Background The US Food and Drug Administration (FDA) required a reevaluation of cardiovascular (CV) outcomes in the RECORD trial. This provided an opportunity to assess the implications of event ...adjudication by 2 groups and quantify the differences as well as to use new FDA end point definitions in development. Methods Original data were used to systematically identify all potential deaths, myocardial infarctions (MIs), and strokes. Site investigators were approached for additional source documents and information about participants lost to follow-up. Suspected events were adjudicated using standard procedures, and the results were compared with the original trial outcomes. Results Follow-up for mortality was 25,833 person-years, including an additional 328 person-years identified during the reevaluation effort. A total of 184 CV or unknown-cause deaths (88 rosiglitazone, 96 metformin/sulfonylurea), 128 participants with an MI (68 rosiglitazone, 60 metformin/sulfonylurea), and 113 participants with a stroke (50 rosiglitazone, 63 metformin/sulfonylurea) were included. The hazard ratio (HR) for rosiglitazone versus metformin/sulfonylurea for the end point of CV (or unknown cause) death, MI, or stroke was 0.95 (95% CI 0.78-1.17) compared with 0.93 (95% CI 0.74-1.15) for the original RECORD results. Treatment comparisons for MI (HR 1.13, 95% CI 0.80-1.59) and mortality (HR 0.86, 95% CI 0.68-1.08) were also the same compared with the original RECORD results. Sensitivity analyses were also consistent with the original RECORD results. Analyses using the FDA definitions showed similar results. Conclusions Only a modest number of additional person-years of follow-up were ascertained from this reevaluation of CV end points in RECORD. Observed HRs and CIs from these analyses using the original RECORD or new FDA end point definitions showed similar treatment effects of rosiglitazone compared with the original RECORD results.
Summary Background Treatment with prasugrel and aspirin improves outcomes compared with clopidogrel and aspirin for patients with acute coronary syndrome who have had angiography and percutaneous ...coronary intervention; however, no clear benefit has been shown for patients managed first with drugs only. We assessed outcomes from the TRILOGY ACS trial based on whether or not patients had coronary angiography before treatment was chosen. Methods TRILOGY ACS ( ClinicalTrials.gov number NCT00699998 ) was a randomised controlled trial, done at more than 800 sites worldwide. Patients with non-ST-elevation acute coronary syndrome who were selected for management without revascularisation were randomly assigned to clopidogrel or prasugrel. The primary endpoint was cardiovascular death, myocardial infarction, or stroke at 30 months. In the present analysis we assessed differences in the primary endpoint by angiography status and whether the effects of treatment on the primary endpoint differed between patients who had angiography before enrolment and those who had not. Findings 7243 patients younger than 75 years were included in the TRILOGY ACS primary analysis. 3085 (43%) had angiography at baseline, 4158 (57%) had not. Fewer patients who had angiography reached the primary endpoint at 30 months compared with those who did not have angiography, according to Kaplan-Meier analysis (281/3085 12·8% vs 480/4158 16·5%, adjusted hazard ratio HR 0·63, 95% CI 0·53–0·75; p<0·0001). The proportion of patients who reached the primary endpoint was lower in the prasugrel group than in the clopidogrel group for those who had angiography (122/1524 10·7% vs 159/1561 14·9%, HR 0·77, 95% CI 0·61–0·98; p=0·032) but did not differ between groups in patients who did not have angiography (242/2096 16·3% vs 238/2062 16·7%, HR 1·01, 0·84–1·20; p=0·94; pinteraction =0·08). Overall, TIMI major bleeding and GUSTO severe bleeding were rare. Bleeding outcomes tended to be higher with prasugrel but did not differ significantly between treatment groups in either angiography cohort. Interpretation Among patients who had angiography who took prasugrel there were fewer cardiovascular deaths, myocardial infarctions, or strokes than in those who took clopidogrel. This result needs to be corroborated, but it is consistent with previous trials of more versus less intensive antiplatelet treatment. When angiography is done for acute coronary syndrome and anatomic coronary disease confirmed, the benefits and risks of intensive antiplatelet treatment exist whether the patient is treated with drugs or percutaneous coronary intervention. Funding Daiichi Sankyo, Eli Lilly.
Background This analysis compares 1-year vein graft patency and major adverse cardiac and cerebral events (MACCE death, myocardial infarction, or stroke) in on-pump and off-pump patients enrolled in ...PREVENT IV (the PRoject of Ex-vivo Vein graft ENgineering via Transfection IV). Methods The PREVENT IV was a multicenter (107 sites) randomized trial of edifoligide to prevent vein graft failure from neointimal hyperplasia in 3,014 patients undergoing primary, isolated coronary artery bypass grafting (CABG) with at least two vein grafts. One-year angiographic follow-up was completed on 1,920 patients (4,736 grafts) with MACCE follow-up on 99.4% of enrolled patients. Results In all, 2,377 procedures (78.9%) were on pump and 637 (21.1%) were off pump. On-pump patients had more chronic lung disease (17% versus 11%; p < 0.001), congestive heart failure (10% versus 7%; p = 0.03), lower mean ejection fraction (50% versus 55%; p < 0.001), and worse target artery quality (good 63.8% versus 68.1%; fair 26.4% versus 22.7%; poor 9.8% versus 9.2%; p < 0.001). Vein graft failure (more than 75% graft stenosis) in on- versus off-pump patients was 25.3% versus 25.7% ( p = 0.62). After adjusting for differences in significant predictors of vein graft failure (target artery quality, surgery time, endoscopic vein harvest, more than 1 distal anastomosis/graft, and patient weight), the odds of vein graft failure was 0.82 (95% confidence interval: 0.67 to 1.00; p = 0.05) for on-pump versus off-pump patients. One-year mortality for on- versus off-pump patients was 3.3% versus 2.5% ( p = 0.30); and MACCE was 15.4% versus 11.3% ( p = 0.01). The adjusted hazard ratio for 1-year MACCE was 1.31 (95% confidence interval: 1.01–1.69; p = 0.01) for on pump versus off pump. Conclusions Observed saphenous vein failure rate was 25% in both groups. One-year clinical outcomes (MACCE) were better with off-pump than with on-pump CABG, suggesting benefits not related to vein graft patency.
Background Edifoligide, an E2F transcription factor decoy, does not prevent vein graft failure or adverse clinical outcomes at 1 year in patients undergoing coronary artery bypass grafting (CABG). We ...compared the 5-year clinical outcomes of patients in PREVENT IV treated with edifoligide and placebo to identify predictors of long-term clinical outcomes. Methods A total of 3,014 patients undergoing CABG with at least 2 planned vein grafts were enrolled. Kaplan-Meier curves were generated to compare the long-term effects of edifoligide and placebo. A Cox proportional hazards model was constructed to identify factors associated with 5-year post-CABG outcomes. The main outcome measures were death, myocardial infarction (MI), repeat revascularization, and rehospitalization through 5 years. Results Five-year follow-up was complete in 2,865 patients (95.1%). At 5 years, patients randomized to edifoligide and placebo had similar rates of death (11.7% and 10.7%, respectively), MI (2.3% and 3.2%), revascularization (14.1% and 13.9%), and rehospitalization (61.6% and 62.5%). The composite outcome of death, MI, or revascularization occurred at similar frequency in patients assigned to edifoligide and placebo (26.3% and 25.5%, respectively; hazard ratio 1.03 95% CI 0.89-1.18, P = .721). Factors associated with death, MI, or revascularization at 5 years included peripheral and/or cerebrovascular disease, time on cardiopulmonary bypass, lung disease, diabetes mellitus, and congestive heart failure. Conclusions Up to a quarter of patients undergoing CABG will have a major cardiac event or repeat revascularization procedure within 5 years of surgery. Edifoligide does not affect outcomes after CABG; however, common identifiable baseline and procedural risk factors are associated with long-term outcomes after CABG.
Background In 2010, after regulatory review of rosiglitazone licensing, the US Food and Drug Administration (FDA) requested a reevaluation of cardiovascular end points in the RECORD trial. Methods ...Automated screening of the original clinical trial database and manual case report form review were performed to identify all potential cardiovascular and noncardiovascular deaths, and nonfatal myocardial infarction (MI) and stroke events. Search techniques were used to find participants lost to follow-up, and sites were queried for additional source documents. Suspected events underwent blinded adjudication using both original RECORD end point definitions and new FDA end point definitions, before analysis by the Duke Clinical Research Institute. Results The reevaluation effort included an additional 328 person-years of follow-up. Automated screening identified 396 suspected deaths, 2,052 suspected MIs, and 468 suspected strokes. Manual review of documents by Duke Clinical Research Institute clinical events classification (CEC) coordinators identified an additional 31 suspected deaths, 49 suspected MIs, and 28 suspected strokes. There were 127 CEC queries issued requesting additional information on suspected deaths; 43 were closed with no site response, 61 were closed with a response that no additional data were available, and additional data were received for 23. Seventy CEC queries were issued requesting additional information for suspected MI and stroke events; 31 were closed with no site response, 20 were closed with a response that no additional data were available, and 19 resulted in additional data. Conclusions Comprehensive procedures were used for rigorous event reascertainment and readjudication in a previously completed open-label, global clinical trial. These procedures used in this unique situation were consistent with other common approaches in the field, were enhanced to address the FDA concerns about the original RECORD trial results, and could be considered by clinical trialists designing event readjudication protocols for drug development programs that have been completed.
Myocardial infarction (MI) after coronary artery bypass grafting (CABG) is associated with significant morbidity and mortality. Frequency, management, mechanisms, and angiographic and clinical ...outcomes associated with perioperative MI remain poorly understood. PREVENT IV was a multicenter, randomized, placebo-controlled trial of edifoligide in 3,014 patients undergoing CABG. Angiographic and 2-year clinical follow-up were complete for 1,920 and 2,956 patients, respectively. Perioperative MI was defined as creatinine kinase-MB increase ≥10 times the upper limit of normal or ≥5 times the upper limit of normal with new 30-ms Q waves within 24 hours of surgery. Baseline characteristics, in-hospital management, and angiographic and clinical outcomes of patients with and without perioperative MI were compared. Perioperative MI occurred in 294 patients (9.8%). Patients with perioperative MI had longer surgery (250 vs 230 minutes; p <0.001), more on-pump surgery (83% vs 78%; p = 0.048), and worse target-artery quality (p <0.001). Patients with perioperative MI more frequently underwent angiography within 30 days of enrollment (1.7% vs 0.6%; p = 0.021). One-year angiographic vein graft failure occurred in 62.4% of patients with and 43.8% of patients without perioperative MI (p <0.001). Two-year composite clinical outcome (death, MI, or revascularization) was worse in patients with perioperative MI before (19.4% vs 15.2%; p = 0.039) and after (hazard ratio 1.33, 95% confidence interval 1.00 to 1.76, p = 0.046) adjusting for differences in significant predictors. In conclusion, perioperative MI was relatively common, was associated with worse outcomes, and mechanisms other than vein graft failure accounted for a substantial proportion of these MIs. Further research is needed into the prevention and treatment of perioperative MI in patients undergoing CABG.
Background There is limited information about the association between diabetes, its treatment, and long-term angiographic and clinical outcomes in patients undergoing coronary artery bypass graft ...surgery (CABG). We evaluated the association of diabetes and its treatment with 1-year angiographic graft failure and 5-year clinical outcomes in patients undergoing CABG. Methods Using data from 3,014 patients in PREVENT IV, we analyzed angiographic and clinical outcomes in patients with and without diabetes and among those who did and did not receive insulin before CABG. Logistic regression and Cox proportional hazards models were used to adjust for differences in baseline variables. Results Overall, 1,139 (37.8%) patients had diabetes. Of these, 305 (26.8%) received insulin. One-year rates of vein graft failure were similar in patients with and without diabetes but, among diabetics, tended to be higher in patients who received insulin compared with those who did not. At 5 years, rates of death, myocardial infarction, or revascularization were higher among patients with compared with those without diabetes (adjusted hazard ratio 1.57; 95% CI 1.26-1.96; P < .001) and, among diabetics, higher among those who received insulin (adjusted hazard ratio 1.15; 95% CI 1.02-1.30; P = .02). Conclusions Patients with diabetes had similar rates of vein graft failure but worse clinical outcomes than patients without diabetes. Patients who received insulin had significantly worse clinical outcomes than patients who did not receive insulin. Further studies to better understand the mechanism behind these findings and to improve the outcomes of patients with insulin-requiring diabetes undergoing CABG surgery are warranted.
Background Current practice related to the management of atrial fibrillation (AF) complicating coronary artery bypass grafting (CABG) is uncertain. Methods We examined management of post-CABG AF in ...the PREVENT-IV trial, and we explored patterns of use of postoperative rhythm versus rate control and anticoagulation for AF by geographic region and type of site. We also compared outcomes of patients who developed post-CABG AF (663) with those who did not (2,131). Results The incidence of AF was 24%. Post-CABG AF was treated with a rhythm control strategy in 81% of patients and with warfarin in 23% of patients. Although there were significant variations across sites in the management of post-CABG AF, patterns of use of postoperative rhythm versus rate control and anticoagulation did not differ by geographic region or by whether or not the enrolling site was an academic institution. Mortality was higher in patients with post-CABG AF than patients without AF at 30 days (1.5% vs 0.7%, P = .01) but not at 3 years (6.9% vs 4.9%, P = .41). There was a trend toward a higher risk of mortality or stroke at 30 days in patients with AF (2.4% vs 1.9%, P = .08). Conclusion Although a rhythm control strategy was used in most of the patients in this trial and the overall rate of use of warfarin was low, the significance of these findings is uncertain because of the lack of data from randomized clinical trials. The substantial variations in the management of post-CABG AF across sites are likely because of definitive data on the most effective therapies, highlighting the need for clinical trials on rate versus rhythm control and on anticoagulation for AF in this setting.
Background Secondary prevention medications are beneficial after acute coronary syndromes, but these benefits are less clear after coronary artery bypass graft surgery. We investigated whether ...greater use of secondary prevention medications after coronary artery bypass graft surgery is associated with improved clinical outcomes. Methods Patients undergoing coronary artery bypass graft surgery in the PREVENT IV trial (n = 2970) were surveyed for use of antiplatelet agents, β-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and lipid-lowering agents after hospital discharge and at 1 year. Patients were categorized based on their percentage use of indicated medications after hospital discharge. Cox modeling was used to determine the association between medication use categories and rates of death or myocardial infarction through 2 years after adjustment for clinical factors, the number of indicated medications, and treatment propensity. Results Rates of use of antiplatelet agents and lipid-lowering agents were high at discharge and at 1 year, but use of β-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was suboptimal. There was a stepwise association between medication use at discharge and patient outcomes ( p for trend = 0.014). Patients taking 50% or less of indicated medications at discharge had a significantly higher 2-year rate of death or myocardial infarction (8.0% versus 4.2%; adjusted hazard ratio, 1.69; 95% confidence interval, 1.12 to 2.55; p = 0.013) than those taking all indicated medications. Conclusions Greater use of indicated secondary prevention medications after coronary artery bypass graft surgery is associated with a lower 2-year rate of death or myocardial infarction. These data underscore the importance of appropriate secondary prevention measures to improve long-term clinical outcomes after coronary artery bypass graft surgery.
Objective Limited information exists on the impact of preoperative renal dysfunction on internal thoracic artery and saphenous vein graft failure and 2-year clinical outcomes in patients undergoing ...coronary artery bypass surgery. Methods We studied the impact of preoperative renal dysfunction (creatinine clearance < 60 mL/min) on 1-year internal thoracic artery and saphenous vein graft failure (defined as ≥ 75% angiographic stenosis) and 2-year clinical events (death; death or myocardial infarction; and death, myocardial infarction, or revascularization) in 3014 patients undergoing coronary artery bypass surgery enrolled in the Project of Ex-vivo Vein Graft Engineering via Transfection-IV study. Results Of 2973 patients (98.6%) with preoperative measurement of renal function, 440 (14.8%) had renal dysfunction. Most baseline comorbidities were higher in these patients. Two-year clinical events were higher in patients with preoperative renal dysfunction (adjusted death, myocardial infarction, or revascularization, hazard ratio 1.21, 95% confidence interval 0.97–1.50; adjusted death or myocardial infarction, hazard ratio 1.35, 95% confidence interval 1.05–1.74; adjusted death, hazard ratio 1.47, 95% confidence interval 0.98–2.21). However, saphenous vein graft (odds ratio 1.02, 95% confidence interval 0.79–1.33) and internal thoracic artery (odds ratio 0.76, 95% confidence interval 0.40–1.44) failure were similar in the 2 groups. Conclusion Although the risk of adverse clinical events is higher in patients with preoperative renal dysfunction, that of internal thoracic artery and saphenous vein graft failure is not. This suggests that factors other than graft failure account for the worse clinical outcomes in this high-risk cohort. Further studies are needed to identify other mechanisms of these worse outcomes so that appropriate measures can be developed to improve long-term outcomes in patients with renal dysfunction undergoing coronary artery bypass surgery.
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