Objectives This study sought to characterize major bleeding on the basis of the components of the major bleeding definition, to explore major bleeding by location, to define 30-day mortality after a ...major bleeding event, and to identify factors associated with major bleeding. Background Apixaban was shown to reduce the risk of major hemorrhage among patients with atrial fibrillation in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. Methods All patients who received at least 1 dose of a study drug were included. Major bleeding was defined according to the criteria of the International Society on Thrombosis and Haemostasis. Factors associated with major hemorrhage were identified using a multivariable Cox model. Results The on-treatment safety population included 18,140 patients. The rate of major hemorrhage among patients in the apixaban group was 2.13% per year compared with 3.09% per year in the warfarin group (hazard ratio HR 0.69, 95% confidence interval CI: 0.60 to 0.80; p < 0.001). Compared with warfarin, major extracranial hemorrhage associated with apixaban led to reduced hospitalization, medical or surgical intervention, transfusion, or change in antithrombotic therapy. Major hemorrhage followed by mortality within 30 days occurred half as often in apixaban-treated patients than in those receiving warfarin (HR 0.50, 95% CI: 0.33 to 0.74; p < 0.001). Older age, prior hemorrhage, prior stroke or transient ischemic attack, diabetes, lower creatinine clearance, decreased hematocrit, aspirin therapy, and nonsteroidal anti-inflammatory drugs were independently associated with an increased risk. Conclusions Apixaban, compared with warfarin, was associated with fewer intracranial hemorrhages, less adverse consequences following extracranial hemorrhage, and a 50% reduction in fatal consequences at 30 days in cases of major hemorrhage.
Atrial fibrillation (AF) is associated with increased risk of stroke that can be attenuated with vitamin K antagonists (VKAs). Vitamin K antagonist use is limited, in part, by the high incidence of ...complications when patients' international normalized ratios (INRs) deviate from the target range. The primary objective of ARISTOTLE is to determine if the factor Xa inhibitor, apixaban, is noninferior to warfarin at reducing the combined endpoint of stroke (ischemic or hemorrhagic) and systemic embolism in patients with AF and at least 1 additional risk factor for stroke. We have randomized 18,206 patients from over 1,000 centers in 40 countries. Patients were randomly assigned in a 1:1 ratio to receive apixaban or warfarin using a double-blind, double-dummy design. International normalized ratios are monitored and warfarin (or placebo) is adjusted aiming for a target INR range of 2 to 3 using a blinded, encrypted point-of-care device. Minimum treatment is 12 months, and maximum expected exposure is 4 years. Time to accrual of at least 448 primary efficacy events will determine treatment duration. The key secondary objectives are to determine if apixaban is superior to warfarin for the combined endpoint of stroke (ischemic or hemorrhagic) and systemic embolism, and for all-cause death. These will be tested after the primary objective using a closed test procedure. The noninferiority boundary is 1.38; apixaban will be declared noninferior if the 95% CI excludes the possibility that the primary outcome rate with apixaban is >1.38 times higher than with warfarin. ARISTOTLE will determine whether apixaban is noninferior or superior to warfarin in preventing stroke and systemic embolism; whether apixaban has particular benefits in the warfarin-naïve population; whether it reduces the combined rate of stroke, systemic embolism, and death; and whether it impacts bleeding.
Summary Background In the ARISTOTLE trial, the rate of stroke or systemic embolism was reduced by apixaban compared with warfarin in patients with atrial fibrillation (AF). Patients with AF and ...previous stroke or transient ischaemic attack (TIA) have a high risk of stroke. We therefore aimed to assess the efficacy and safety of apixaban compared with warfarin in prespecified subgroups of patients with and without previous stroke or TIA. Methods Between Dec 19, 2006, and April 2, 2010, patients were enrolled in the ARISTOTLE trial at 1034 clinical sites in 39 countries. 18 201 patients with AF or atrial flutter were randomly assigned to receive apixaban 5 mg twice daily or warfarin (target international normalised ratio 2·0–3·0). The median duration of follow-up was 1·8 years (IQR 1·4–2·3). The primary efficacy outcome was stroke or systemic embolism, analysed by intention to treat. The primary safety outcome was major bleeding in the on-treatment population. All participants, investigators, and sponsors were masked to treatment assignments. In this subgroup analysis, we estimated event rates and used Cox models to compare outcomes in patients with and without previous stroke or TIA. The ARISTOTLE trial is registered with ClinicalTrials.gov , number NTC00412984. Findings Of the trial population, 3436 (19%) had a previous stroke or TIA. In the subgroup of patients with previous stroke or TIA, the rate of stroke or systemic embolism was 2·46 per 100 patient-years of follow-up in the apixaban group and 3·24 in the warfarin group (hazard ratio HR 0·76, 95% CI 0·56 to 1·03); in the subgroup of patients without previous stroke or TIA, the rate of stroke or systemic embolism was 1·01 per 100 patient-years of follow-up with apixaban and 1·23 with warfarin (HR 0·82, 95% CI 0·65 to 1·03; p for interaction=0·71). The absolute reduction in the rate of stroke and systemic embolism with apixaban versus warfarin was 0·77 per 100 patient-years of follow-up (95% CI −0·08 to 1·63) in patients with and 0·22 (−0·03 to 0·47) in those without previous stroke or TIA. The difference in major bleeding with apixaban compared with warfarin was 1·07 per 100 patient-years (95% CI 0·09–2·04) in patients with and 0·93 (0·54–1·32) in those without previous stroke or TIA. Interpretation The effects of apixaban versus warfarin were consistent in patients with AF with and without previous stroke or TIA. Owing to the higher risk of these outcomes in patients with previous stroke or TIA, the absolute benefits of apixaban might be greater in this population. Funding Bristol-Myers Squibb and Pfizer.
Background The perceived risk of serious bleeding is an obstacle to the use of oral anticoagulation in East Asia. The efficacy and safety of apixaban in East Asian patients with atrial fibrillation ...are unknown. Methods ARISTOTLE included 18,201 patients with nonvalvular atrial fibrillation randomized to apixaban 5 mg twice daily or warfarin. The efficacy and safety of apixaban and warfarin among patients recruited from East Asia (n = 1,993) were compared with those recruited from outside East Asia (n = 16,208). Results Compared with warfarin, apixaban resulted in a consistent reduction in stroke or systemic embolism in East Asian (hazard ratio HR 0.74, 95% CI 0.50-1.10) and non–East Asian (HR 0.81, 95% CI 0.66-0.99) patients (interaction P = .70). Consistent benefits of apixaban over warfarin were also seen for major bleeding in East Asian (HR 0.53, 95% CI 0.35-0.80) and non–East Asian (HR 0.72, 95% CI 0.62-0.83) patients (interaction P = .17). There was a greater reduction in major or clinically relevant nonmajor bleeding with apixaban compared with warfarin in East Asian (HR 0.49, 95% CI 0.35-0.67) than in non–East Asian (HR 0.71, 95% CI 0.63-0.79) patients (interaction P = .03). Numerically higher rates of intracranial bleeding were seen in East Asian patients with warfarin but not with apixaban. Conclusions Apixaban resulted in similar reductions in stroke or systemic embolism and major bleeding and greater reductions in major or clinically relevant nonmajor bleeding in patients from East Asia. Warfarin is associated with more intracranial bleeding, particularly in patients from East Asia.
Background In the PLATO trial, ticagrelor was superior to clopidogrel in reducing cardiovascular events among patients with acute coronary syndrome (ACS) at the expense of increased nonfatal ...bleeding. Because Asian patients, when compared with non-Asian patients, are believed to be more susceptible to bleeding, we evaluated the effects of ticagrelor compared with clopidogrel in Asian (n = 1,106) and non-Asian (n = 17,515) patients with acute coronary syndrome enrolled in the PLATO study. Methods and Results Interaction between Asian/non-Asian and primary efficacy end point (a composite of vascular death, myocardial infarction, and stroke) and net clinical benefit (composite of primary efficacy end point and coronary artery bypass graft CABG surgery or non–CABG-related major bleeding) were evaluated with a Cox proportional hazards model. Baseline demographics and comorbidities were different between Asians and non-Asians. The overall cardiovascular event rates were higher in Asians, but bleeding rates were similar. Despite these observed differences, the effects of ticagrelor versus clopidogrel were not significantly different between Asians and non-Asians with respect to the primary efficacy outcome (hazard ratio for Asians vs non-Asians, 0.84 95% CI 0.61-1.17 vs 0.85 95% CI 0.77-0.93, P = .974), net clinical benefit (0.85 95% CI 0.65-1.11 vs 0.93 95% CI 0.86-0.99, P = .521), or individual efficacy end points. There was no significant interaction for bleeding (PLATO major bleeding, 1.02 95% CI 0.70-1.49 vs 1.04 95% CI 0.95-1.14, P = .938) and other related adverse events with ticagrelor compared with clopidogrel between Asians and non-Asians. Conclusions We observed consistency of effects in Asian patients receiving ticagrelor and clopidogrel in the PLATO study. The relatively modest number of Asian patients in this analysis supports further investigation of larger cohorts to confirm our observations.
Background Antiplatelet therapy is essential treatment for acute coronary syndromes (ACS). Current therapies, however, have important limitations affecting their clinical success. Ticagrelor, the ...first reversible oral P2Y12 receptor antagonist, provides faster, greater, and more consistent adenosine diphosphate–receptor inhibition than clopidogrel. The phase III PLATelet inhibition and patient Outcomes (PLATO) trial is designed to test the hypothesis that ticagrelor compared with clopidogrel will result in a lower risk of recurrent thrombotic events in a broad patient population with ACS. Methods PLATO is an international, randomized, double-blind, event-driven trial involving >18,000 patients hospitalized for ST-elevation ACS with scheduled primary percutaneous coronary intervention or for non–ST-elevation ACS. After loading doses of ticagrelor 180 mg or clopidogrel 300 mg in a double-blind, double-dummy fashion (with provision for additional 300 mg clopidogrel at percutaneous coronary intervention), patients will receive ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily for 6 to 12 months on top of acetylsalicylic acid. The primary efficacy end point is time to first occurrence of death from vascular causes, myocardial infarction, or stroke. The primary safety variable is PLATO-defined major bleeding. An extensive substudy program will explore the pathophysiology of ACS, indicators of prognosis and response to treatment, mechanisms of effect and safety of the study medications, health economics, and quality of life. Conclusion The PLATO study will provide a pivotal comparison of the efficacy and safety of ticagrelor with those of clopidogrel in ACS patients, together with extensive information on treatment outcomes in different subsets of ACS in a broad patient population.
Background Inflammation has been associated with cardiovascular disease and the burden of atrial fibrillation (AF). In this study we evaluate inflammatory biomarkers and future cardiovascular events ...in AF patients in the RE-LY study. Methods Interleukin-6 (IL-6), C-reactive protein (CRP) (n = 6,187), and fibrinogen (n = 4,893) were analyzed at randomization; outcomes were evaluated by Cox models and C-statistics. Results Adjusted for clinical risk factors IL-6 was independently associated with stroke or systemic embolism ( P = .0041), major bleedings ( P = .0001), vascular death ( P < .0001), and a composite thromboembolic outcome (ischemic stroke, systemic embolism, myocardial infarction, pulmonary embolism and vascular death) ( P < .0001). CRP was independently related to myocardial infarction ( P = .0047), vascular death ( P = .0004), and the composite thromboembolic outcome ( P = .0001). When further adjusted for cardiac (troponin and N-terminal fragment B-type natriuretic peptide NT-proBNP) and renal (cystatin-C) biomarkers on top of clinical risk factors IL-6 remained significantly related to vascular death ( P < .0001), major bleeding ( P < .0170) and the composite thromboembolic outcome ( P < .0001), and CRP to myocardial infarction (.0104). Fibrinogen was not associated with any outcome. C-index for stroke or systemic embolism increased from 0.615 to 0.642 ( P = .0017) when adding IL-6 to the clinically used CHA2 DS2 -VASc risk score with net reclassification improvement of 28%. Conclusion In patients with AF, IL-6 is related to higher risk of stroke and major bleeding, and both markers are related to higher risk of vascular death and the composite of thromboembolic events independent of clinical risk factors. Adjustment for cardiovascular biomarkers attenuated the prognostic value, although IL-6 remained related to mortality, the composite of thromboembolic events, and major bleeding, and CRP to myocardial infarction.
Objectives The aim of this study was to evaluate the prognostic value of high-sensitivity troponin T (hs-TnT) in addition to clinical risk factors and the CHA2 DS2 VASc (congestive heart failure, ...hypertension, 75 years of age and older, diabetes mellitus, previous stroke or transient ischemic attack, vascular disease, 65 to 74 years of age, female) risk score in patients with atrial fibrillation (AF). Background The level of troponin is a powerful predictor of cardiovascular events and mortality. Methods A total of 14,897 patients with AF were randomized to treatment with apixaban or warfarin in the ARISTOTLE (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) trial. The associations between baseline hs-TnT levels and outcomes were evaluated using adjusted Cox regression models. Results Levels of hs-TnT were measurable in 93.5% of patients; 75% had levels >7.5 ng/l, 50% had levels >11.0 ng/l, and 25% had levels >16.7 ng/l. During a median 1.9-year period, the annual rates of stroke or systemic embolism ranged from 0.87% in the lowest hs-TnT quartile to 2.13% in the highest hs-TnT quartile (adjusted hazard ratio HR: 1.94; 95% confidence interval CI: 1.35 to 2.78; p = 0.0010). The annual rates in the corresponding groups ranged from 0.46% to 4.24% (adjusted HR: 4.31; 95% CI: 2.91 to 6.37; p < 0.0001) for cardiac death and from 1.26% to 4.21% (adjusted HR: 1.91; 95% CI: 1.43 to 2.56; p = 0.0001) for major bleeding. Adding hs-TnT levels to the CHA2 DS2 VASc score improved the C statistic from 0.620 to 0.635 for stroke or systemic embolism (p = 0.0226), from 0.592 to 0.711 for cardiac death (p < 0.0001), and from 0.591 to 0.629 for major bleeding (p < 0.0001). Apixaban reduced rates of stroke, mortality, and bleeding regardless of the hs-TnT level. Conclusions Levels of hs-TnT are often elevated in patients with AF. The hs-TnT level is independently associated with an increased risk of stroke, cardiac death, and major bleeding and improves risk stratification beyond the CHA2 DS2 VASc risk score. The benefits of apixaban as compared with warfarin are consistent regardless of the hs-TnT level. (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation ARISTOTLE; NCT00412984 )
This is the first evaluation of dabigatran, an oral direct thrombin inhibitor, in patients with atrial fibrillation (AF). Patients (n = 502) were randomized to receive blinded doses of 50-, 150-, or ...300-mg dabigatran twice daily alone or combined with 81- or 325-mg aspirin or open-label warfarin administered to achieve an international normalized ratio of 2 to 3 for 12 weeks. Dabigatran plasma concentrations, activated partial thromboplastin time, d -dimer, urinary 11-dehydrothromboxane B2 (DTB2), and liver function were measured at baseline and at 1, 2, 4, 8, and 12 weeks. Clinical end points were assessed according to the treatment received at the time of the event. Overall, 92% of patients completed the study. Major hemorrhages were limited to the group treated with 300-mg dabigatran plus aspirin (4 of 64), and the incidence was significant versus 300-mg dabigatran alone (0 of 105, p <0.02). Total bleeding events were more frequent in the 300-mg (39 of 169, 23%) and 150-mg (30 of 169, 18%) dabigatran groups compared with the 50-mg groups (7 of 107, 7%; p = 0.0002 and p = 0.01, respectively). Thromboembolic events were limited to the 50-mg dabigatran dose groups (2 of 107, 2%). The mean trough d -dimer measurements were suppressed for the 2 highest doses of dabigatran and warfarin (international normalized ratio of 2 to 3). Aminotransferase levels >3 times the upper limit of normal were observed in 0.9% of the dabigatran recipients and in none of the warfarin recipients. Two dabigatran recipients had aminotransferase levels >5 times the upper limit of normal as a result of gallstones, which resolved. Trough activated partial thromboplastin time values were 1.2, 1.5, and 1.8 times the baseline level for the 50-, 150-, and 300-mg dabigatran groups, respectively. DTB2 concentrations after 12 weeks of 50-, 150-, and 300-mg dabigatran treatment were increased by 31%, 17%, and 23%, respectively, versus baseline (p = 0.02, p = 0.03, and p = 0.0004). In conclusion, major bleeding events were limited to patients treated with dabigatran 300 mg plus aspirin and thromboembolic episodes were limited to the 50-mg dabigatran groups. The 2 highest doses of dabigatran suppress d -dimer concentrations. Serious liver toxicity was not seen. The significance of the increase of DTB2 concentrations in dabigatran-treated patients needs resolution.
Vitamin K antagonists (VKAs) are effective for stroke prevention in patients with atrial fibrillation (AF) but are difficult to use. Dabigatran etexilate is a prodrug that is rapidly converted to the ...active direct thrombin inhibitor dabigatran. It is administered in a fixed dose without laboratory monitoring and is being compared with warfarin (international normalized ratio 2-3) in the RE-LY trial. Two doses of dabigatran (110 and 150 mg BID) are being evaluated. RE-LY is a phase 3, prospective, randomized, open-label multinational (44 countries) trial of patients with nonvalvular AF and at least 1 risk factor for stroke. Recruitment concluded with a total of 18,113 patients. Patients who were VKA-naive and experienced are included in balanced proportions. The primary outcome is stroke (including hemorrhagic) or systemic embolism. Safety outcomes are bleeding, liver function abnormalities, and other adverse events. Adjudication of end points is blinded to drug assignment. The trial is expected to accrue a minimum of 450 events with a minimum 1-year of follow-up. RE-LY is the largest AF stroke prevention trial yet undertaken. It is unique because it includes equal numbers of VKA-experienced and naive patients and evaluates 2 different dosages of dabigatran, which may allow tailoring of dosing to individual patient needs. The worldwide site distribution and broad range of stroke risk further increase the general applicability of the trial. Results are expected in 2009.
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