Background To further explore the impact of smoking on antiplatelet activity and treatment response, we evaluated time-dependent relationships between smoking status with on-treatment platelet ...reactivity and clinical outcomes for prasugrel vs. clopidogrel in patients with acute coronary syndromes managed medically without revascularization. Methods and Results A total of 7062 patients aged <75 years from the primary TRILOGY ACS cohort randomized to prasugrel vs. clopidogrel were evaluated through 30 months by baseline and time-dependent smoking status with adjusted proportional-hazards models. A total of 1613 participants (23%) were included in a platelet function sub-study evaluating serial P2Y12 reaction unit (PRU) measurements. Current smokers (n = 1566 22%) at baseline had fewer comorbidities compared with non-smokers; nearly half quit smoking during follow-up. Although median on-treatment PRU values were lower with prasugrel vs. clopidogrel, persistent smokers had lower serial PRU values in both treatment groups compared with non-smokers, with no differential interaction of treatment response by smoking status. The frequency of cardiovascular death, myocardial infarction, or stroke in current smokers was significantly lower with prasugrel (11.7%) vs. clopidogrel (18.6%), but there was no difference in non-smokers (13.8% vs. 13.7%), with significant interaction between treatment and baseline smoking status ( P = .0002). Bleeding events occurred more frequently in prasugrel-treated patients with no significant interaction between treatment and baseline smoking status. Conclusions Among medically managed ACS patients <75 years of age, the risk of ischemic outcomes was significantly reduced with prasugrel vs. clopidogrel among smokers vs. non-smokers. No interaction between on-treatment platelet reactivity and smoking status was found.
Factors Associated With Major Bleeding Events Goodman, Shaun G., MD, MSc; Wojdyla, Daniel M., MS; Piccini, Jonathan P., MD ...
Journal of the American College of Cardiology,
03/2014, Volume:
63, Issue:
9
Journal Article
Peer reviewed
Open access
Objectives This study sought to report additional safety results from the ROCKET AF (Rivaroxaban Once-daily oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of ...Stroke and Embolism Trial in Atrial Fibrillation). Background The ROCKET AF trial demonstrated similar risks of stroke/systemic embolism and major/nonmajor clinically relevant bleeding (principal safety endpoint) with rivaroxaban and warfarin. Methods The risk of the principal safety and component bleeding endpoints with rivaroxaban versus warfarin were compared, and factors associated with major bleeding were examined in a multivariable model. Results The principal safety endpoint was similar in the rivaroxaban and warfarin groups (14.9 vs. 14.5 events/100 patient-years; hazard ratio: 1.03; 95% confidence interval: 0.96 to 1.11). Major bleeding risk increased with age, but there were no differences between treatments in each age category (<65, 65 to 74, ≥75 years; pinteraction = 0.59). Compared with those without (n = 13,455), patients with a major bleed (n = 781) were more likely to be older, current/prior smokers, have prior gastrointestinal (GI) bleeding, mild anemia, and a lower calculated creatinine clearance and less likely to be female or have a prior stroke/transient ischemic attack. Increasing age, baseline diastolic blood pressure (DBP) ≥90 mm Hg, history of chronic obstructive pulmonary disease or GI bleeding, prior acetylsalicylic acid use, and anemia were independently associated with major bleeding risk; female sex and DBP <90 mm Hg were associated with a decreased risk. Conclusions Rivaroxaban and warfarin had similar risk for major/nonmajor clinically relevant bleeding. Age, sex, DBP, prior GI bleeding, prior acetylsalicylic acid use, and anemia were associated with the risk of major bleeding. (An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation: NCT00403767 )
Abstract Background Certain alleles of the CYP2C19 gene are associated with higher platelet reactivity and increased ischemic events among patients treated with clopidogrel. However, the relationship ...of CYP2C19 genotype and outcomes in medically managed patients with acute coronary syndromes (ACS) is not known. Objectives This study sought to assess the effect of CYP2C19 genotype on ischemic outcomes in patients with ACS initially managed medically without revascularization who were randomized to either clopidogrel or prasugrel. Methods We classified patients as extensive metabolizers (EM) or reduced metabolizers (RM) based on CYP2C19 genotype and evaluated ischemic outcomes and platelet reactivity. Among 9,326 patients enrolled from 2008 to 2011, 5,736 participated in the genetics cohort; of these, 2,236 had platelet function testing data. Results There was no association between CYP2C19 metabolizer status (EM vs. RM) and the primary composite endpoint of cardiovascular death, myocardial infarction (MI), or stroke (hazard ratio HR: 0.86). EM and RM patients had similar rates of the primary endpoint whether treated with prasugrel (HR: 0.82) or clopidogrel (HR: 0.91; p for interaction = 0.495). After adjusting for clinical and treatment variables, EM patients had a lower risk of MI versus RM patients (HR: 0.80), but risks of other outcomes were similar. RM patients had significantly higher mean P2Y12 reaction units versus EM patients when treated with clopidogrel (39.93), but not with prasugrel (3.87). Conclusions CYP2C19 metabolizer status is not associated with the composite outcome of cardiovascular death, MI, or stroke in medically managed ACS patients treated with clopidogrel or prasugrel. Our findings do not support routine CYP2C19 genetic testing in this population. (A Comparison of Prasugrel and Clopidogrel in Acute Coronary Syndrome Subjects TRILOGY ACS; NCT00699998 )
Objective Acute coronary syndrome (ACS) trials typically use a composite primary outcome (myocardial infarction MI, stroke, or cardiovascular death), but differential patient characteristics, timing, ...and consequences associated with individual component end points as first events have not been well studied. We compared patient characteristics and prognostic significance associated with first cardiovascular events in the post-ACS setting for initially stabilized patients. Methods We combined patient-level data from 4 trials of post-ACS antithrombotic therapies (PLATO, APPRAISE-2, TRACER, and TRILOGY ACS) to characterize the timing of and characteristics associated with first cardiovascular events (MI, stroke, or cardiovascular death). Landmark analysis at 7 days after index ACS presentation was used to focus on spontaneous, postdischarge events that were not confounded by in-hospital procedural complications. Using a competing risk framework, we tested for differential associations between prespecified covariates and the occurrence of nonfatal stroke vs MI as the first event, and we examined subsequent events after the first nonfatal event. Results Among 46,694 patients with a median follow-up of 358 (25th, 75th percentiles 262, 486) days, a first ischemic event occurred in 4,307 patients (9.2%) as follows: MI in 5.8% (n = 2,690), stroke in 1.0% (n = 477), and cardiovascular death in 2.4% (n = 1,140). Older age, prior stroke/transient ischemic attack, prior atrial fibrillation, and higher diastolic blood pressure were associated with a significantly greater risk of stroke vs MI, whereas prior percutaneous coronary intervention was associated with a greater risk of MI vs stroke. Second events occurred in 32% of those with a first nonfatal stroke at a median of 13 (3, 59) days after the first event and in 32% of those with a first nonfatal MI at a median of 35 (5, 137) days after the first event. The most common second event was a recurrent MI among those with MI as the first event and cardiovascular death among those with stroke as the first event. Conclusions Approximately 9% of patients experienced a first cardiovascular event in the post-ACS setting during a median follow-up of 1 year. Although the profile and prognostic implications of stroke vs MI as the first nonfatal event differ substantially, approximately one-third of these patients experienced a second event, typically soon after the first event. These findings have implications for improving post-ACS care and influencing the design of future cardiovascular trials.
Background Concomitant use of proton-pump inhibitors (PPIs) has been implicated in diminished antiplatelet response to clopidogrel and an increased risk of ischemic events, but primarily among ...patients undergoing percutaneous coronary intervention. We sought to examine the potential influence of interactions between PPIs and clopidogrel versus prasugrel on platelet reactivity and clinical outcomes after acute coronary syndromes (ACS) in patients managed medically without revascularization. Methods This analysis from the TRILOGY ACS trial focused upon the 7,243 ACS patients aged <75 years who were managed without revascularization, randomized to clopidogrel or prasugrel, and followed for a median of 17 months. Proton-pump inhibitor type and use were assessed at each study visit, and 2,049 of the patients in this cohort underwent serial platelet reactivity assessments. Results Proton-pump inhibitor use (23%) was similar between the clopidogrel and prasugrel groups at baseline and throughout the study. Median on-treatment platelet reactivity values were consistently lower with prasugrel versus clopidogrel irrespective of PPI use. For the primary end point (composite of cardiovascular death, myocardial infarction MI, or stroke), PPI use modified the unadjusted treatment effect of prasugrel versus clopidogrel (interaction P = .02). After adjusting for differences in baseline characteristics, this treatment effect modification was attenuated for the composite end point (interaction P = .06) but was significant for the MI component end point (interaction P = .01). Similarly, among patients on a PPI, the frequency of MI was significantly lower with prasugrel versus clopidogrel (hazard ratio = 0.61; 95% CI 0.42-0.88). These findings were similar by PPI type (omeprazole and pantoprazole). Conclusions Among ACS patients managed without revascularization, use of PPIs did not result in a differential antiplatelet response between prasugrel versus clopidogrel but was associated with a lower incidence of MI with prasugrel. These hypothesis-generating findings suggest that factors besides platelet reactivity may underlie the differential risk of MI observed by treatment assignment with PPI use.
Background Women with acute coronary syndromes (ACS) are less likely to undergo invasive revascularization than men, but sex-specific differences in long-term outcomes and platelet reactivity among ...medically managed ACS patients remain uncertain. We examined sex-specific differences in long-term ischemic and bleeding outcomes and platelet reactivity for medically managed ACS patients randomized to prasugrel versus clopidogrel plus aspirin. Methods Data from 9,326 patients enrolled in TRILOGY ACS were analyzed to determine differences in long-term ischemic and bleeding outcomes between women (n = 3,650 39%) and men (n = 5,676 61%) randomized to prasugrel 10 mg/d (5 mg/d for patients ≥75 years and/or <60 kg) versus clopidogrel 75 mg/d. Sex-specific differences in 30-day platelet reactivity were analyzed in 2,564 (27%) patients participating in a platelet function substudy. Results Compared with men, women were older, weighed less, were less likely to have prior myocardial infarction or revascularization, and had lower baseline creatinine clearance and hemoglobin level values. Rates of the composite of cardiovascular death/myocardial infarction/stroke (20.2% vs 19.1%; P = .56), all-cause mortality (12.2% vs 11.7%; P = .88), and Global Use of Strategies to Open Occluded Arteries severe/life-threatening/moderate bleeding (3.8% vs 2.8%; P = .74) through 30 months were similar in women versus men. After adjustment, women had significantly lower risk for ischemic outcomes and all-cause mortality. There were no sex-specific, treatment-related differences in 30-day platelet reactivity. Conclusions Long-term ischemic and bleeding outcomes in medically managed ACS patients were similar for women versus men, as was treatment-related platelet reactivity. Women had a higher baseline risk profile and, after adjustment, significantly lower risk of the primary composite end point and all-cause death through 30 months.
Advances in technique and adjunctive medication have improved outcome of ST-segment elevation myocardial infarction (STEMI) patients. However, the timely delivery and administration of reperfusion ...strategies to all eligible patients remain challenging. Currently, up to one-third of eligible STEMI patients in industrialized countries worldwide receive no specific reperfusion treatment, a problem that is rectified by the development and implementation of STEMI networks, as also recommended by the latest European Society of Cardiology and American College of Cardiology/American Heart Association guidelines. Indeed, over the last 5 years, published figures demonstrate that STEMI networks increase the percentage of patients treated by any reperfusion strategy, and the percentage of patients receiving treatment within the recommended time frames has also improved, thereby reducing in-hospital and long-term mortality to very low levels. This manuscript demonstrates how STEMI networks can be adapted to local needs and circumstances against pre-existing barriers and despite the heterogeneity in local situations, patient's characteristics, treatment delays, and distances for transfer. Modern and efficacious networks must be prepared to offer both primary percutaneous coronary intervention and thrombolytic therapy, preferably prehospital, as long as primary percutaneous coronary intervention cannot be guaranteed to all individuals within the recommended timeline.
Randomized controlled trials support the use of an early invasive strategy in high-risk patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS). Although risk increases with age, ...limited data are available to support this strategy in older patients. The aims of this study were to examine temporal trends in the management and outcomes of NSTE ACS in elderly patients and to explore reasons for the lower use of early angiography in the aged population. Data from 11,732 patients with NSTE ACS were collected from 3 consecutive Canadian registries (ACS I, ACS II, and Global Registry of Acute Coronary Events GRACE/GRACE2 ) from 1999 to 2007. Rates of in-hospital cardiac catheterization, revascularization, infarction or reinfarction, and death were stratified by age (<65, 65 to 74, and ≥75 years). Although overall, rates of in-hospital catheterization and revascularization increased over time (p <0.001), the largest increase occurred in patients aged <65 years. The strongest independent negative predictor of the use of cardiac catheterization was age ≥75 years (adjusted odds ratio 0.45, 95% confidence interval 0.37 to 0.56, p <0.001). Use of an early invasive approach was associated with a reduction in 1-year mortality across all age groups, but the absolute difference was greatest in patients aged ≥75 years. The underestimation of risk by physicians (ascertained in ACS II) was the most common reason for choosing a conservative strategy. In conclusion, despite an overall increased use of an early invasive strategy, elderly patients with NSTE ACS remain significantly less likely to undergo cardiac catheterization and revascularization and are often erroneously perceived to be at low risk by their physicians. Future studies should determine whether more aggressive treatment of these high-risk elderly patients improves outcomes.
Abstract Background Patients with acute coronary syndrome (ACS), especially those receiving medical management without revascularization, are at high risk for spontaneous myocardial infarction (MI), ...but its frequency and predictors are unknown. Objectives This study sought to characterize spontaneous MI events in a randomized population during 30 months of follow-up and develop a prediction model for spontaneous MI to assign risk of spontaneous MI events in ACS populations. Methods We analyzed data from the randomized TRILOGY ACS (TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medically manage Acute Coronary Syndromes) trial of aspirin plus prasugrel or clopidogrel following ACS. The trial included 9,326 patients with non–ST-segment elevation myocardial infarction (NSTEMI)/unstable angina (UA) who were managed medically without planned revascularization. Our study population included 9,294 patients. A multivariable Cox proportional hazards model was developed to determine predictors of time to first spontaneous MI event through 30 months. After model validation, we developed a calculator for model implementation. Results Among 9,294 patients, 695 spontaneous MI events occurred over a median of 17 months, representing 94% of adjudicated MI events (n = 737). The Kaplan-Meier event rate of spontaneous MI through 30 months was 10.7%. The strongest predictors of spontaneous MI were older age, NSTEMI versus UA as index event, diabetes mellitus, no pre-randomization angiography, and higher baseline creatinine values. The model exhibited good predictive capabilities ( c -index = 0.732) and had good calibration, especially for patients with low-to-moderate risk of spontaneous MI. Conclusions Spontaneous MI following a medically managed UA/NSTEMI event is common. Baseline characteristics can be used to predict subsequent risk of spontaneous MI in this population. These findings provide insight into the long-term natural history of medically managed UA/NSTEMI patients and could be used to optimize risk stratification and treatment of these patients. (A Comparison of Prasugrel and Clopidogrel in Acute Coronary Syndrome Subjects TRILOGY ACS; NCT00699998 )
Objectives This study sought to investigate the outcomes following cardioversion or catheter ablation in patients with atrial fibrillation (AF) treated with warfarin or rivaroxaban. Background There ...are limited data on outcomes following cardioversion or catheter ablation in AF patients treated with factor Xa inhibitors. Methods We compared the incidence of electrical cardioversion (ECV), pharmacologic cardioversion (PCV), or AF ablation and subsequent outcomes in patients in a post hoc analysis of the ROCKET AF (Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation) trial. Results Over a median follow-up of 2.1 years, 143 patients underwent ECV, 142 underwent PCV, and 79 underwent catheter ablation. The overall incidence of ECV, PCV, or AF ablation was 1.45 per 100 patient-years (n = 321; 1.44 n = 161 in the warfarin arm, 1.46 n = 160 in the rivaroxaban arm). The crude rates of stroke and death increased in the first 30 days after cardioversion or ablation. After adjustment for baseline differences, the long-term incidence of stroke or systemic embolism (hazard ratio HR: 1.38; 95% confidence interval CI: 0.61 to 3.11), cardiovascular death (HR: 1.57; 95% CI: 0.69 to 3.55), and death from all causes (HR: 1.75; 95% CI: 0.90 to 3.42) were not different before and after cardioversion or AF ablation. Hospitalization increased after cardioversion or AF ablation (HR: 2.01; 95% CI: 1.51 to 2.68), but there was no evidence of a differential effect by randomized treatment (p value for interaction = 0.58). The incidence of stroke or systemic embolism (1.88% vs. 1.86%) and death (1.88% vs. 3.73%) were similar in the rivaroxaban-treated and warfarin-treated groups. Conclusions Despite an increase in hospitalization, there were no differences in long-term stroke rates or survival following cardioversion or AF ablation. Outcomes were similar in patients treated with rivaroxaban or warfarin. (An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation ROCKET AF; NCT00403767 )
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