myocardial Infarction thrombus grade ≥3) was a pre-specified subgroup. Results The primary outcome of cardiovascular (CV) death, MI, cardiogenic shock, or heart failure was not different at 1 year with thrombus aspiration in patients with high thrombus burden (8.1% vs. 8.3% thrombus aspiration; hazard ratio [HR]: 0.97; 95% confidence interval [CI]: 0.84 to 1.13) or low thrombus burden (6.0% vs. 5.0% thrombus aspiration; HR: 1.22; 95% CI: 0.73 to 2.05; interaction p = 0.41). However, among patients with high thrombus burden, stroke at 30 days was more frequent with thrombus aspiration (31 [0.7%] thrombus aspiration vs. 16 [0.4%] PCI alone, HR: 1.90; 95% CI: 1.04 to 3.48). In the high thrombus burden group, thrombus aspiration did not significantly improve CV mortality at 30 days (HR: 0.78; 95% CI: 0.61 to 1.01; p = 0.06) and at 1 year (HR: 0.88; 95% CI: 0.72 to 1.09; p = 0.25). Irrespective of treatment assignment, high thrombus burden was an independent predictor of death (HR: 1.78; 95% CI: 1.05 to 3.01). Conclusions In patients with high thrombus burden, routine thrombus aspiration did not improve outcomes at 1 year and was associated with an increased rate of stroke. High thrombus burden is still an important predictor of outcome in STEMI. (A Trial of routine aspiration ThrOmbecTomy with PCI vs. PCI ALone in patients with STEMI [TOTAL]; NCT01149044)

Thrombus aspiration in ST-segment–elevation myocardial infarction has been an area of intense debate among interventional cardiologists. A prior single-center trial (n=1071) observed an unexpected nearly 50% reduction in mortality with routine thrombus aspiration.1 These findings led to the development of the randomized trial of routine aspiration TOTAL (Thrombectomy With PCI Versus PCI Alone in Patients With STEMI; n=10 732).2 During the conduct of the TOTAL trial, thrombus aspiration was recommended by guidelines and was commonly used in clinical practice and believed to improve patient outcomes. In the TOTAL trial, thrombus aspiration did not reduce the primary outcome of cardiovascular death, myocardial infarction, cardiogenic shock, or heart failure at 180 days but was associated with a significant increase in stroke at 30 days. The objective of this research letter is to show the importance of a data monitoring committee (DMC) continuing a trial despite emerging treatment findings. A Cox proportional hazards model was used to compare patients randomized to thrombus aspiration with percutaneous coronary intervention (PCI) and PCI alone. A modified intent-to-treat analysis was prespecified to include only patients who underwent PCI because patients were randomized before angiography. Outcomes presented are at 30 days given that during early analyses data at longer-term follow-up had few patients and were not reliable. The data were compiled from actual DMC reports. The outcomes analyzed for this article include the primary outcome (cardiovascular death, myocardial infarction, cardiogenic shock, or heart failure), death, and stroke. The stopping guidelines for efficacy were exceeding a difference of 4 …

Objective To determine if virtual care with remote automated monitoring (RAM) technology versus standard care increases days alive at home among adults discharged after non-elective surgery during the covid-19 pandemic. Design Multicentre randomised controlled trial. Setting 8 acute care hospitals in Canada. Participants 905 adults (≥40 years) who resided in areas with mobile phone coverage and were to be discharged from hospital after non-elective surgery were randomised either to virtual care and RAM (n=451) or to standard care (n=454). 903 participants (99.8%) completed the 31 day follow-up. Intervention Participants in the experimental group received a tablet computer and RAM technology that measured blood pressure, heart rate, respiratory rate, oxygen saturation, temperature, and body weight. For 30 days the participants took daily biophysical measurements and photographs of their wound and interacted with nurses virtually. Participants in the standard care group received post-hospital discharge management according to the centre’s usual care. Patients, healthcare providers, and data collectors were aware of patients’ group allocations. Outcome adjudicators were blinded to group allocation. Main outcome measures The primary outcome was days alive at home during 31 days of follow-up. The 12 secondary outcomes included acute hospital care, detection and correction of drug errors, and pain at 7, 15, and 30 days after randomisation. Results All 905 participants (mean age 63.1 years) were analysed in the groups to which they were randomised. Days alive at home during 31 days of follow-up were 29.7 in the virtual care group and 29.5 in the standard care group: relative risk 1.01 (95% confidence interval 0.99 to 1.02); absolute difference 0.2% (95% confidence interval −0.5% to 0.9%). 99 participants (22.0%) in the virtual care group and 124 (27.3%) in the standard care group required acute hospital care: relative risk 0.80 (0.64 to 1.01); absolute difference 5.3% (−0.3% to 10.9%). More participants in the virtual care group than standard care group had a drug error detected (134 (29.7%) v 25 (5.5%); absolute difference 24.2%, 19.5% to 28.9%) and a drug error corrected (absolute difference 24.4%, 19.9% to 28.9%). Fewer participants in the virtual care group than standard care group reported pain at 7, 15, and 30 days after randomisation: absolute differences 13.9% (7.4% to 20.4%), 11.9% (5.1% to 18.7%), and 9.6% (2.9% to 16.3%), respectively. Beneficial effects proved substantially larger in centres with a higher rate of care escalation. Conclusion Virtual care with RAM shows promise in improving outcomes important to patients and to optimal health system function. Trial registration ClinicalTrials.gov NCT04344665 .

Background and objectives Hyperphosphatemia is common among recipients of maintenance dialysis and is associated with a higher risk of mortality and cardiovascular events. A large randomized trial is needed to determine whether lowering phosphate concentrations with binders improves patient-important outcomes. To inform such an effort we conducted a pilot randomized controlled trial. Design, setting, participants, & measurements We conducted a randomized controlled trial of prevalent hemodialysis recipients already receiving calcium carbonate as a phosphate binder at five Canadian centers between March 31, 2014 and October 2, 2014. Participants were randomly allocated to 26 weeks of an intensive phosphate goal of 2.33–4.66 mg/dl (0.75–1.50 mmol/L) or a liberalized target of 6.20–7.75 mg/dl (2.00–2.50 mmol/L) by titrating calcium carbonate using a dosing nomogram. The primary outcome was the difference in the change in serum phosphate from randomization to 26 weeks. Results Fifty-three participants were randomized to the intensive group and 51 to the liberalized group. The median (interquartile range) daily dose of elemental calcium at 26 weeks was 1800 (1275–3000) mg in the intensive group, and 0 (0–500) mg in the liberalized group. The mean (SD) serum phosphate at 26 weeks was 4.53 (1.12) mg/dl (1.46 [0.36] mmol/L) in the intensive group and 6.05 (1.40) mg/dl (1.95 [0.45] mmol/L) in the liberalized group. Phosphate concentration in the intensive group declined by 1.24 (95% confidence interval, 0.75 to 1.74) mg/dl (0.40 [95% confidence interval, 0.24 to 0.56] mmol/L) compared with the liberalized group. There were no statistically significant differences between the two groups in the risk of hypercalcemia, hypocalcemia, parathyroidectomy, or major vascular events. Conclusions It is feasible to achieve and maintain a difference in serum phosphate concentrations in hemodialysis recipients by titrating calcium carbonate. A large trial is needed to determine if targeting a lower serum phosphate concentration improves patient-important outcomes.

Initiation of blockade of the renin-angiotensin system may cause an acute decrease in glomerular filtration rate (GFR): the prognostic significance of this is unknown. We did a post hoc analysis of patients with, or at risk for, vascular disease, in two randomized controlled trials: Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and the Telmisartan Randomized AssessmeNt Study in ACE iNtolerant participants with cardiovascular Disease (TRANSCEND), whose median follow-up was 56 months. In 9340 patients new to renin-angiotensin system blockade, who were then randomized to renin-angiotensin system blockade, a fall in GFR of 15% or more at 2 weeks after starting renin-angiotensin system blockade was seen in 1480 participants (16%), with persistence at 8 weeks in 700 (7%). Both acute increases and decreases in GFR after initiation of renin-angiotensin system blockade were associated with tendencies, mostly not statistically significant, to increased risk of cardiovascular outcomes, which occurred in 1280 participants, and of microalbuminuria, which occurred in 864. Analyses of creatinine-based outcomes were suggestive of regression to the mean. In more than 3000 patients randomized in TRANSCEND to telmisartan or placebo, there was no interaction between acute change in GFR and renal or cardiovascular benefit from telmisartan. Thus, both increases and decreases in GFR on initiation of renin-angiotensin system blockade are common, and may be weakly associated with increased risk of cardiovascular and renal outcomes. Changes do not predict increased benefit from therapy.

BackgroundWe previously reported that there was no significant difference at 30 days or at 1 year in the rate of the composite outcome of death, stroke, myocardial infarction, or renal failure 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 the results at 5 years (the end of the trial). MethodsA total of 4752 patients (from 19 countries) who had coronary artery disease were randomly assigned to undergo off-pump or on-pump CABG. For this report, we analyzed a composite outcome of death, stroke, myocardial infarction, renal failure, or repeat coronary revascularization (either CABG or percutaneous coronary intervention). The mean follow-up period was 4.8 years. ResultsThere were no significant differences between the off-pump group and the on-pump group in the rate of the composite outcome (23.1% and 23.6%, respectively; hazard ratio with off-p...

Background Approximately 10% of patients presenting with myocardial infarction (MI) do not have obstructive coronary artery disease (MINOCA). The role of antiplatelet therapy and outcomes in this group remain unclear. We assessed prognosis and the effect of an intensified clopidogrel regimen in MINOCA patients. Methods We analyzed data from the CURRENT-OASIS 7 trial, which randomized 25,086 patients with acute coronary syndromes (ACS) referred for early intervention to receive either double-dose (600mg day 1; 150mg days 2–7; then 75mg daily) or standard-dose (300mg day 1; then 75mg daily) clopidogrel. We evaluated clinical outcomes at 30-days in patients with versus without obstructive CAD and in relation to standard versus double-dose clopidogrel. Results Overall, 23,783 MI patients were included, of which 1,599 (6.7%) had MINOCA. MINOCA patients were younger, more frequently presented with non-ST-segment elevation MI and had fewer comorbidities. Rates of all-cause mortality (0.7% versus 2.4%, p=0.0046), cardiovascular mortality (0.6 versus 2.2%, p=0.0056), repeat MI (0.5% versus 2.3%, p=0.0009) and major bleedings (0.7% versus 2.5%, p=0.0001) were significantly lower among patients with MINOCA versus those with obstructive CAD. Compared with the standard-dose clopidogrel regimen, the double-dose regimen appeared to increase the risk of cardiovascular death, MI or stroke in MINOCA patients (0.8% versus 2.1%, hazard ratio (HR) 2.74, P=0.033). There was no difference in those with obstructive CAD (4.7% versus 4.4%, HR 0.93, P=0.226; P-for-interaction=0.023) (see Figure 1A). Major bleeding did not occur more frequently in MINOCA patients with double- versus standard-dose clopidogrel regimen (0.7% versus 0.6%, (HR 1.16 (95% CI 0.35–3.80), p=0.805), but their rate was higher In MI patients with obstructive CAD (2.7% versus 2.2% (HR 1.26 (95% CI 1.06–1.49), p=0.008) (Figure 1B). Figure 1A & B Conclusions Compared to MI patients with obstructive CAD, patients presenting with MINOCA represent a distinct cohort, which is generally younger, has a higher NSTEMI prevalence and fewer comorbidities. Their risk for adverse events, especially repeat MI, stroke, death, and bleeding, is low ( Acknowledgement/Funding The CURRENT-OASIS 7 trial was sponsored by Sanofi-Aventis and Bristol-Myers Squibb.

Background Cardiac surgery patients are at high risk for postoperative bleeding. Intravenous (IV) tranexamic acid (TxA) is a commonly used antifibrinolytic drug, but is associated with postoperative seizures. We conducted this pilot randomized controlled trial (RCT) to determine the feasibility of a larger trial that will be designed to investigate the impact of TxA administration route, intrapericardial (IP) vs IV, on postoperative bleeding and seizures. Methods In this single-center, double-blinded, pilot RCT we enrolled adult patients undergoing nonemergent on-pump cardiac operations through a median sternotomy. Participants were randomized to IP or IV TxA groups. The primary outcomes were cumulative chest tube drainage, transfusion requirements, and incidence of postoperative seizures. Results A total of 97 participants were randomized to the intervention and control groups. Baseline characteristics were similar in both groups. Most participants underwent a CABG and/or aortic valve replacement. There was no statistical difference. The IP TxA group was found to have a tendency for less chest tube drainage in comparison to the IV TxA group, 500.5 (370.0-700.0) and 540.0 (420.0-700.0) mL, respectively, which was not statistically significant (P = 0.2854). Fewer participants in the IP TxA group with cardiac tamponade and/or required a reoperation for bleeding and fewer packed red blood cell transfusions. None of the IP TxA group developed seizure vs one from the IV TxA group. Conclusion This is the first known pilot RCT to investigate the role of TxA route of administration in open cardiac surgery. Intrapericardial TxA shows promising results with decreased bleeding, transfusion requirements, reoperations, and postoperative seizures. A larger RCT is needed to confirm these results and lead to a change in practice.

Background and objectives Mineralocorticoid receptor antagonism reduces morbidity and mortality in patients with heart failure, but the safety of these drugs in patients receiving dialysis is unclear. This study evaluated whether hyperkalemia and/or hypotension limited the use of eplerenone, a selective mineralocorticoid receptor antagonist, in hemodialysis patients. Design, setting, participants, & measurements This was a randomized controlled trial of prevalent patients receiving hemodialysis at five Canadian centers. Participants were randomly allocated to 13 weeks of eplerenone titrated to 50 mg daily ( n =77) or a matching placebo ( n =77). The primary outcome was permanent discontinuation of the drug because of hyperkalemia or hypotension. Secondary outcomes included hyperkalemia, hypotension, and cardiovascular events. Results Seventy-five eplerenone-treated patients and 71 placebo-treated patients were included in the per protocol population. The primary outcome occurred in three patients (4.0%) in the eplerenone group and two (2.8%) in the placebo group, for an absolute risk difference of 1.2 percentage points (95% confidence interval, −4.7 to 7.1 percentage points). Eplerenone was interpreted as noninferior to placebo with respect to the primary outcome ( i.e., a discontinuation rate for these reasons >10% was excluded). In the eplerenone group, nine patients (11.7%) developed hyperkalemia (potassium level >6.5 mEq/L), compared with two patients (2.6%) in the placebo group (relative risk, 4.5; 95% confidence interval, 1.0 to 20.2). There was no significant effect on predialysis or postdialysis BP. Conclusion Eplerenone increased the risk of hyperkalemia but did not result in an excess need to permanently discontinue the drug. Further trials are required to determine whether mineralocorticoid receptor antagonism improves cardiovascular outcomes in patients receiving long-term dialysis.

Avoidance of death, disability, dementia, and cognitive dysfunction (DDCD) are high priorities for people in aging societies. Evidence is mounting that these conditions are associated with impaired glycemic control.The aim of this study was to assess the strength of relationship between the degree of glucose elevation and the development of the composite elements of DDCD that impede successful/healthy aging in a population at high risk for cardiovascular disease. DESIGN, SETTING, PARTICIPANTS, AND MAIN OUTCOME MEASURE: The relationship between baseline fasting plasma glucose values and DDCD was determined among 31 227 participants of the Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE intolerant Subjects With Cardiovascular Disease studies followed up for a median of 4.7 years. Several statistical models were used for the entire cohort and for those with and without normal fasting plasma glucose (ie,5.6 mmol/L) or a history of diabetes mellitus.After adjusting for age and sex, a diagnosis of diabetes mellitus was associated with an approximately 1.6 greater odds of DDCD; every 1 mmol/L higher baseline fasting plasma glucose value was associated with a 1.09 (95% confidence interval 1.07, 1.10) greater odds. These associations persisted in the multivariate models (a 1.08 95% confidence interval 1.07, 1.1 greater odds after adjustment for age, sex, education, and depression).In individuals with high cardiovascular risk, a direct relationship exists between levels of dysglycemia and the risk of DDCD. Further research is needed to understand the mechanisms underlying such an association and whether benefits can be derived from preventative strategies.

The primary outcome occurred in 347 of 5033 patients (6.9%) in the thrombectomy group versus 351 of 5030 patients (7.0%) in the PCI-alone group (hazard ratio in the thrombectomy group, 0.99; 95% confidence interval [CI], 0.85 to 1.15; P = 0.86). The rates of cardiovascular death (3.1% with thrombectomy vs. 3.5% with PCI alone; hazard ratio, 0.90; 95% CI, 0.73 to 1.12; P = 0.34) and the primary outcome plus stent thrombosis or target-vessel revascularization (9.9% vs. 9.8%; hazard ratio, 1.00; 95% CI, 0.89 to 1.14; P = 0.95) were also similar. Stroke within 30 days occurred in 33 patients (0.7%) in the thrombectomy group versus 16 patients (0.3%) in the PCI-alone group (hazard ratio, 2.06; 95% CI, 1.13 to 3.75; P = 0.02). Conclusions In patients with STEMI who were undergoing primary PCI, routine manual thrombectomy, as compared with PCI alone, did not reduce the risk of cardiovascular death, recurrent myocardial infarction, cardiogenic shock, or NYHA class IV heart failure within 180 days but was associated with an increased rate of stroke within 30 days. (Funded by Medtronic and the Canadian Institutes of Health Research; TOTAL ClinicalTrials.gov number, NCT01149044.)

Objectives The purpose of this study was to determine the efficacy and safety of radial versus femoral access in women undergoing coronary angiography/intervention. Background The risk of bleeding and vascular access site complications are higher in women than in men. Methods In a pre-specified RIVAL (RadIal Vs femorAL access for coronary intervention) subgroup analysis, we compared outcomes in women (n = 1,861) and men (n = 5,160) randomized to radial versus femoral access. Results Overall, women were at higher risk of major vascular complications compared with men (4.7% vs. 1.7%; p Conclusions Women undergoing coronary angiography and PCI have a higher risk of vascular access site complications compared with men, and radial access is an effective method to reduce these complications.

Background Prior Studies have suggested better outcomes in smokers compared with nonsmokers receiving clopidogrel (“smoker's paradox”). The impact of a more intensive clopidogrel regimen on ischemic and bleeding risks in smokers with acute coronary syndromes requiring percutaneous coronary interventions remains unclear. Methods and Results We analyzed 17 263 acute coronary syndrome patients undergoing percutaneous coronary intervention from the CURRENT ‐ OASIS 7 (Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events—Seventh Organization to Assess Strategies in Ischemic Symptoms) trial, which compared double‐dose (600 mg day 1;150 mg days 2–7; then 75 mg daily) versus standard‐dose (300 mg day 1; then 75 mg daily) clopidogrel in acute coronary syndrome patients. The primary outcome was cardiovascular death, myocardial infarction, or stroke at 30 days. Interactions between treatment allocation and smoking status (current smokers versus nonsmokers) were evaluated. Overall, 6394 patients (37.0%) were current smokers. For the comparison of double‐ versus standard‐dose clopidogrel, there were significant interactions in smokers and nonsmokers for the primary outcome ( P =0.031) and major bleeding ( P =0.002). Double‐ versus standard‐dose clopidogrel reduced the primary outcome among smokers by 34% (hazard ratio [ HR ] 0.66, 95% confidence interval [ CI ], 0.50–0.87, P =0.003), whereas in nonsmokers, there was no apparent benefit ( HR 0.96, 95% CI , 0.80–1.14, P =0.61). For major bleeding, there was no difference between the groups in smokers ( HR 0.77, 95% CI , 0.48–1.24, P =0.28), whereas in nonsmokers, the double‐dose clopidogrel regimen increased bleeding ( HR 1.89, 95% CI , 1.37–2.60, P HR 0.41, 95% CI , 0.24–0.71) and nonsmokers ( HR 0.63, 95% CI , 0.42–0.93; P for interaction=0.19). Conclusions In smokers, a double‐dose clopidogrel regimen reduced major cardiovascular events and stent thrombosis after percutaneous coronary intervention, with no increase in major bleeding. This suggests that clopidogrel dosing in patients with acute coronary syndromes should be personalized, taking into consideration both ischemic and bleeding risk. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT 00335452.

Aims Preliminary studies suggest that direct stenting (DS) during percutaneous coronary intervention (PCI) may reduce microvascular obstruction and improve clinical outcome. Thrombus aspiration may facilitate DS. We assessed the impact of DS on clinical outcome and myocardial reperfusion and its interaction with thrombus aspiration among ST-segment elevation myocardial infarction (STEMI) patients undergoing PCI. Methods and results Patient-level data from the three largest randomized trials on routine manual thrombus aspiration vs. PCI only were merged. A 1:1 propensity matched population was created to compare DS and conventional stenting. Synergy between DS and thrombus aspiration was assessed with interaction P-values in the final models. In the unmatched population (n= 17 329), 32% underwent DS and 68% underwent conventional stenting. Direct stenting rates were higher in patients randomized to thrombus aspiration as compared with PCI only (41% vs. 22%; P < 0.001). Patients undergoing DS required less contrast (162mL vs. 172mL; P< 0.001) and had shorter fluoroscopy time (11.1min vs. 13.3 min; P< 0.001). After propensity matching (n= 10 944), no significant differences were seen between DS and conventional stenting with respect to 30-day cardiovascular death [1.7% vs. 1.9%; hazard ratio 0.88, 95% confidence interval (CI) 0.55-1.41; P=0.60; Pinteraction = 0.96) and 30-day stroke or transient ischaemic attack (0.6% vs. 0.4%; odds ratio 1.02; 95% CI 0.14-7.54; P=0.99; Pinteraction = 0.81). One-year results were similar. No significant differences were seen in electrocardiographic and angiographic myocardial reperfusion measures. Conclusion Direct stenting rates were higher in patients randomized to thrombus aspiration. Clinical outcomes and myocardial reperfusion measures did not differ significantly between DS and conventional stenting and there was no interaction with thrombus aspiration.

Background The purpose of this study was to determine the cost implications of the Coronary Artery Bypass Graft Off or On Pump Revascularization Study (CORONARY) at 1 year. Methods Country-specific healthcare costs were obtained from public databases or local experts from each country in the CORONARY trial. Purchasing power parities were applied to these costs of consumed healthcare resources. Analyses of subgroups included in the CORONARY clinical trial were also conducted. Costs are reported in US dollars. Results After 1 year, the total cost per patient in the off-pump coronary artery bypass graft surgery (CABG) arm was $9,650 ($9,216 to $10,285) compared with $9,583 ($9,239 to $9,988) for the on-pump CABG arm; that resulted in a nonsignificant increase of $68 (−$575 to $710). Similar findings were noted for various subgroups. There were also no differences due to late conversions. Conclusions The CORONARY trial demonstrated that off-pump CABG was clinically as safe and effective as on-pump CABG with no difference in costs. Thus, the decision as to which method to choose is free from costs considerations and should be based on patient preference and surgeon expertise (Coronary Artery Bypass Graft [CABG] Off or On Pump Revascularization Study [CORONARY]; clinicaltrials.gov NCT00463294).

Heart rate was proposed as an emergent cardiovascular (CV) risk factor. Previous studies have shown associations between increased heart rate and CV risk in various populations. We aimed to evaluate the prognostic relevance of heart rate in a large contemporaneous medically optimized cohort of patients with stable chronic CV disease. In a post hoc analysis of the ONTARGET/TRANSCEND trials, we evaluated associations between baseline and average heart rate in trial with CV risk in 31, 531 patients followed for a median of 5 years. The primary outcome, major vascular events (MVE), was a composite of CV death, myocardial infarction (MI), stroke, and congestive heart failure (CHF). Pre-specified secondary outcomes included all-cause death and the individual components of the primary outcome. Associations between heart rate and outcomes were computed with heart rate as a continuous variable, baseline heart rate >70 vs ≤70 bpm, and across heart rate quintiles, adjusting for other markers of risk, beta-blocker and non-dihydropyridine calcium channel blocker use. For each 10 bpm increase in baseline and average heart rate, we observed a significant increase in risk of MVE, CV death, CHF and all-cause death. There was a continuous relationship between MVE and baseline and, more importantly, average in-trial heart rate, with no observed threshold. MVE, CV death, stroke, CHF, and all-cause death increased across heart rate quintiles. There was no association between MI and HR. Results were consistent in clinically relevant subgroups. There were modest but significant improvements in C-statistic and in statistical measures of model calibration for models that included heart rate for MVE, CV death, CHF and all-cause death. This large study examined and quantitated associations between heart rate and CV events in a contemporary medically optimized population with stable CV disease. Resting and, in particular, in-trial average heart rate are independently associated with significant increases in CV events and all-cause death.

Objectives The authors sought to compare the radiation dose between radial and femoral access. Background Small trials have shown an increase in the radiation dose with radial compared with femoral access, but many were performed during the operators9 learning curve of radial access. Methods Patients were randomized to radial or femoral access, as a part of the RIVAL (RadIal Vs. femorAL) trial (N = 7,021). Fluoroscopy time was prospectively collected in 5740 patients and radiation dose quantified as air kerma in 1,445 patients and dose-area product (DAP) in 2,255 patients. Results Median fluoroscopy time was higher with radial versus femoral access (9.3 vs. 8.0 min, p Conclusions Radiation dose as measured by air kerma was nominally higher with radial versus femoral access, but differences were present only in lower-volume centers and operators. High-volume centers have the lowest radiation dose irrespective of which access site approach that they use. (A Trial of Trans-radial Versus Trans-femoral Percutaneous Coronary Intervention (PCI) Access Site Approach in Patients With Unstable Angina or Myocardial Infarction Managed With an Invasive Strategy [RIVAL]; NCT01014273)

Benznidazole is recommended for treatment of Chagas infection. Effects of combination therapy with benznidazole and posaconazole have not been tested in Trypanosoma cruzi carriers.The purpose of this study was to determine whether posaconazole alone or combined with benznidazole were superior to benznidazole monotherapy in eliminating T. cruzi parasites measured by real time polymerase chain reaction (RT-PCR) in asymptomatic Chagas carriers.A prospective, multicenter randomized placebo-controlled study was conducted in 120 subjects from Latin America and Spain who were randomized to 4 groups: posaconazole 400 mg twice a day (b.i.d.); benznidazole 200 mg + placebo b.i.d.; benznidazole 200 mg b.i.d. + posaconazole 400 mg b.i.d.; or placebo 10 mg b.i.d. T. cruzi deoxyribonucleic acid was detected by RT-PCR at 30, 60, 90, 120, 150, 180, and 360 days. The primary efficacy outcome is the proportion of subjects with persistent negative RT-PCR by day 180; the secondary outcome was negative RT-PCR at 360 days.Only 13.3% of those receiving posaconazole and 10% receiving placebo achieved the primary outcome, compared with 80% receiving benznidazole + posaconazole and 86.7% receiving benznidazole monotherapy (p 0.0001 vs. posaconazole/placebo). Posaconazole monotherapy or posaconazole combined with benznidazole achieved high RT-PCR conversion rates during treatment (30 days; 93.3% and 88.9% and 60 days; 90%, and 92.3%) that were similar to benznidazole (89.7% and 89.3%); all were superior to placebo or posaconazole (10% and 16.7%, p 0.0001). This was not observed at 360 days; benznidazole + posaconazole and benznidazole monotherapy (both 96%) versus placebo (17%) and posaconazole (16%, p 0.0001). Serious adverse events were rare (6 patients) and were observed in the benznidazole-treated patients. Permanent discontinuation was reported in 19 patients (31.7%) receiving either benznidazole monotherapy or combined with posaconazole.Posaconazole demonstrated trypanostatic activity during treatment, but it is ineffective long-term in asymptomatic T. cruzi carriers. Benznidazole monotherapy is superior to posaconazole, with high RT-PCR conversion rates sustained at 1 year. Side effects lead to therapy discontinuation in 32%. No advantages were observed with combined therapy versus benznidazole monotherapy. (A Study of the Use of Oral Posaconazole [POS] in the Treatment of Asymptomatic Chronic Chagas Disease [P05267] [STOP CHAGAS]: NCT01377480).

Summary Background Two large trials have reported contradictory results at 1 year after thrombus aspiration in ST elevation myocardial infarction (STEMI). In a 1-year follow-up of the largest randomised trial of thrombus aspiration, we aimed to clarify the longer-term benefits, to help guide clinical practice. Methods The trial of routine aspiration ThrOmbecTomy with PCI versus PCI ALone in Patients with STEMI (TOTAL) was a prospective, randomised, investigator-initiated trial of routine manual thrombectomy versus percutaneous coronary intervention (PCI) alone in 10 732 patients with STEMI. Eligible adult patients (aged ≥18 years) from 87 hospitals in 20 countries were enrolled and randomly assigned (1:1) within 12 h of symptom onset to receive routine manual thrombectomy with PCI or PCI alone. Permuted block randomisation (with variable block size) was done by a 24 h computerised central system, and was stratified by centre. Participants and investigators were not masked to treatment assignment. The trial did not show a difference at 180 days in the primary outcome of cardiovascular death, myocardial infarction, cardiogenic shock, or heart failure. However, the results showed improvements in the surrogate outcomes of ST segment resolution and distal embolisation, but whether or not this finding would translate into a longer term benefit remained unclear. In this longer-term follow-up of the TOTAL study, we report the results on the primary outcome (cardiovascular death, myocardial infarction, cardiogenic shock, or heart failure) and secondary outcomes at 1 year. Analyses of the primary outcome were by modified intention to treat and only included patients who underwent index PCI. This trial is registered with ClinicalTrials.gov, number NCT01149044. Findings Between Aug 5, 2010, and July 25, 2014, 10 732 eligible patients were enrolled and randomly assigned to thrombectomy followed by PCI (n=5372) or to PCI alone (n=5360). After exclusions of patients who did not undergo PCI in each group (337 in the PCI and thrombectomy group and 331 in the PCI alone group), the final study population comprised 10 064 patients (5035 thrombectomy and 5029 PCI alone). The primary outcome at 1 year occurred in 395 (8%) of 5035 patients in the thrombectomy group compared with 394 (8%) of 5029 in the PCI alone group (hazard ratio [HR] 1·00 [95% CI 0·87–1·15], p=0·99). Cardiovascular death within 1 year occurred in 179 (4%) of the thrombectomy group and in 192 (4%) of 5029 in the PCI alone group (HR 0·93 [95% CI 0·76–1·14], p=0·48). The key safety outcome, stroke within 1 year, occurred in 60 patients (1·2%) in the thrombectomy group compared with 36 (0·7%) in the PCI alone group (HR 1·66 [95% CI 1·10–2·51], p=0·015). Interpretation Routine thrombus aspiration during PCI for STEMI did not reduce longer-term clinical outcomes and might be associated with an increase in stroke. As a result, thrombus aspiration can no longer be recommended as a routine strategy in STEMI. Funding Canadian Institutes of Health Research, Canadian Network and Centre for Trials Internationally, and Medtronic Inc.

Background: Moderate alcohol consumption may reduce cardiovascular events, but little is known about its effect on atrial fibrillation in people at high risk of such events. We examined the association between moderate alcohol consumption and the risk of incident atrial fibrillation among older adults with existing cardiovascular disease or diabetes. Methods: We analyzed data for 30 433 adults who participated in 2 large antihypertensive drug treatment trials and who had no atrial fibrillation at baseline. The patients were 55 years or older and had a history of cardiovascular disease or diabetes with end-organ damage. We classified levels of alcohol consumption according to median cut-off values for low, moderate and high intake based on guidelines used in various countries, and we defined binge drinking as more than 5 drinks a day. The primary outcome measure was incident atrial fibrillation. Results: A total of 2093 patients had incident atrial fibrillation. The age- and sex-standardized incidence rate per 1000 person-years was 14.5 among those with a low level of alcohol consumption, 17.3 among those with a moderate level and 20.8 among those with a high level. Compared with participants who had a low level of consumption, those with higher levels had an increased risk of incident atrial fibrillation (adjusted hazard ratio [HR] 1.14, 95% confidence interval [CI] 1.04–1.26, for moderate consumption; 1.32, 95% CI 0.97–1.80, for high consumption). Results were similar after we excluded binge drinkers. Among those with moderate alcohol consumption, binge drinkers had an increased risk of atrial fibrillation compared with non–binge drinkers (adjusted HR 1.29, 95% CI 1.02–1.62). Interpretation: Moderate to high alcohol intake was associated with an increased incidence of atrial fibrillation among people aged 55 or older with cardiovascular disease or diabetes. Among moderate drinkers, the effect of binge drinking on the risk of atrial fibrillation was similar to that of habitual heavy drinking.

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.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.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).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.

Background— We sought to determine the association between influenza vaccination and major adverse vascular events because the association remains uncertain. Methods and Results— A total of 31 546 participants were enrolled from 40 countries. Eligibility included age ≥55 years and known vascular disease. The primary outcome was a composite of death resulting from cardiovascular causes, myocardial infarction, or stroke during 4 influenza seasons (2003–2007). Influenza vaccination was associated with a lower risk of the outcome during 3 influenza seasons (defined using World Health Organization FluNet reports): 2004 to 2005 (adjusted odds ratio [OR], 0.62; 95% confidence interval [CI], 0.50–0.77), 2005 to 2006 (adjusted OR, 0.69; 95% CI, 0.53–0.91), and 2006 to 2007 (adjusted OR, 0.52; 95% CI, 0.42–0.65), the same years that circulating influenza matched the vaccine antigen. In 2003 to 2004, there was an incomplete match between circulating influenza and the vaccine antigen, and there was no association between influenza vaccination and the outcome (adjusted OR, 0.96; 95% CI, 0.73–1.27). However, tests of potential biases in the analyses revealed associations between influenza vaccination and outcome during noninfluenza seasons except 2003 to 2004. The summary ORs in the influenza season (OR, 0.65; 95% CI, 0.58–0.74]) and noninfluenza season (OR, 0.66; 95% CI, 0.57–0.76) were almost identical. The reduction in risk of noncardiovascular death associated with the influenza vaccine ranged from 73% to 79%. Conclusion— Although initial analyses suggest that influenza vaccination was associated with reduced risk of major adverse vascular events during influenza seasons when the influenza vaccine matched the circulating virus, sensitivity analyses revealed that risk of bias remained. A randomized trial is needed to definitively address this question.

Background— A daily single capsule (polycap) of 3 blood pressure (BP) lowering drugs (hydrochlorthiazide, 12.5 mg; atenolol, 50 mg; ramipril, 5 mg) at low doses, simvastatin (20 mg), and aspirin (100 mg) has been demonstrated to be well tolerated and to reduce BP and low-density lipoprotein cholesterol. We examined the incremental effects of 2 (full dose) plus K + supplementation versus single polycap (low dose) on risk factors and tolerability. Methods and Results— After a run-in period, 518 individuals with previous vascular disease or diabetes mellitus from 27 centers in India were randomly assigned to a single-dose polycap or to 2 capsules of the polycap plus K + supplementation for 8 weeks. The effects on BP, heart rate (HR), serum lipids, serum and urinary K + , and tolerability were assessed using an intention-to-treat analysis. The full-dose polycap (plus K + supplementation) reduced BP by a further 2.8 mm Hg systolic and 1.7 mm Hg diastolic, compared with that observed with the low-dose polycap ( P =0.003; P =0.001), but there were no differences in HR (0.1 bpm). The differences in total and low-density lipoprotein cholesterol between the full-dose and low-dose polycap was 7.2 mg/dL ( P =0.014) and 6.6 mg/dL ( P =0.006), respectively, but there were no differences in high-density lipoprotein cholesterol or triglycerides. The rates of discontinuation of the study drug after randomization were similar in the 2 groups (6.9% low dose versus 7.8% full dose). Conclusions— The full-dose polycap (plus K + supplementation) reduces BP and low-density lipoprotein cholesterol to a greater extent compared with the low dose, with similar tolerability. Therefore, the full-dose polycap should potentially lead to larger benefits. Clinical Trial Registration— URL: http://www.ctri.nic.in . Unique identifier: CTRI/2010/091/000054.

Objectives We sought to determine whether the blood pressure (BP) levels at which cardiovascular (CV) protection is achieved differ between diabetic and nondiabetic patients from the ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial). Background Greater absolute benefits of BP reductions have been claimed for diabetic as compared with nondiabetic patients. Methods A total of 25,584 patients (9,603 diabetic), older than 55 years, at high CV risk were randomized to ramipril, telmisartan, or both and observed for 4.6 years. We pooled the treatment arms to examine the relationships between BP and the primary composite outcome (CV death, nonfatal myocardial infarction or stroke, or hospitalized heart failure) and its components. Results The primary outcome occurred in 1,938 (20.2%) diabetic patients and in 2,276 (14.2%) nondiabetic patients. Compared with nondiabetic patients, diabetic patients had a significantly higher risk for the primary endpoint (hazard ratio [HR]: 1.48; 95% confidence interval [CI]: 1.38 to 1.57) and CV death (HR: 1.56; 95% CI: 1.42 to 1.71); myocardial infarction (HR: 1.30 (95% CI: 1.17 to 1.46); stroke (HR: 1.39; 95% CI: 1.23 to 1.56); and congestive heart failure hospitalization (HR: 2.06; 95% CI: 1.82 to 2.32). The CV risk was significantly higher in diabetic than in nondiabetic patients regardless of the systolic BP changes during treatment. In both diabetic and nondiabetic patients, progressively greater systolic BP reductions were accompanied by reduced risk for the primary outcome only if baseline systolic BP levels ranged from 143 to 155 mm Hg; except for stroke, there was no benefit in fatal or nonfatal CV outcomes by reducing systolic BP below 130 mm Hg. Conclusions The relationship between BP and overall CV risk had a similar pattern in diabetic and nondiabetic patients over a wide range of baseline and in-treatment BP values although, for the same systolic BP, a higher risk is observed in diabetic patients. (Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial [ONTARGET]; NCT00153101 )

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.

The degree of albuminuria predicts cardiovascular and renal outcomes, but it is not known whether changes in albuminuria also predict similar outcomes. In two multicenter, multinational, prospective observational studies, a central laboratory measured albuminuria in 23,480 patients with vascular disease or high-risk diabetes. We quantified the association between a greater than or equal to twofold change in albuminuria in spot urine from baseline to 2 years and the incidence of cardiovascular and renal outcomes and all-cause mortality during the subsequent 32 months. A greater than or equal to twofold increase in albuminuria from baseline to 2 years, observed in 28%, associated with nearly 50% higher mortality (HR 1.48; 95% CI 1.32 to 1.66), and a greater than or equal to twofold decrease in albuminuria, observed in 21%, associated with 15% lower mortality (HR 0.85; 95% CI 0.74 to 0.98) compared with those with lesser changes in albuminuria, after adjustment for baseline albuminuria, BP, and other potential confounders. Increases in albuminuria also significantly associated with cardiovascular death, composite cardiovascular outcomes (cardiovascular death, myocardial infarction, stroke, and hospitalization for heart failure), and renal outcomes including dialysis or doubling of serum creatinine (adjusted HR 1.40; 95% CI 1.11 to 1.78). In conclusion, in patients with vascular disease, changes in albuminuria predict mortality and cardiovascular and renal outcomes, independent of baseline albuminuria. This suggests that monitoring albuminuria is a useful strategy to help predict cardiovascular risk.

Summary Background Small trials have suggested that radial access for percutaneous coronary intervention (PCI) reduces vascular complications and bleeding compared with femoral access. We aimed to assess whether radial access was superior to femoral access in patients with acute coronary syndromes (ACS) who were undergoing coronary angiography with possible intervention. Methods The RadIal Vs femorAL access for coronary intervention (RIVAL) trial was a randomised, parallel group, multicentre trial. Patients with ACS were randomly assigned (1:1) by a 24 h computerised central automated voice response system to radial or femoral artery access. The primary outcome was a composite of death, myocardial infarction, stroke, or non-coronary artery bypass graft (non-CABG)-related major bleeding at 30 days. Key secondary outcomes were death, myocardial infarction, or stroke; and non-CABG-related major bleeding at 30 days. A masked central committee adjudicated the primary outcome, components of the primary outcome, and stent thrombosis. All other outcomes were as reported by the investigators. Patients and investigators were not masked to treatment allocation. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, NCT01014273. Findings Between June 6, 2006, and Nov 3, 2010, 7021 patients were enrolled from 158 hospitals in 32 countries. 3507 patients were randomly assigned to radial access and 3514 to femoral access. The primary outcome occurred in 128 (3·7%) of 3507 patients in the radial access group compared with 139 (4·0%) of 3514 in the femoral access group (hazard ratio [HR] 0·92, 95% CI 0·72–1·17; p=0·50). Of the six prespecified subgroups, there was a significant interaction for the primary outcome with benefit for radial access in highest tertile volume radial centres (HR 0·49, 95% CI 0·28–0·87; p=0·015) and in patients with ST-segment elevation myocardial infarction (0·60, 0·38–0·94; p=0·026). The rate of death, myocardial infarction, or stroke at 30 days was 112 (3·2%) of 3507 patients in the radial group compared with 114 (3·2%) of 3514 in the femoral group (HR 0·98, 95% CI 0·76–1·28; p=0·90). The rate of non-CABG-related major bleeding at 30 days was 24 (0·7%) of 3507 patients in the radial group compared with 33 (0·9%) of 3514 patients in the femoral group (HR 0·73, 95% CI 0·43–1·23; p=0·23). At 30 days, 42 of 3507 patients in the radial group had large haematoma compared with 106 of 3514 in the femoral group (HR 0·40, 95% CI 0·28–0·57; p Interpretation Radial and femoral approaches are both safe and effective for PCI. However, the lower rate of local vascular complications may be a reason to use the radial approach. Funding Sanofi-Aventis, Population Health Research Institute, and Canadian Network for Trials Internationally (CANNeCTIN), an initiative of the Canadian Institutes of Health Research.

A recent clinical trial showed harmful renal effects with the combined use of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin-II receptor blockers (ARB) in people with diabetes or vascular disease. We examined the benefits and risks of these agents in people with albuminuria and one or more cardiovascular risk factors.MEDLINE, EMBASE and Renal Health Library were searched for trials comparing ACEI, ARB or their combination with placebo or with one another in people with albuminuria and one or more cardiovascular risk factor.Eighty-five trials (21,708 patients) were included. There was no significant reduction in the risk of all-cause mortality or fatal cardiac-cerebrovascular outcomes with ACEI versus placebo, ARB versus placebo, ACEI versus ARB or with combined therapy with ACEI + ARB versus monotherapy. There was a significant reduction in the risk of nonfatal cardiovascular events with ACEI versus placebo but not with ARB versus placebo, ACEI versus ARB or with combined therapy with ACEI + ARB versus monotherapy. Development of end-stage kidney disease and progression of microalbuminuria to macroalbuminuria were reduced significantly with ACEI versus placebo and ARB versus placebo but not with combined therapy with ACEI + ARB versus monotherapy.ACEI and ARB exert independent renal and nonfatal cardiovascular benefits while their effects on mortality and fatal cardiovascular disease are uncertain. There is a lack of evidence to support the use of combination therapy. A comparative clinical trial with ACE, ARB and its combination in people with albuminuria and a cardiovascular risk factor is warranted.

Preliminary studies suggest that direct stenting (DS) during percutaneous coronary intervention (PCI) may reduce microvascular obstruction and improve clinical outcome. Thrombus aspiration may facilitate direct stenting. We assessed the impact of DS on myocardial reperfusion and clinical outcome and

Background We quantified the impact of lifestyle and dietary modifications on chronic kidney disease (CKD) by estimating population-attributable fractions (PAFs). Study Design Observational cohort study. Setting & Participants Middle-aged adults with type 2 diabetes but without severe albuminuria from the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET; n=6,916). Factors Modifiable lifestyle/dietary risk factors, such as physical activity, size of social network, alcohol intake, tobacco use, diet, and intake of various food items. Outcomes The primary outcome was CKD, ascertained as moderate to severe albuminuria or ≥5% annual decline in estimated glomerular filtration rate (eGFR) after 5.5 years. The competing risk for death was considered. PAF was defined as the proportional reduction in CKD or mortality (within 5.5 years) that would occur if exposure to a risk factor was changed to an optimal level. Results At baseline, median urinary albumin-creatinine ratio and eGFR were 6.6 (IQR, 2.9-25.0) mg/mmol and 71.5 (IQR, 58.1-85.9) mL/min/1.73m 2 , respectively. After 5.5 years, 704 (32.5%) participants developed albuminuria, 1,194 (55.2%) had a ≥5% annual eGFR decline, 267 (12.3%) had both, and 1,022 (14.8%) had died. Being physically active every day has PAFs of 5.1% (95% CI, 0.5%-9.6%) for CKD and 12.3% (95% CI, 4.9%-19.1%) for death. Among food items, increasing vegetable intake would have the largest impact on population health. Considering diet, weight, physical activity, tobacco use, and size of social network, exposure to less than optimum levels gives PAFs of 13.3% (95% CI, 5.5%-20.9%) for CKD and 37.5% (95% CI, 27.8%-46.7%) for death. For the 17.8 million middle-aged Americans with diabetes, improving 1 of these lifestyle behaviors to the optimal range could reduce the incidence or progression of CKD after 5.5 years by 274,000 and the number of deaths within 5.5 years by 405,000. Limitations Ascertainment of changes in kidney measures does not precisely match the definitions for incidence or progression of CKD. Conclusions Healthy lifestyle and diet are associated with less CKD and mortality and may have a substantial impact on population kidney health.

Background: Although the prevalence of chronic kidney disease (CKD) is ∼30% in the group of people with diabetes, data on interventions in the very early stage of the disease are still missing. Furthermore, the effects of modifiable lifestyle factors such as nutrition on incidence and progression of CKD in patients with diabetes in Europe remain elusive. Methods: We analyzed whether diet quality and adherence to dietary guidelines using the modified Alternate Healthy Eating Index (mAHEI) score was associated with CKD incidence or progression after 5.5 years in 3088 European participants of the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) with type 2 diabetes and baseline normo- or micro-albuminuria. Death was considered as a competing risk in the multinomial logit regression models, which were adjusted for age, gender, duration of diabetes, ONTARGET randomization, baseline albuminuria and glomerular filtration rate (GFR). We also estimated the potential impact on population health of improvement in diet quality. Results: At study end, 450 (14.6%) participants had died and 926 (30%) had experienced the renal endpoint of incidence or progression of CKD, of which 422 (13.7%) participants had progressed to micro- or macro-albuminuria, 596 (19.3%) had a GFR-decline of >5% per year and 18 (0.6%) had developed end-stage renal disease. Participants in the healthiest tertile of the mAHEI score had a decreased risk of incidence or progression of CKD (odds ratio 0.8, 95% confidence interval 0.68–0.94) and death (0.65, 0.52–0.81) compared with participants in the least healthy tertile. If individuals with a suboptimal dietary quality (e.g. mAHEI < 28) were able to improve their diet to an mAHEI of 28, 3.2% of CKD incidence or progression and 10.0% of deaths might be avoided in 5.5 years. Conclusions: If the association between diet and these endpoints is causal, then optimizing diet quality in individuals with diabetes who have no CKD or very early CKD would have substantial population benefits in terms of prevention of CKD incidence or progression and mortality in this high-risk population.

Background— Activated clotting time (ACT) is widely used to guide unfractionated heparin dosing during percutaneous coronary intervention. However, its value in predicting complications is controversial in the modern era. We sought to examine the relationship between ACT and outcomes in non–ST-segment–elevation acute coronary syndrome patients. Methods and Results— In the Fondaparinux With Unfractionated Heparin During Revascularization in Acute Coronary Syndromes (FUTURA/OASIS-8) trial, 2026 patients with non–ST-segment–elevation acute coronary syndrome treated with fondaparinux 2.5 mg/d and undergoing percutaneous coronary intervention were randomized to low-dose unfractionated heparin (50 U/kg) or standard-dose unfractionated heparin (85 U/kg or 60 U/kg with glycoprotein IIb/IIIa inhibitors, with ACT guidance). No difference was shown for major bleeding and there was a trend toward a reduction in ischemic events with standard-dose unfractionated heparin. To clarify the additional value of ACT guidance, we analyzed with logistic modeling peri–percutaneous coronary intervention outcomes according to peak ACT as a linear function. A threshold effect was then investigated. No linear correlation was found between ACT and thrombotic or bleeding events. In patients not receiving planned glycoprotein IIb/IIIa inhibitors, a significant increase in rates of death, myocardial infarction, and target vessel revascularization was identified in patients with an ACT≤300 s (4.86% versus 2.78%; adjusted odds ratio, 1.84; 95% confidence interval, 1.06–3.21; P =0.03). No threshold was found for hemorrhagic complications in patients with or without glycoprotein IIb/IIIa inhibitors. Conclusions— Non–ST-segment–elevation acute coronary syndrome patients undergoing percutaneous coronary intervention with an ACT≤300 s are at increased risk of thrombotic complications. ACT, however, does not predict hemorrhagic complications. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00790907.

Aims Manual thrombectomy has been proposed as a strategy to reduce thrombus burden during primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI). However, the effectiveness of manual thrombectomy in reducing thrombus burden is uncertain. In this substudy of the TOTAL (ThrOmbecTomy versus PCI ALone) trial, we compared the thrombus burden at the culprit lesion using optical coherence tomography (OCT) in patients treated with thrombectomy vs. PCI-alone. Methods and results The TOTAL trial ( N = 10 732) was an international, multicentre, randomized trial of thrombectomy (using the Export catheter, Medtronic Cardiovascular, Santa Rosa, CA, USA) in STEMI patients treated with primary PCI. The OCT substudy prospectively enrolled 214 patients from 13 sites in 5 countries. Optical coherence tomography was performed immediately after thrombectomy or PCI-alone and then repeated after stent deployment. Thrombus quantification was performed by an independent core laboratory blinded to treatment assignment. The primary outcome of pre-stent thrombus burden as a percentage of segment analysed was 2.36% (95% CI: 1.73–3.22) in the thrombectomy group and 2.88% (95% CI: 2.12–3.90) in the PCI-alone group ( P = 0.373). Absolute pre-stent thrombus volume was not different (2.99 vs. 3.74 mm3, P = 0.329). Other secondary outcomes of pre-stent quadrants of thrombus, post–stent atherothrombotic burden, and post-stent atherothrombotic volume were not different between groups. Conclusion Manual thrombectomy did not reduce pre-stent thrombus burden at the culprit lesion compared with PCI-alone. Both strategies were associated with low thrombus burden at the lesion site after the initial intervention to restore flow.

Abstract— Excessively high and low achieved blood pressure (BP) may be associated with a bad outcome in patients with coronary artery disease, the J curve phenomenon. The effect of BP changes from baseline in relation with the subsequent risk of stroke and myocardial infarction (MI) is unknown. Of the 25 620 patients randomized in the Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) study, we selected 19 102 patients with coronary artery disease at baseline. BP at entry was 141/82 mm Hg, and its average decrease during follow-up was 7/6 mm Hg. BP entered the analysis as time-varying variable modeled with restricted cubic splines. After adjustment for several potential determinants of reverse causality, a change in BP from baseline by –34/–21 mm Hg (10th percentile) was associated with a lesser risk of stroke without any significant increase in the risk of MI. A rise in systolic/diastolic BP from baseline by 20/10 mm Hg (90th percentile) was associated with an increased risk of stroke, whereas the risk of MI increased with systolic BP and not with diastolic BP. In conclusion, in patients with coronary artery disease and initially free from congestive heart failure, a BP reduction from baseline over the examined BP range had little effect on the risk of MI and predicted a lower risk of stroke. An increase in systolic BP from baseline increased the risk of stroke and MI. The relationships of BP with risk were much steeper for stroke than for MI. A treatment-induced BP reduction over the explored range seems to be safe in patients with coronary artery disease. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00153101.

Aims TOTAL ( N = 10 732), a randomized trial of routine manual thrombectomy vs. percutaneous coronary intervention alone in ST elevation myocardial infarction, showed no difference in the primary efficacy outcome but a significant increase in stroke. We sought to understand these findings. Methods and results A detailed analysis of stroke timing, stroke severity, and stroke subtype was performed. Strokes were adjudicated by neurologists blinded to treatment assignment. Stroke within 30 days, the primary safety outcome, was increased [33 (0.7%) vs. 16 (0.3%), hazard ratio (HR) 2.06; 95% confidence interval (CI) 1.13–3.75]. The difference in stroke was apparent within 48 h [15 (0.3%) vs. 5 (0.1%), HR 3.00; 95% CI 1.09–8.25]. There was an increase in strokes within 180 days with minor or no disability (Rankin 0–2) [18 (0.4%) vs. 13 (0.3%) HR 1.38; 95% CI 0.68–2.82] and in strokes with major disability or fatal (Rankin 3–6) [35 (0.7%) vs. 13 (0.3%), HR 2.69; 95% CI 1.42–5.08]. Most of the absolute difference was due to an increase in ischaemic strokes within 180 days [37 (0.7%) vs. 21 (0.4%), HR 1.71; 95% CI 1.03–3.00], but there was also an increase in haemorrhagic strokes [10 (0.2%) vs. 2 (0.04%), HR 4.98; 95% CI 1.09–22.7]. Patients that had a stroke had a mortality of 30.8% within 180 days vs. 3.4% without a stroke ( P < 0.001). A meta-analysis of randomized trials ( N = 21 173) showed an increase in risk of stroke (odds ratio 1.59; 95% CI 1.11–2.27) but a trend towards reduction in mortality odds ratio (odds ratio 0.87; 95% CI 0.76–1.00). Conclusion Thrombectomy was associated with a significant increase in stroke. Based on these findings, future trials must carefully collect stroke to determine safety in addition to efficacy.

To examine the association between Mini-Mental State Examination (MMSE) score and motor vehicle crash (MVC) risk in a large cohort of community-dwelling participants with cardiovascular disease (CVD) or diabetes mellitus.Prospective observational study.Participants enrolled in the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial and Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease clinical trial, which included individuals aged 55 and older with CVD or diabetes mellitus.Totally 17,538 frequent drivers (defined as driving at least once per week) who had completed a baseline MMSE.Involvement in a MVC as the driver.Baseline MMSE score was divided into four categories: 30, 27-29, 24-26, and24. The median MMSE score was 29 (interquartile range 27-30), and 726 (4.1%) has a MMSE score of less than 24 at baseline. After a mean follow-up of 4.5 years, 1,068 (6.1%) participants were drivers in a MVC. Lower scores were not associated with future MVCs (MMSE score 29-27, hazard ratio (HR)=1.06, 95% confidence interval (CI)=0.93-1.22); MMSE score 26-24, HR=0.96, 95% CI=0.78-1.19; MMSE score24, HR=0.72, 95% CI=0.50-1.05) on multivariable analysis. A MVC within the previous 2 years (HR=2.68, 95% CI=2.29-3.13) was the strongest predictor of future MVCs. Other clinical factors associated with greater MVC risk were depression, falls within the previous year, sleep apnea, and lower baseline systolic blood pressure.In a population of frequent drivers, the MMSE does not predict MVCs. Other clinical factors have a stronger association with MVC risk.

The purpose of this study was to determine the efficacy and safety of radial versus femoral access in women undergoing coronary angiography/intervention.The risk of bleeding and vascular access site complications are higher in women than in men.In a pre-specified RIVAL (RadIal Vs femorAL access for coronary intervention) subgroup analysis, we compared outcomes in women (n=1,861) and men (n=5,160) randomized to radial versus femoral access.Overall, women were at higher risk of major vascular complications compared with men (4.7% vs. 1.7%; p0.0001). Major vascular complications were significantly reduced with radial access in women (3.1% vs. 6.1%; hazard ratio [HR]: 0.5; 95% confidence interval [CI]: 0.32 to 0.78; p=0.002) and in men (0.7% vs. 2.8%; HR: 0.27; 95% CI: 0.17 to 0.45; p0.0001; interaction p=0.092). Crossover rates were higher with radial compared with femoral access in women (11.1% vs. 1.9%; HR: 5.88; p0.0001) and men (6.3% vs. 1.9%; HR: 3.32; p0.0001; interaction p=0.054). Percutaneous coronary intervention (PCI) success rates were similar irrespective of access site (women: HR: 1.05; p=0.471; men: HR: 1.00; p=0.888; interaction p=0.674), with no differences in PCI complications. In multivariable analyses, female sex was an independent predictor of major vascular complications (HR: 2.39; 95% CI: 1.76 to 3.25; p0.0001). There were consistent findings for women and men, with no difference for the primary composite endpoint of death, myocardial infarction, stroke, and non-coronary artery bypass grafting bleeding (women: 3.9% vs. 5.0%; HR: 0.77; 95% CI: 0.50 to 1.19; men: 3.54% vs. 3.5%; HR: 1.00; 95% CI: 0.75 to -1.34; interaction p=0.325).Women undergoing coronary angiography and PCI have a higher risk of vascular access site complications compared with men, and radial access is an effective method to reduce these complications.

This observational study examined the association between modifiable lifestyle and social factors on the incidence and progression of early chronic kidney disease (CKD) among those with type 2 diabetes. All 6972 people from the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) with diabetes but without macroalbuminuria were studied. CKD progression was defined as decline in GFR of more than 5% per year, progression to end-stage renal disease, microalbuminuria, or macroalbuminuria at 5.5 years. Lifestyle/social factors included tobacco and alcohol use, physical activity, stress, financial worries, the size of the social network and education. Adjustments were made for known risks such as age, diabetes duration, GFR, albuminuria, gender, body mass index, blood pressure, fasting plasma glucose, and angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers use. Competing risk of death was considered. At study end, 31% developed CKD and 15% had died. The social network score (SNS) was a significant independent risk factor of CKD and death, reducing the risk by 11 and 22% when comparing the third to the first tertile of the SNS (odds ratios of CKD 0.89 and death 0.78). Education showed a significant association with CKD but stress and financial worries did not. Those with moderate alcohol consumption had a significantly decreased CKD risk compared with nonusers. Regular physical activity significantly decreased the risk of CKD. Thus, lifestyle is a determinant of kidney health in people at high cardiovascular risk with diabetes.

BACKGROUND fractures are a major health concern among the elderly. People at risk for cardiovascular disease (CVD) are at an increased risk for fractures. The aim of this study was to assess the individual and combined effect of the CVD risk factors of smoking, alcohol consumption and physical activity on fracture risk in a large sample of older individuals with CVD or diabetes with end-organ damage. METHODS we analysed data for 26,335 adults, aged 55 years or older, who participated in two large antihypertensive drug treatment trials and who had no previous fracture at baseline. Lifestyle factors were assessed by the standardised questionnaire and their individual and combined effects on incident fracture risk were modelled using Cox proportional hazard regression. RESULTS during the 56-month follow-up, 1,079 incident fractures occurred; 508 (6.51%) among women and 571 (3.08%) among men. Smoking [hazard ratio (HR) 1.52, 95% confidence interval (CI) 1.27-1.82] and low physical activity (HR: 1.19, 95% CI: 1.05-1.36) were associated with an increased risk of any fracture, while high alcohol intake showed a directional, but non-significant, relationship with fracture risk (HR: 1.09, 95% CI: 0.64-1.84). Compared with participants with no lifestyle risk factors, those having one, two, or three risk factors had an increased risk of a future fracture (HR: 1.17, 95% CI: 1.03-1.34 for one risk factor; HR: 1.73, 95% CI: 1.38-2.16 for two risk factors; and HR: 2.37, 95% CI: 0.88-6.36 for three risk factors; P for trend

Patients are often advised to reduce sodium and potassium intake, but supporting evidence is limited. To help provide such evidence we estimated 24 h urinary sodium and potassium excretion in 28,879 participants at high cardiovascular risk who were followed for a mean of 4.5 years in the ONTARGET and TRANSCEND trials. The primary outcome was eGFR decline of 30% or more or chronic dialysis. Secondary outcomes were eGFR decline of 40% or more or chronic dialysis, doubling of serum creatinine or chronic dialysis, an over 5%/year loss of eGFR, progression of albuminuria, and hyperkalemia. Multinomial logit regression with multivariable fractional polynomials, adjusted for confounders, determined the association between urinary sodium and potassium excretion and renal outcomes, with death as a competing risk. The primary outcome occurred in 2,052 (7.6%) patients. There was no significant association between sodium and any renal outcome (primary outcome odds ratio 0.99; 95% CI 0.89-1.09 for highest [median 6.2 g/day] vs. lowest third [median 3.3 g/day]). Higher potassium was associated with lower odds of all renal outcomes (primary outcome odds ratio 0.74; 95% CI 0.67-0.82 for highest [median 2.7 g/day] vs. lowest third [median 1.7 g/day], except hyperkalemia nonsignificant. Thus, urinary potassium, but not sodium, excretion predicted clinically important renal outcomes. Our findings do not support routine low sodium and potassium diets for prevention of renal outcomes in people with vascular disease with or without chronic kidney disease.

Objectives The study sought to evaluate the relationship between procedural volume and outcomes with radial and femoral approach. Background RIVAL (RadIal Vs. femorAL) was a randomized trial of radial versus femoral access for coronary angiography/intervention (N = 7,021),which overall did not show a difference in primary outcome of death, myocardial infarction, stroke, or non-coronary artery bypass graft major bleeding. Methods In pre-specified subgroup analyses, the hazard ratios for the primary outcome were compared among centers divided by tertiles and among individual operators. A multivariable Cox proportional hazards model was used to determine the independent effect of center and operator volumes after adjusting for other variables. Results In high-volume radial centers, the primary outcome was reduced with radial versus femoral access (hazard ratio [HR]: 0.49; 95% confidence interval [CI]: 0.28 to 0.87) but not in intermediate-(HR: 1.23; 95% CI: 0.88 to 1.72) or low-volume centers (HR: 0.83; 95% CI: 0.52 to 1.31; interaction p 0.021). High-volume centers enrolled a higher proportion of ST-segment elevation myocardial infarction (STEMI). After adjustment for STEMI, the benefit of radial access persisted at high-volume radial centers. There was no difference in the primary outcome between radial and femoral access by operator volume: high-volume operators (HR: 0.79; 95% CI: 0.48 to 1.28), intermediate (HR: 0.87; 95% CI: 0.60 to 1.27), and low (HR: 1.10; 95% CI: 0.74 to 1.65; interaction p 0.536). However, in a multivariable model, overall center volume and radial center volume were independently associated with the primary outcome but not femoral center volume (overall percutaneous coronary intervention volume HR: 0.92, 95% CI: 0.88 to 0.96; radial volume HR: 0.88, 95% CI: 0.80 to 0.97; and femoral volume HR: 1.00, 95% CI: 0.94 to 1.07; p 0.98). Conclusions Procedural volume and expertise are important, particularly for radial percutaneous coronary intervention. (A Trial of Trans-radial Versus Trans-femoral Percutaneous Coronary Intervention [PCI] Access Site Approach in Patients With Unstable Angina or Myocardial Infarction Managed With an Invasive Strategy [RIVAL]; NCT01014273) (C) 2014 by the American College of Cardiology Foundation (Less)