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Background: ROCKET AF demonstrated the efficacy and safety of rivaroxaban compared with warfarin for the prevention of stroke and systemic embolism (SE) in patients with atrial fibrillation (AF). We examined baseline characteristics and outcomes in patients enrolled in Latin America compared with the rest of the world (ROW)., Methods: ROCKET AF enrolled 14,264 patients from 45 countries. Of these, 1,878 (13.2%) were from 7 Latin American countries. The clinical characteristics and outcomes (adjusted by baseline characteristics) of these patients were compared with 12,293 patients from the ROW. Treatment outcomes of rivaroxaban compared with warfarin were also stratified by region., Results: The annual rate of stroke/SE was similar in those from Latin American and ROW (P= .63), but all-cause and vascular death were significantly higher than in ROW (HR 1.40, 95% CI 1.20-1.64; HR 1.38, 95% CI 1.14-1.68; P< .001). Rates of major or nonmajor clinically relevant bleeding tended to be lower in Latin America (HR 0.89, 95% CI 0.80-1.0; P= .05). Rates of stroke and/or SE were similar with rivaroxaban and warfarin in patients from Latin America and ROW (HR 0.83, 95% CI 0.54-1.29 vs HR 0.89, 95% CI 0.75-1.07; interaction P= .77)., Conclusions: Patients with AF in Latin America had similar rates of stroke and/or SE, higher rates of vascular death, and lower rates of bleeding compared with patients in the ROW. The effect of rivaroxaban compared with warfarin in Latin America was similar to the ROW. Further studies analyzing patient- and country-specific determinants of these regional differences in Latin America are warranted., (Copyright © 2021. Published by Elsevier Inc.)

Background: We investigated the impact of polyvascular disease in patients enrolled in ROCKET AF., Methods: Cox regression models were used to assess clinical outcomes and treatment effects of rivaroxaban compared with warfarin in patients with atrial fibrillation and coronary, peripheral, or carotid artery disease, or any combination of the 3., Results: A total of 655 (4.6%) patients had polyvascular disease (≥2 disease locations), and 3,391 (23.8%) had single-arterial bed disease. Patients with polyvascular disease had similar rates of stroke/systemic embolism but higher rates of cardiovascular and bleeding events when compared with those without vascular disease. Use of rivaroxaban compared with warfarin was associated with higher rates of stroke in patients with polyvascular disease (hazard ratio [HR] 2.41, 95% CI 1.05-5.54); however, this was not seen in patients with single-bed (HR 0.90, 95% CI 0.64-1.28) or no vascular disease (HR 0.85, 95% CI 0.69-1.04; interaction P = .058). There was a significant interaction for major or nonmajor clinically relevant bleeding in patients with polyvascular (HR 1.23, 95% CI 0.91-1.65) and single-bed vascular disease (HR 1.30, 95% CI 1.13-1.49) treated with rivaroxaban compared with warfarin when compared with those without vascular disease (HR 0.95, 95% CI 0.87-1.04; interaction P = .0006). Additional antiplatelet therapy in this population did not improve stroke or cardiovascular outcomes., Conclusion: The use of rivaroxaban compared with warfarin was associated with a higher risk of stroke and bleeding in patients with polyvascular disease enrolled in ROCKET AF. Further studies are needed to understand the optimal management of this high-risk population., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Patients with peripheral artery disease (PAD) undergoing a lower-extremity revascularization are at heightened risk for ischemic cardiac and limb events. Although intensification of antithrombotic therapy after revascularization has demonstrated benefit in coronary disease populations, this approach has not been well studied or shown consistent benefit in PAD. Recent trial evidence demonstrated that a treatment strategy of rivaroxaban added to background antiplatelet therapy reduced ischemic risk in patients following recent acute coronary syndromes, as well as in patients with stable atherosclerotic vascular disease. Whether these benefits extend to the population of patients with symptomatic lower-extremity PAD undergoing revascularization is the objective of the VOYAGER PAD trial., Study Design: VOYAGER PAD is an international randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of rivaroxaban in symptomatic PAD patients undergoing a peripheral surgical and/or endovascular revascularization. Patients are randomized in a 1:1 ratio to either rivaroxaban 2.5 mg twice daily or placebo, on a background of low-dose aspirin (100 mg daily). In addition, the use of a limited course of P2Y 12 inhibition is allowed at the discretion of the site investigator. The primary efficacy end point is a novel composite of myocardial infarction, ischemic stroke, cardiovascular death, acute limb ischemia, and major amputation of vascular etiology. The primary safety end point is major bleeding according to the Thrombolysis in Myocardial Infarction definition. Enrolment began in August 2015 and will complete randomization of at least 6,500 patients by January 2018. This event-driven trial is expected to observe outcomes over a mean patient follow-up of 30 months., Conclusions: VOYAGER PAD is evaluating the efficacy of rivaroxaban added to background antiplatelet therapy to reduce major cardiovascular and limb ischemic vascular outcomes in the high-risk population of PAD patients undergoing peripheral revascularization., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: We aimed to investigate the relationship between aspirin use and clinical outcomes in patients enrolled in Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (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, death, and major or nonmajor clinically relevant (NMCR) bleeding were compared between groups. Multivariable modeling was done adjusting for baseline risk factors., Results: A total of 5,205 (36.5%) patients were receiving aspirin at baseline (mean dose 99.2mg); 30.6% of those had known CAD. Patients receiving aspirin were more likely to have prior myocardial infarction (22% vs 14%; P<.001) and heart failure (68% vs 59%; P<.001). Relative efficacy of rivaroxaban versus warfarin was similar with and without aspirin use for both stroke/systemic embolism (P=.95 for interaction), and major or NMCR bleeding (P=.76 for interaction). After adjustment, aspirin use was associated with similar rates of stroke/systemic embolism (hazard ratio [HR] 1.16, 95% CI 0.98-1.37; P=.094) but higher rates of all-cause death (HR 1.27, 95% CI 1.13-1.42; P<.0001) and major or NMCR bleeding (HR 1.32, 95% CI 1.21-1.43; P<.0001). There was a significant interaction between no CAD at baseline and aspirin for all-cause death (P=.009)., Conclusions: 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., (Copyright © 2016 Elsevier Inc. All rights reserved.)

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 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 = .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 = .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 were 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., (Copyright © 2016 Elsevier Inc. All rights reserved.)

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., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

This white paper provides a summary of presentations and discussions that were held at an Anticoagulant-Induced Bleeding and Reversal Agents Think Tank co-sponsored by the Cardiac Safety Research Consortium and the US Food and Drug Administration (FDA) at the FDA's White Oak Headquarters on April 22, 2014. Attention focused on a development pathway for reversal agents for the novel oral anticoagulants (NOACs). This is important because anticoagulation is still widely underused for stroke prevention in patients with atrial fibrillation. Undertreatment persists, although NOACs, in general, overcome some of the difficulties associated with anticoagulation provided by vitamin K antagonists. One reason for the lack of a wider uptake is the absence of NOAC reversal agents. As there are neither widely accepted academic and industry standards nor a definitive regulatory policy on the development of such reversal agents, this meeting provided a forum for leaders in the fields of cardiovascular clinical trials and cardiovascular safety to discuss the issues and develop recommendations. Attendees included representatives from pharmaceutical companies; regulatory agencies; end point adjudication specialist groups; contract research organizations; and active, academically based physicians. There was wide and solid consensus that NOACs overall offer improvements in convenience, efficacy, and safety compared with warfarin, even without reversal agents. Still, it was broadly accepted that it would be helpful to have reversal agents available for clinicians to use. Because it is not feasible to do definitive outcomes studies demonstrating a reversal agent's clinical benefits, it was felt that these agents could be approved for use in life-threatening bleeding situations if the molecules were well characterized preclinically, their pharmacodynamic and pharmacokinetic profiles were well understood, and showed no harmful adverse events in early human testing. There was also consensus that after such approval, efforts should be made to augment the available clinical information until such time as there is a body of evidence to demonstrate real-world clinical outcomes with the reversal agents. No recommendations were made for more generalized use of these agents in the setting of non-life-threatening situations. This article reflects the views of the authors and should not be construed to represent FDA's views or policies., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: A simple device to rapidly evaluate platelet function may aid in optimizing glycoprotein IIb/IIIa inhibition during percutaneous coronary intervention (PCI). We prospectively studied platelet function in 250 patients receiving abciximab or eptifibatide during PCI., Methods and Results: The platelet function analyzer PFA-100 (Dade-Behring, Deerfield, Ill) measures platelet function by determining the time to occlusion of an aperture in a biochemically active membrane as whole blood flows under high shear conditions. Platelet aggregation causes aperture occlusion, and results are reported as a closure time (CT). All patients received either abciximab or eptifibatide, along with aspirin and heparin; patients undergoing stent implantation received aspirin and a thienopyridine postprocedure. The CT was measured at baseline and 10 minutes, 4 hours, 12 hours (abciximab-only), and 24 hours after the bolus. Profound inhibition was exhibited in most patients shortly after the platelet inhibitor bolus and during the course of therapy. We observed recovery of platelet function 12 hours after discontinuation of abciximab, with a high degree of interpatient variability, and ongoing profound platelet inhibition 4 to 6 hours after the discontinuation of eptifibatide. Among patients treated with abciximab, patients who were obese recovered from platelet inhibition sooner than patients who were not obese, whereas patients who were elderly had delayed recovery compared with patients who were not elderly. Failure to achieve maximal platelet inhibition (nonclosure) at 10 minutes indicated a possible association with adverse clinical events at the 6-month follow-up examination (60% vs 20%)., Conclusions: PFA-100 is a rapid simple assay used as a means of assessing inhibition of platelet aggregation during PCI performed with glycoprotein IIb/IIIa inhibition. Failure to achieve nonclosure early after the initiation of abciximab therapy warrants further investigation because there may be an association with adverse cardiac events at 6-month follow-up.

Background: This study analyzed relationships among heparin dosage, patient characteristics, and 30-day outcome because optimal unfractionated-heparin dosing in acute coronary syndromes remains uncertain., Methods: Patients (n = 5335) randomized to heparin therapy in the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb trial were studied. The heparin dose was adjusted to a target activated partial thromboplastin time (aPTT) and normalized for the patient's weight. Mortality and cardiac (re)infarction within 30 days and their association with patient characteristics and heparin dosing were evaluated., Results: The lowest mortality rate appeared with a heparin dose of approximately 14 U/kg/h or an aPTT of approximately 70 seconds. Heparin dosing was a significant predictor of outcome after adjusting for presenting coronary syndrome; a trend remained after adjusting for other baseline differences. This association was lost when adjusted for the aPTT result. Patients who died early appeared to have lower heparin dosing than those with later mortality (P =.012). Heparin "resistance" with relatively high heparin dosages and low aPTT values did not increase the risk for adverse outcome., Conclusions: There is a defined, dose-associated benefit of unfractionated heparin in acute coronary syndromes similar to that seen previously in thrombolytic-treated infarctions. Heparin therapy is complicated by its complex biologic interactions and relatively crude measures of its effect. Better measures of heparin effectiveness and strategies need to be developed with either better antithrombin agents or adjunctive therapies such as antiplatelet regimens to treat patients who require benefits beyond that supplied by unfractionated heparin.

Background: The platelet function analyzer PFA-100 (Dade Behring, Miami, Fla) evaluates platelet function by determining the time to occlusion of an aperture in a membrane coated with collagen and adenosine diphosphate or epinephrine as whole blood flows under shear stress conditions. Platelet aggregation causes aperture occlusion, and results are reported as closure time (CT). Interindividual variability is observed in the level of platelet inhibition achieved with use of the current abciximab dosing regimen (0.25-mg/kg bolus + 10-microg/min infusion for 12 hours). The relationships between specific levels of platelet inhibition and clinical efficacy and safety have not been fully established., Methods and Results: We prospectively studied platelet function in 27 patients receiving abciximab during percutaneous coronary intervention. This evaluation included determinations of platelet-rich plasma aggregometry, receptor occupancy studies (D3 assay), and CT measurements at baseline and 10 minutes, 4 hours, 12 hours, and 24 hours after the bolus. All patients received abciximab, aspirin, and heparin; patients undergoing coronary stent implantation received aspirin and ticlopidine after the procedure. CT results were reported within 10 minutes after initiation of testing. For 96% of patients, CT was 300 seconds (maximum CT) immediately after abciximab bolus and remained so throughout the infusion. At 24 hours we observed variable recovery from platelet inhibition and in 72% of patients CT returned to normal (< or =130 seconds)., Conclusions: Findings with the PFA-100 were similar to results observed with platelet aggregometry and receptor occupancy measurements. Most patients treated with abciximab exhibit normalized platelet function at 24 hours despite moderate levels of receptor occupancy, suggesting dissociation between occupancy and function.

Background: Thrombocytopenia is infrequently associated with abciximab therapy but may contribute to hemorrhagic risk. Factors associated with development of thrombocytopenia, the role of weight-adjustment in concomitant heparin administration, and clinical outcomes in patients with thrombocytopenia are not well defined., Methods and Results: Pooled data from 3 placebo-controlled, randomized trials (EPIC, EPILOG, and EPISTENT) of abciximab therapy during percutaneous coronary intervention identified 178 patients (2. 4% of 7290 patients) in whom thrombocytopenia (platelet count <100 x 10(9)/L) developed after enrollment. Multivariate regression analysis identified age (>65 years; P <.001), weight (<90 kg; P =. 023), baseline platelet count (<200 x 10(9)/L; P <.001), abciximab therapy (P =.002), and enrollment into the EPIC trial (P <.001) to be associated with development of thrombocytopenia. Major and minor nonsurgical hemorrhage and transfusion were more frequent (all P <. 001) in thrombocytopenic patients. Although the primary composite clinical end point of these trials (death, myocardial infarction, or urgent revascularization to 30 days) was observed with similar frequency in patients with (11.2%) and those without (7.9%; P =.114) thrombocytopenia, 30-day mortality rate was higher in thrombocytopenic patients (8.4% vs 0.6%, respectively; P <.001). This excess mortality rate persisted after excluding patients in whom thrombocytopenia was first noted after the performance of coronary bypass surgery (4.8% vs 0.6%; P <.001). Among patients in whom thrombocytopenia developed during these trials, those who received prophylactic abciximab had fewer primary end point events (7.1% vs 23.1%; P =.056) and had a lower 30-day mortality rate (3.5% vs 15.4%; P =.048) than patients with thrombocytopenia who had received prophylactic placebo., Conclusions: Thrombocytopenia associated with abciximab therapy for percutaneous coronary intervention was more frequent in older, lighter-weight patients, those with lower baseline platelet counts, and in those patients who were enrolled into the EPIC trial. Both bleeding and transfusion events occur more frequently in patients with thrombocytopenia. Patients in whom thrombocytopenia developed during these trials had increased mortality rates to 30 days not attributable to the performance of coronary bypass surgery. Among patients with thrombocytopenia, those who received prophylactic abciximab had better clinical outcomes including survival than those who did not.

Platelet glycoprotein (GP) IIb-IIIa receptor antagonists are being used with increasing frequency in the settings of percutaneous coronary interventions and acute ischemic syndromes. The development of thrombocytopenia after GP IIb-IIIa blockade has been observed to some extent with all parenteral GP IIb-IIIa inhibitors studied to date and could potentially limit their effectiveness. The incidence and severity of thrombocytopenia has varied in large clinical trials with GP IIb-IIIa inhibitors, presumably as a consequence of the different structural and pharmacokinetic characteristics of the agents, the dose administered and duration of use, repetition of exposure, and the various drugs coadministered with these agents. Certain baseline characteristics may be predictive. In most cases, severe thrombocytopenia associated with the use of GP IIb-IIIa receptor antagonists was readily reversible with platelet transfusion and was not usually associated with major clinical sequelae. Although the exact mechanisms responsible for thrombocytopenia after GP IIb-IIIa blockade are poorly understood, an immune mechanism is suggested in which the binding of the antagonist to GP IIb-IIIa receptors leads to the exposure of ligand-induced binding sites recognized by preexisting or induced antibodies. Alternatively, the receptor-drug metabolite complex itself may induce an immune response. All patients receiving parenteral GP IIb-IIIa inhibitors should be monitored within 24 hours of initiation of therapy for the development of thrombocytopenia. An algorithm for the detection and management of thrombocytopenia after GP IIb-IIIa inhibitor therapy is proposed.

Despite a clinical trials experience in excess of 30,000 randomized patients, there is no definitive answer or agreement as to the relation between the level of inhibition of platelet aggregation and clinical outcome. Work with abciximab in the setting of percutaneous intervention would suggest that a level of platelet inhibition in excess of 80% provides the most favorable clinical benefit. Whether this applies to the small molecule inhibitors such as eptifibatide, tirofiban, and lamifiban is unknown and will require testing of the hypothesis in large-scale clinical trials. In the acute coronary syndromes, only the peptide and nonpeptide inhibitors have been studied independent of a need for percutaneous intervention. The level of platelet inhibition required to achieve maximal clinical benefit is unknown and awaits data from the large-scale unstable angina and myocardial infarction trials. Issues of combining heparin with GP IIb/IIIa inhibition and the platelet-altering effects of thrombolysis must be considered when examining what might be the optimal level of platelet inhibition that provides maximal efficacy while maintaining safety. Long-term therapy with the oral platelet inhibitors poses a particular challenge in determining an optimal level of treatment that renders clinical effectiveness while preserving safety. Large, ongoing clinical trials with these agents should provide insight into this question. Finally, given the complexity of using such potent therapies in any individual patient, there is a need for improved monitoring of the platelet inhibitory effect. Standard platelet aggregometry has its problems and limitations, as described, and is not a test that has wide-scale applicability. Whole blood aggregometry and other methods of rapidly assessing platelet function at the point of care have promise in this arena. In a clinical trial, such technology might allow better delineation of the population's pharmacodynamic response to an agent because it could be more widely applied and therefore more patients would be studied. In clinical practice, patients could be dosed individually so that a range of platelet inhibition could be achieved that was believed to provide optimal benefit and safety.