Comparison of risk factor reduction and tolerability of a full-dose polypill (with potassium) versus low-dose polypill (polycap) in individuals at high risk of cardiovascular diseases: the Second Indian Polycap Study (TIPS-2) investigators.

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.

Early invasive compared with a selective invasive strategy in women with non-ST-elevation acute coronary syndromes: a substudy of the OASIS 5 trial and a meta-analysis of previous randomized trials.

AIMS: The aim of this study was to compare benefits and risks of a routine invasive compared with a selective invasive strategy in women with non-ST-elevation acute coronary syndromes. METHODS AND RESULTS: We randomly assigned 184 women, either to a routine or to a selective invasive strategy as a substudy to the OASIS 5 trial, who were followed for 2 years. Meta-analysis of data from previous randomized trials was also done. There were no significant differences between the two treatment strategies in the primary outcome death/myocardial infarction (MI)/stroke [21.0 vs. 15.4%, HR = 1.46, 95% CI (0.73-2.94)], in the secondary outcome death/MI [18.8 vs. 14.3%, HR = 1.39, 95% CI (0.67-2.88)], or separately analysed outcomes MI [12.9 vs. 13.3%, HR = 0.95, 95% CI (0.42-2.19)] or stroke [2.3 vs. 4.4%, HR = 0.67, 95% CI (0.12-3.70)]. However, there were significantly more deaths after 1 year (8.8 vs. 1.1%, HR = 9.01, 95% CI (1.11-72.90) and a higher rate of major bleeding at 30 days [8.8 vs. 1.1%, HR = 11.45, 95% CI (1.43-91.96)] in the routine invasive strategy group. A meta-analysis including 2692 women in previous randomized trials, with a gender perspective, showed no significant difference in the composite outcome death/MI, OR = 1.18, 95% CI (0.92-1.53) but a higher mortality with a routine invasive strategy for women, OR = 1.51, 95% CI (1.00-2.29). CONCLUSION: The rate of death, MI, or stroke in women was not different in patients treated with a routine invasive strategy compared with a selective invasive strategy, but there was a concerning trend towards higher mortality. When combined with data from previous trials, there does not appear to be a benefit of an early invasive strategy in women with ACS, which differs from the results in men. These data emphasize the lack of clear evidence in favour of an invasive strategy in women and suggest caution in extrapolating the results from men to women.

Radial versus femoral access for coronary angiography and intervention in patients with acute coronary syndromes (RIVAL): a randomised, parallel group, multicentre trial.

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<0·0001). Pseudoaneurysm needing closure occurred in seven of 3507 patients in the radial group compared with 23 of 3514 in the femoral group (HR 0·30, 95% CI 0·13-0·71; p=0·006). 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.

Dose comparisons of clopidogrel and aspirin in acute coronary syndromes.

BACKGROUND: Clopidogrel and aspirin are widely used for patients with acute coronary syndromes and those undergoing percutaneous coronary intervention (PCI). However, evidence-based guidelines for dosing have not been established for either agent. METHODS: We randomly assigned, in a 2-by-2 factorial design, 25,086 patients with an acute coronary syndrome who were referred for an invasive strategy to either double-dose clopidogrel (a 600-mg loading dose on day 1, followed by 150 mg daily for 6 days and 75 mg daily thereafter) or standard-dose clopidogrel (a 300-mg loading dose and 75 mg daily thereafter) and either higher-dose aspirin (300 to 325 mg daily) or lower-dose aspirin (75 to 100 mg daily). The primary outcome was cardiovascular death, myocardial infarction, or stroke at 30 days. RESULTS: The primary outcome occurred in 4.2% of patients assigned to double-dose clopidogrel as compared with 4.4% assigned to standard-dose clopidogrel (hazard ratio, 0.94; 95% confidence interval [CI], 0.83 to 1.06; P=0.30). Major bleeding occurred in 2.5% of patients in the double-dose group and in 2.0% in the standard-dose group (hazard ratio, 1.24; 95% CI, 1.05 to 1.46; P=0.01). Double-dose clopidogrel was associated with a significant reduction in the secondary outcome of stent thrombosis among the 17,263 patients who underwent PCI (1.6% vs. 2.3%; hazard ratio, 0.68; 95% CI, 0.55 to 0.85; P=0.001). There was no significant difference between higher-dose and lower-dose aspirin with respect to the primary outcome (4.2% vs. 4.4%; hazard ratio, 0.97; 95% CI, 0.86 to 1.09; P=0.61) or major bleeding (2.3% vs. 2.3%; hazard ratio, 0.99; 95% CI, 0.84 to 1.17; P=0.90). CONCLUSIONS: In patients with an acute coronary syndrome who were referred for an invasive strategy, there was no significant difference between a 7-day, double-dose clopidogrel regimen and the standard-dose regimen, or between higher-dose aspirin and lower-dose aspirin, with respect to the primary outcome of cardiovascular death, myocardial infarction, or stroke. (Funded by Sanofi-Aventis and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00335452.)

Safety and feasibility of early hospital discharge in ST-segment elevation myocardial infarction--a prospective and randomized trial in low-risk primary percutaneous coronary intervention patients (the Safe-Depart Trial).

BACKGROUND: Patients with ST-segment elevation myocardial infarction (STEMI) have traditionally been hospitalized for 5 to 7 days to monitor for serious complications such as heart failure, arrhythmias, reinfarction, and death. The Zwolle Primary Percutaneous Coronary Intervention (PCI) Index is an externally validated risk score that has been used to identify low-risk STEMI patients who have undergone primary PCI and can safely be discharged from hospital within 72 hours. Previous studies have shown that many low-risk patients remain in hospital significantly longer. METHODS: We randomly assigned 54 low-risk STEMI patients treated with primary or rescue PCI to 1 of 2 groups. Patients in the intervention group (n = 27) were actively targeted for early hospital discharge (48-72 hours) and received outpatient follow-up with an advanced practice nurse (APN). In the control group (n = 27), discharge planning and follow-up were left to the treating physician, and there was no added nursing intervention. The 2 primary outcomes of this pilot study were to demonstrate feasibility and safety. Secondary outcomes included compliance with medications, smoking cessation, attendance at cardiac rehabilitation, and quality of life, measured in both groups at 6 weeks time. RESULTS: In the intervention group, 74% of patients were discharged within 72 hours, 100% had follow-up with the APN within 3 days (74% in person, 26% by phone), and 100% had >/= 3 APN follow-ups in total, meeting our prespecified criteria for feasibility. The median length of stay was 55 hours in both groups. There were no deaths in either group, and there was no difference in rehospitalization between patients in the intervention and control groups (8% vs 4%, P = .56). There was no difference in rates of medication compliance, smoking cessation, attendance at cardiac rehabilitation, or quality of life between the 2 groups, although our small pilot study was not powered to detect a difference in these outcomes. CONCLUSION: In low-risk STEMI patients treated with primary or rescue PCI, a strategy of early hospital discharge facilitated by close nursing follow-up is feasible. Although our study did not identify differences in compliance or quality of life between the 2 groups, it did provide a functional study design for a larger trial powered to detect these important clinical end points.

Early versus delayed invasive intervention in acute coronary syndromes.

BACKGROUND: Earlier trials have shown that a routine invasive strategy improves outcomes in patients with acute coronary syndromes without ST-segment elevation. However, the optimal timing of such intervention remains uncertain. METHODS: We randomly assigned 3031 patients with acute coronary syndromes to undergo either routine early intervention (coronary angiography < or = 24 hours after randomization) or delayed intervention (coronary angiography > or = 36 hours after randomization). The primary outcome was a composite of death, myocardial infarction, or stroke at 6 months. A prespecified secondary outcome was death, myocardial infarction, or refractory ischemia at 6 months. RESULTS: Coronary angiography was performed in 97.6% of patients in the early-intervention group (median time, 14 hours) and in 95.7% of patients in the delayed-intervention group (median time, 50 hours). At 6 months, the primary outcome occurred in 9.6% of patients in the early-intervention group, as compared with 11.3% in the delayed-intervention group (hazard ratio in the early-intervention group, 0.85; 95% confidence interval [CI], 0.68 to 1.06; P=0.15). There was a relative reduction of 28% in the secondary outcome of death, myocardial infarction, or refractory ischemia in the early-intervention group (9.5%), as compared with the delayed-intervention group (12.9%) (hazard ratio, 0.72; 95% CI, 0.58 to 0.89; P=0.003). Prespecified analyses showed that early intervention improved the primary outcome in the third of patients who were at highest risk (hazard ratio, 0.65; 95% CI, 0.48 to 0.89) but not in the two thirds at low-to-intermediate risk (hazard ratio, 1.12; 95% CI, 0.81 to 1.56; P=0.01 for heterogeneity). CONCLUSIONS: Early intervention did not differ greatly from delayed intervention in preventing the primary outcome, but it did reduce the rate of the composite secondary outcome of death, myocardial infarction, or refractory ischemia and was superior to delayed intervention in high-risk patients. (ClinicalTrials.gov number, NCT00552513.)

Prognostic importance of weight loss in chronic heart failure and the effect of treatment with angiotensin-converting-enzyme inhibitors: an observational study.

BACKGROUND: Weight loss in chronic heart failure is linked to impaired survival. We aimed to assess the frequency of weight loss in patients with this disease, whether the degree of weight loss predicts mortality, and whether weight loss can be prevented by angiotensin-converting-enzyme (ACE) inhibitors. METHODS: We investigated weight changes in 1929 patients from the SOLVD trial who had chronic heart failure, were free of oedema at baseline, and survived for at least 4 months after trial entry. Meanfollow-up was 35 months (SD 13). We analysed the effect of weight loss at cutpoints of 5%, 7.5%, 10%, 15% (a priori), and 6% (post hoc) to identify which one best predicted outcome. To validate results, we analysed data for 619 patients in the V-HeFT II trial. FINDINGS: 817 (42%) patients in the SOLVD trial had weight loss from baseline of 5% or more. At 8 months follow-up, all cutpoints for weight loss were significantly associated with impaired survival after adjustment for age, sex, New York Heart Association class, left ventricular ejection fraction, and treatment allocation. Weight loss of 6% or more at any time during follow-up was the strongest predictor of impaired survival (adjusted hazard ratio 2.10, 95% CI 1.77-2.49; p<0.0001). Patients on the ACE inhibitor enalapril had a lower hazard of 6% or more weight loss than did those not taking the drug (adjusted reduction 19%, p=0.0054). Results from analyses of V-HeFT II data lent support to our findings. INTERPRETATION: Weight loss occurs frequently in patients with chronic heart disease, its reversal is rare, and when present, it is independently linked to impaired survival. Weight loss of more than 6% should be used to define the presence of cachexia in patients with chronic heart failure. In chronic heart failure, treatment with an ACE inhibitor reduces the risk of weight loss.