Background Cardiovascular risk models remain incomplete. Small-molecule metabolites may reflect underlying disease and, as such, serve as novel biomarkers of cardiovascular risk. Methods We studied ...2,023 consecutive patients undergoing cardiac catheterization. Mass spectrometry profiling of 69 metabolites and lipid assessments were performed in fasting plasma. Principal component analysis reduced metabolites to a smaller number of uncorrelated factors. Independent relationships between factors and time-to-clinical events were assessed using Cox modeling. Clinical and metabolomic models were compared using log-likelihood and reclassification analyses. Results At median follow-up of 3.1 years, there were 232 deaths and 294 death/myocardial infarction (MI) events. Five of 13 metabolite factors were independently associated with mortality: factor 1 (medium-chain acylcarnitines: hazard ratio HR 1.12 95% CI, 1.04-1.21, P = .005), factor 2 (short-chain dicarboxylacylcarnitines: HR 1.17 1.05-1.31, P = .005), factor 3 (long-chain dicarboxylacylcarnitines: HR 1.14 1.05-1.25, P = .002); factor 6 (branched-chain amino acids: HR 0.86 0.75-0.99, P = .03), and factor 12 (fatty acids: HR 1.19 1.06-1.35, P = .004). Three factors independently predicted death/MI: factor 2 (HR 1.11 1.01-1.23, P = .04), factor 3 (HR 1.13 1.04-1.22, P = .005), and factor 12 (HR 1.18 1.05-1.32, P = .004). For mortality, 27% of intermediate-risk patients were correctly reclassified (net reclassification improvement 8.8%, integrated discrimination index 0.017); for death/MI model, 11% were correctly reclassified (net reclassification improvement 3.9%, integrated discrimination index 0.012). Conclusions Metabolic profiles predict cardiovascular events independently of standard predictors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary Background An antithrombotic drug is needed that safely reduces cardiovascular events in patients undergoing percutaneous coronary intervention (PCI). We therefore assessed the tolerability ...and safety of SCH 530348—an oral platelet protease-activated receptor-1 antagonist. Methods We randomly assigned patients aged 45 years or older and undergoing non-urgent PCI or coronary angiography with planned PCI to an oral loading dose of SCH 530348 (10 mg, 20 mg, or 40 mg) or matching placebo in a 3:1 ratio in a multicentre international study. Those in the SCH 530348 group who subsequently underwent PCI (primary PCI cohort) continued taking an oral maintenance dose (0·5 mg, 1·0 mg, or 2·5 mg per day), and patients in the placebo group continued placebo for 60 days. The primary endpoint was the incidence of clinically significant major or minor bleeding according to the thrombolysis in myocardial infarction (TIMI) scale. Both investigators and patients were unaware of treatment allocation. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00132912. Findings 257 patients were assigned to placebo and 773 to SCH 530348. The primary endpoint occurred in 2 (2%) of 129, 3 (3%) of 120, and 7 (4%) of 173 patients, respectively, in the SCH 530348 10 mg, 20 mg, and 40 mg groups compared with 5 (3%) of 151 patients in the placebo group (p=0·5786). TIMI major plus minor bleeding occurred in 3 (2%) of 136, 5 (4%) of 139, and 4 (3%) of 138 patients given SCH 530348 0·5 mg, 1·0 mg, and 2·5 mg once per day, respectively (p=0·7561). Interpretation Oral SCH 530348 was generally well tolerated and did not cause increased TIMI bleeding, even when administered concomitantly with aspirin and clopidogrel. Further testing in phase III trials to accurately define the safety and efficacy of SCH 530348 is warranted. Funding Schering-Plough Research Institute.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
3.
Predictors of contemporary coronary artery bypass grafting outcomes Weisel, Richard D., MD; Nussmeier, Nancy, MD; Newman, Mark F., MD ...
Journal of thoracic and cardiovascular surgery/The Journal of thoracic and cardiovascular surgery/The journal of thoracic and cardiovascular surgery,
12/2014, Volume:
148, Issue:
6
Journal Article
Peer reviewed
Open access
Objectives The study objective was to identify the predictors of outcomes in a contemporary cohort of patients from the Reduction in cardiovascular Events by acaDesine in patients undergoing CABG ...(RED-CABG) trial. Despite the increasing risk profile of patients who undergo coronary artery bypass grafting, morbidity and mortality have remained low, and identification of the current predictors of adverse outcomes may permit new treatments to further improve outcomes. Methods The RED-CABG trial was a multicenter, randomized, double-blind, placebo-controlled study that determined that acadesine did not reduce adverse events in moderately high-risk patients undergoing nonemergency coronary artery bypass grafting. The primary efficacy end point was a composite of all-cause death, nonfatal stroke, or the need for mechanical support for severe left ventricular dysfunction through postoperative day 28. Logistic regression modeling with stepwise variable selection identified which prespecified baseline characteristics were associated with the primary outcome. A second logistic model included intraoperative variables as potential covariates. Results The 4 independent preoperative risk factors predictive of the composite end point were (1) a history of heart failure (odds ratio, 2.9); (2) increasing age (odds ratio, 1.033 per decade); (3) a history of peripheral vascular disease (odds ratio, 1.6); and (4) receiving aspirin before coronary artery bypass grafting (odds ratio, 0.5), which was protective. The duration of the cardiopulmonary bypass (odds ratio, 1.8) was the only intraoperative variable that contributed to adverse outcomes. Conclusions Patients who had heart failure and preserved systolic function had a similar high risk of adverse outcomes as those with low ejection fractions, and new approaches may mitigate this risk. Recognition of patients with excessive atherosclerotic burden may permit perioperative interventions to improve their outcomes. The contemporary risks of coronary artery bypass grafting have changed, and their identification may permit new methods to improve outcomes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background Among patients presenting with ST-segment elevation myocardial infarction (STEMI) for primary percutaneous coronary intervention (PCI), the associations between clinical outcomes and both ...baseline renal function and the development of acute kidney injury (AKI) have not been reported in a trial population with unselected baseline renal function. Methods Patients enrolled in the APEX-AMI trial who underwent primary PCI for the treatment of STEMI were categorized according to ( a ) baseline renal function and ( b ) the development of AKI. Patient characteristics, clinical outcomes, and treatment patterns were analyzed according to baseline renal function and the development of AKI. A prediction model for AKI after primary PCI for STEMI was also developed. Results A total of 5,244 patients were included in this analysis and stratified according to baseline estimated glomerular filtration rate (eGFR) (milliliters per minute per 1.73 m2 ) of >90, 60 to 90, 30 to 59, or <30 or as dialysis dependent. Patients with lower eGFR were older, more often female, and less often treated with evidence-based medicines and had worse angiographic outcomes and higher mortality. The rates of AKI for patients with a baseline eGFR of >90, 60 to 90, 30 to 59, and <30 were 2.5%, 4.1%, 8.1%, and 1.6%, respectively ( P < .0001). The strongest predictors of AKI were age and presenting in Killip class III or IV. Conclusions Among patients undergoing primary PCI for STEMI, impaired renal function at presentation and development of post-PCI AKI were highly associated with worse clinical and angiographic outcomes, including death. The risk of developing AKI was low and only modestly associated with baseline renal function.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Gender-related differences in the incidence of bleeding and its relation to subsequent mortality in patients with ST-segment elevation myocardial infarction (STEMI) treated with fibrinolysis are not ...well understood. We studied patients with STEMI receiving fibrinolysis enrolled in 6 clinical trials. Outcomes included moderate or severe bleeding defined using Global Utilization of Strategies to Open Occluded Arteries (GUSTO) criteria and adjusted 1-year mortality (excluding deaths in first 24 hours). Moderate or severe bleeding was 1.9-fold higher in women compared to men (13.3% vs 7.1%, p <0.0001). Bleeding remained higher in women even after adjustment for baseline differences (odd ratios 1.52, 95% confidence interval CI 1.42 to 1.62). In fact, female gender was second most important prognostic factor (Wald chi-square 153.6) after older age (Wald chi-square 241.2) in the multivariable bleeding model. Overall 1-year mortality was similar in women and men after adjusting for prognostically important baseline differences (hazard ratio HR 1.06, 95% CI 0.97 to 1.17). However, after adjustment for baseline confounders and bleeding, female gender was associated with a lower risk of 1-year death. Thus, adjusted 1-year mortality was similar in women compared to men without bleeding (HR 1.08, 95% CI 0.97 to 1.19) but lower in women compared to men with bleeding (HR 0.85, 95% CI 0.73 to 0.98, p for interaction of gender by bleeding = 0.0016). The highest adjusted 1-year mortality was observed in men with bleeding (HR 2.42, 95% CI 2.20 to 2.66) followed by women with bleeding (HR 2.05, 95% CI 1.80 to 2.33) and women without bleeding (HR 1.08, 95% CI 0.97 to 1.19, referent men without bleeding). In conclusion, in patients with fibrinolytic-treated STEMI, women had a higher incidence but lower mortality with bleeding than men. These data highlight the importance of understanding factors associated with gender-related differences in bleeding and represent an opportunity for improving outcomes of women and men with fibrinolytic-treated STEMI.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background Red blood cell distribution width (RDW) strongly predicts clinical outcomes among patients with coronary disease and heart failure. The factors underpinning this association are unknown. ...Methods In 6,447 individuals enrolled in the Measurement to Understand the Reclassification of Disease of Cabarrus/Kannapolis (MURDOCK) Study who had undergone coronary angiography between 2001 and 2007, we used Cox proportional hazards modeling to examine the adjusted association between RDW and death, and death or myocardial infarction (MI). Multiple linear regression using the R2 model selection method was then used to identify clinical factors associated with variation in RDW. Results Median follow-up was 4.2 (interquartile range 2.3-5.9) years, and the median RDW was 13.5% (interquartile range 12.9%-14.3%, clinical laboratory reference range 11.5%-14.5%). Red blood cell distribution width was independently associated with death (adjusted hazard ratio 1.13 per 1% increase in RDW, 95% CI 1.09-1.17), and death or MI (adjusted hazard ratio 1.12, 95% CI 1.08-1.16). Twenty-seven clinical characteristics and laboratory measures were assessed in the multivariable linear regression model; a final model containing 18 variables explained only 21% of the variation in RDW. Conclusions Although strongly associated with death and death or MI, only one-fifth of the variation in RDW was explained by routinely assessed clinical characteristics and laboratory measures. Understanding the latent factors that explain variation in RDW may provide insight into its strong association with risk and identify novel targets to mitigate that risk.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Background Adverse event collection in randomized clinical trials establishes drug safety. Although costly and regulated, it is rarely studied. Methods Adverse event data from 4 clinical trials ...(APPRAISE-2, PLATO, TRACER, TRILOGY ACS) comprising 48,118 participants with acute coronary syndromes were pooled to compare patterns and determinants of reporting. Events were classified as serious (SAE) or nonserious (AE) from hospital discharge to 1 year; study end points were excluded. Results In total, 84,901 events were reported. Of those, 12,266 (14.4%) were SAEs and 72,635 (85.6%) were AEs. Of all participants, 7,823 (16.3%) had SAEs, 18,124 (37.7%) had only AEs, and 22,171 (46.1%) had neither. Nonserious adverse events were distributed across system organ classes: general disorders (11%), infection (10%), gastrointestinal (10%), respiratory (9%), cardiovascular (8.4%), and other (35%). Serious adverse events had a higher proportion of cardiovascular causes (14.0%). Event reporting was highest after hospital discharge, decreasing rapidly during the following 3 months. In a Cox proportional hazards model, chronic obstructive pulmonary disease (hazard ratio 1.58, 95% CI 1.44-1.74), heart failure (1.55, 1.40-1.70), older age, and female sex were independent predictors of more SAEs, whereas enrollment in Eastern Europe (0.63, 0.58-0.69) or Asia (0.84, 0.75-0.94) were independent predictors of fewer SAEs. Conclusions Half of all participants reported adverse events in the year after acute coronary syndrome; most were AEs and occurred within 3 months. The high volume of events, as well as the variation in SAE reporting by characteristics and enrollment region, indicates that efforts to refine event collection in large trials are warranted.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract Background Studies have shown higher bleeding and mortality rates among African Americans who receive fibrinolytic therapy for ST-segment elevation myocardial infarction (STEMI) compared ...with whites; however, the relationship of bleeding risk to mortality has not been evaluated. Methods We studied data from 32,260 STEMI patients receiving fibrinolysis enrolled in the US in 5 clinical trials. Bleeding was defined according to criteria from the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries study. Main outcome measure was adjusted 1-year mortality. Results Despite younger age (median: 57 years vs 61 years) and fewer comorbidities, moderate or severe bleeding occurred more frequently among African-Americans than whites (16.3% vs 14.1%; P = .0147, adjusted OR 1.36; 95% confidence interval CI, 1.14-1.62; P = .0006) as did 1-year mortality (11.5% vs 9.4%). African-American race and moderate or severe bleeding were independently related to 1-year mortality (χ2 9.02, P = .0003 and 148.58, P < .0001, respectively). Mortality was highest among African Americans with bleeding (hazard ratio HR 2.83; 95% CI, 2.08-3.86) followed by whites with bleeding (HR 1.99; 95% CI, 1.78-2.22) and African Americans without bleeding (HR 1.33; 95% CI, 1.02-1.73) (referent whites without bleeding). Conclusions In STEMI patients receiving fibrinolysis, moderate or severe bleeding and mortality were significantly higher in African Americans compared with whites. Bleeding was associated with similarly increased mortality risk in both groups.
Background The association of sustained ventricular tachycardia/fibrillation (VT/VF) with mortality in patients undergoing primary percutaneous coronary intervention (PCI) may vary with baseline ...patient risk and may be associated with higher mortality in patients who have high-risk baseline features but not in the low-risk patient cohort undergoing this procedure. Methods Among the 5,259 ST Elevation Myocardial Infarction (STEMI) patients presenting for primary PCI from the APEX AMI trial, we evaluated the association of VT/VF with outcomes according to underlying risk for 90-day mortality estimated using baseline variables and with a Cox regression model. Results Ventricular tachycardia/fibrillation occurred in 3.6% (63/1,736), 4.9% (87/1,788), and 8.1% (141/1,735) of patients in the low-, intermediate-, and high-tertiles of 90-day predicted death, respectively. Ninety-day death was between 3.2- and 4.8-fold higher in patients with VT/VF compared with those without it in the 3 risk groups (low risk 1.6% vs 0.5%, intermediate risk 5.7% vs1.2%, high risk 33.6% vs 7.7%). Both early (during cardiac catheterization) and late VT/VF (after cardiac catheterization) were associated with high risk of death regardless of baseline risk category. Conclusions The incidence of VT/VF and mortality increased as patients' baseline risk increased, and VT/VF remained an important prognostic marker for the increased risk of clinical adverse events and 90-day mortality irrespective of underlying baseline risk in patients undergoing primary PCI. Thus, even in otherwise low-risk patients, occurrence of VT/VF helps to further identify higher risk cohort that may warrant closer monitoring.
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