Patients With Prior Myocardial Infarction, Stroke, or Symptomatic Peripheral Arterial Disease in the CHARISMA Trial Deepak L. Bhatt, MD, FACC, Marcus D. Flather, MD, Werner Hacke, MD, Peter B. ...Berger, MD, FACC, Henry R. Black, MD, William E. Boden, MD, FACC, Patrice Cacoub, MD, Eric A. Cohen, MD, Mark A. Creager, MD, FACC, J. Donald Easton, MD, Christian W. Hamm, MD, FACC, Graeme J. Hankey, MD, S. Claiborne Johnston, PhD, MD, Koon-Hou Mak, MD, FACC, Jean-Louis Mas, MD, Gilles Montalescot, MD, PhD, Thomas A. Pearson, MD, FACC, P. Gabriel Steg, MD, FACC, Steven R. Steinhubl, MD, FACC, Michael A. Weber, MD, FACC, Liz Fabry-Ribaudo, MSN, RN, Tingfei Hu, MS, Eric J. Topol, MD, FACC, Keith A. A. Fox, MBChB, for the CHARISMA Investigators Dual antiplatelet therapy with clopidogrel plus aspirin has already been validated in the settings of acute coronary syndromes and coronary stenting. We identified 9,478 patients in the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial who were enrolled with documented prior myocardial infarction (MI), ischemic stroke, or symptomatic peripheral arterial disease. The median duration of follow-up was 27.6 months. The rate of cardiovascular death, MI, or stroke was significantly lower in the clopidogrel plus aspirin arm than in the placebo plus aspirin arm: 7.3% versus 8.8% (hazard ratio 0.83, 95% confidence interval 0.72 to 0.96, p = 0.01); this benefit persisted after multivariate modeling and was not dependent on the time from the ischemic event.
Background Atherothrombosis is a common condition affecting individuals worldwide. Its impact on different ethnic groups receiving evidence-based therapy is unclear. We aimed to determine if ...ethnicity is an independent predictor for cardiovascular events and bleeding complications in a contemporary clinical trial on antiplatelet therapy. Methods This was a prospective observational study of 15,603 patients enrolled in the CHARISMA trial followed up every 6 months for a median of 28 months. The primary efficacy end point was the first occurrence of cardiovascular death, myocardial infarction, or stroke. The primary safety end point was bleeding. Results The cohort comprised 12,502 (80.1%) white, 486 (3.1%) black, 775 (5.0%) Asian, and 1,613 (10.3%) Hispanic patients. There was no difference in the occurrence of the primary composite end point among the 4 ethnic groups. Compared with Asians, cardiovascular and all-cause mortality occurred more frequently among black (adjusted hazard 2.19 and 2.04) and Hispanic (adjusted hazard, 1.83 and 1.69) patients. Although the occurrence of severe bleeding was similarly low among the 4 ethnic groups, Asian (adjusted hazard, 2.21) and black (adjusted hazard, 3.06) patients were more likely to have moderate bleeding complications than Hispanic patients. Conclusion In this trial of individuals at risk of vascular events, ethnicity was not a significant, independent predictor of the primary composite cardiovascular event. However, ethnicity was a significant, independent predictor of the secondary outcomes, cardiovascular and all-cause mortality (blacks and Hispanics), and moderate bleeding complications (blacks and Asians).
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 )
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 )
Background The prevalence of both atrial fibrillation (AF) and diabetes mellitus (DM) are rising, and these conditions often occur together. Also, DM is an independent risk factor for stroke in ...patients with AF. We aimed to examine the safety and efficacy of rivaroxaban vs warfarin in patients with nonvalvular AF and DM in a prespecified secondary analysis of the ROCKET AF trial. Methods We stratified the ROCKET AF population by DM status, assessed associations with risk of outcomes by DM status and randomized treatment using Cox proportional hazards models, and tested for interactions between randomized treatments. For efficacy, primary outcomes were stroke (ischemic or hemorrhagic) or non–central nervous system embolism. For safety, the primary outcome was major or nonmajor clinically relevant bleeding. Results The 5,695 patients with DM (40%) in ROCKET AF were younger, were more obese, and had more persistent AF, but fewer had previous stroke (the CHADS2 score includes DM and stroke). The relative efficacy of rivaroxaban and warfarin for prevention of stroke and systemic embolism was similar in patients with (1.74 vs 2.14/100 patient-years, hazard ratio HR 0.82) and without (2.12 vs 2.32/100 patient-years, HR 0.92) DM (interaction P = .53). The safety of rivaroxaban vs warfarin regarding major bleeding (HRs 1.00 and 1.12 for patients with and without DM, respectively; interaction P = .43), major or nonmajor clinically relevant bleeding (HRs 0.98 and 1.09; interaction P = .17), and intracerebral hemorrhage (HRs 0.62 and 0.72; interaction P = .67) was independent of DM status. Adjusted exploratory analyses suggested 1.3-, 1.5-, and 1.9-fold higher 2-year rates of stroke, vascular mortality, and myocardial infarction in DM patients. Conclusions and Relevance The relative efficacy and safety of rivaroxaban vs warfarin was similar in patients with and without DM, supporting use of rivaroxaban as an alternative to warfarin in diabetic patients with AF.
Abstract We investigated stroke outcomes in normal weight (body mass index BMI 18.50-24.99 kg/m2 ), overweight (BMI 25.00-29.99 kg/m2 ), and obese (BMI ≥30 kg/m2 ) patients with AF treated with ...rivaroxaban and warfarin. We compared the incidence of stroke and systemic embolic events (SEE) as well as bleeding events in normal weight (n=3289), overweight (n=5535), and obese (n=5206) patients in a post-hoc analysis of the ROCKET AF trial. Stroke and SEE rates per 100 patient-years were 2.93 in the normal weight group (reference group), 2.28 in the overweight group (adjusted hazard ratio HR 0.81, 95% confidence interval CI: 0.66-0.99, p=0.04), and 1.88 in the obese group (adjusted HR 0.69, 95% CI: 0.55-0.86, p<0.001). The risk of stroke was statistically significantly lower for obese patients with BMI ≥35 compared with normal weight patients in both the rivaroxaban and warfarin groups (rivaroxaban: HR 0.62, 95% CI: 0.40-0.96, p=0.033; warfarin: HR 0.48, 95% CI: 0.31-0.74, p<0.001). In conclusion, among patients with AF treated with anticoagulant therapy, increased BMI was associated with decreased stroke risk. Warfarin and the novel anticoagulant rivaroxoban are effective in stroke prevention in all sub-groups of obese patients.
Background We aimed to investigate the relationship between aspirin use and clinical outcomes in patients enrolled in ROCKET AF; in particular, those with known coronary artery disease (CAD). Methods ...Patients in ROCKET AF, comparing rivaroxaban and warfarin, were analyzed. Aspirin use was assessed at baseline. Stroke and systemic embolism, myocardial infarction (MI), death, and major or non-major clinically relevant (NMCR) bleeding were compared between groups. Multivariable modeling was done adjusting for baseline risk factors. Results A total of 5205 (36.5%) patients were receiving aspirin at baseline (mean dose 99.2 mg), 30.6% of those had known CAD. Patients receiving aspirin were more likely to have prior MI (22% vs. 14%; p < 0.001) and heart failure (68% vs. 59%; p < 0.001). Relative efficacy of rivaroxaban versus warfarin was similar with and without aspirin use for both stroke/systemic embolism (p = 0.95 for interaction), and major or NMCR bleeding (p = 0.76 for interaction). After adjustment, aspirin use was associated with similar rates of stroke/systemic embolism (HR 1.16, 95% CI 0.98–1.37; p = 0.094), but higher rates of all-cause death (HR 1.27, 95% CI 1.13–1.42; p < 0.0001) and major or NMCR bleeding (HR 1.32, 95% CI 1.21–1.43; p < 0.0001). There was a significant interaction between no CAD at baseline and aspirin for all-cause death (p = 0.009). Conclusion Aspirin use at baseline was associated with an increased risk for bleeding and all-cause death in ROCKET AF, a risk most pronounced in patients without known CAD. Although these findings may reflect unmeasured clinical factors, further investigation is warranted to determine optimal aspirin use in patients with AF.
Depression is associated with increased mortality, but it is unclear if this relationship is truly causal.
To determine the relative mortality associated with past and current depression, taking into ...account the effect of frailty.
Prospective longitudinal cohort study of 2565 men aged 75 years or over living in metropolitan Perth, Western Australia, who completed the third wave of assessments of the Health In Men Study throughout 2008.
All-cause mortality data were derived from Australian death records up to June 17, 2013. History of past depression and age of onset of symptoms were obtained from direct questioning and from electronic health record linkage. Diagnosis of current major depressive symptoms followed Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision guidelines. We considered that participants were frail if they showed evidence of impairment in 3 or more of the 5 domains on the fatigue, resistance, ambulation, illnesses, and loss of weight (FRAIL) scale. Other measured factors included age, education, living arrangements, smoking and alcohol history, and physical activity.
558 participants died during mean period of follow-up of 4.2 ± 1.1 years. The annual death rate per thousand was 50 for men without depression, 52 for men with past depression, and 201 for men with major depressive symptoms at baseline. The crude mortality hazard was 4.26 (95% confidence interval = 2.98, 6.09) for men with depression at baseline compared with never depressed men, and 1.79 (95% confidence interval = 1.21, 2.62) after adjustment for frailty. Further decline in mortality hazard was observed after adjustment for other measured factors.
Current, but not past, depression is associated with increased mortality, and this excess mortality is strongly associated with frailty. Interventions designed to decrease depression-related mortality in later life may need to focus on ameliorating frailty in addition to treating depression.
Background We conducted a retrospective analysis examining the association between systolic blood pressure (SBP) or hypertension bracket and stroke risk in patients with atrial fibrillation (AF). ...Methods The study included 14,256 anticoagulated patients in the ROCKET AF trial. Cox proportional hazards models were used to compare the risk of adverse outcomes by European Society of Cardiology hypertension bracket and screening SBP. Results In total, 90.5% of patients had hypertension (55.8% controlled, 34.6% uncontrolled). The adjusted risk of stroke or systemic embolism (SE) increased significantly for every 10 mm Hg increase in screening SBP (hazard ratio HR 1.07, 95% CI confidence interval CI 1.02–1.13). There was a trend toward an increased adjusted risk of stroke or SE in patients with controlled (HR 1.22, 95% CI 0.89–1.66) and uncontrolled hypertension (HR 1.42, 95% CI 1.03–1.95) (P=0.06). In contrast, the adjusted risk of major bleeding was similar between hypertensive brackets and did not vary significantly by screening SBP. The benefit of rivaroxaban versus warfarin in preventing stroke or SE was consistent among patients regardless of SBP (P-interaction=0.69). Conclusions In a trial of anticoagulated patients with AF, increasing screening SBP was independently associated with stroke and SE, and one-third of patients had uncontrolled hypertension. The relative effectiveness and safety of rivaroxaban versus warfarin was consistent across all levels of screening SBP. A single SBP may be an important factor in reducing the overall risk of stroke and SE in anticoagulated patients with AF.
Summary Background Some countries fortify flour with folic acid to prevent neural tube defects but others do not, partly because of concerns about possible cancer risks. We aimed to assess any ...effects on site-specific cancer rates in the randomised trials of folic acid supplementation, at doses higher than those from fortification. Methods In these meta-analyses, we sought all trials completed before 2011 that compared folic acid versus placebo, had scheduled treatment duration at least 1 year, included at least 500 participants, and recorded data on cancer incidence. We obtained individual participant datasets that included 49 621 participants in all 13 such trials (ten trials of folic acid for prevention of cardiovascular disease n=46 969 and three trials in patients with colorectal adenoma n=2652). All these trials were evenly randomised. The main outcome was incident cancer (ignoring non-melanoma skin cancer) during the scheduled treatment period (among participants who were still free of cancer). We compared those allocated folic acid with those allocated placebo, and used log-rank analyses to calculate the cancer incidence rate ratio (RR). Findings During a weighted average scheduled treatment duration of 5·2 years, allocation to folic acid quadrupled plasma concentrations of folic acid (57·3 nmol/L for the folic acid groups vs 13·5 nmol/L for the placebo groups), but had no significant effect on overall cancer incidence (1904 cancers in the folic acid groups vs 1809 cancers in the placebo groups, RR 1·06, 95% CI 0·99–1·13, p=0·10). There was no trend towards greater effect with longer treatment. There was no significant heterogeneity between the results of the 13 individual trials (p=0·23), or between the two overall results in the cadiovascular prevention trials and the adenoma trials (p=0·13). Moreover, there was no significant effect of folic acid supplementation on the incidence of cancer of the large intestine, prostate, lung, breast, or any other specific site. Interpretation Folic acid supplementation does not substantially increase or decrease incidence of site-specific cancer during the first 5 years of treatment. Fortification of flour and other cereal products involves doses of folic acid that are, on average, an order of magnitude smaller than the doses used in these trials. Funding British Heart Foundation, Medical Research Council, Cancer Research UK, Food Standards Agency.
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