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Background: Patients with peripheral artery disease (PAD) are at heightened risk of acute limb ischemia (ALI), a thrombotic event associated with amputation, disability, and mortality. Previous lower extremity revascularization (LER) is associated with increased ALI risk in chronic PAD. However, the pattern of risk, clinical correlates, and outcomes after ALI early after LER are not well-studied, and effective therapies to reduce ALI post-LER are lacking. Methods: The VOYAGER PAD trial (Vascular Outcomes Study of ASA [Acetylsalicylic Acid] Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD; rNCT02504216) randomized patients with PAD undergoing LER to rivaroxaban 2.5 mg twice daily or placebo on a background of low-dose aspirin. The primary outcome was a composite of ALI, major amputation of vascular cause, myocardial infarction, ischemic stroke, or cardiovascular death. ALI was prospectively ascertained and adjudicated by a blinded committee. The cumulative incidence of ALI was calculated using Kaplan-Meier estimates, and Cox proportional hazards models were used to generate hazard ratios and associated CIs. Analyses were performed as intention-to-treat. Results: Among 6564 patients followed for a median of 2.3 years, 382 (5.8%) had a total of 508 ALI events. In placebo patients, the 3-year cumulative incidence of ALI was 7.8%. After multivariable modeling, previous LER, baseline ankle-brachial index P =0.0001), with benefit starting early (HR, 0.45 [95% CI, 0.24–0.85]; P =0.0068 at 30 days). Benefit was present for severe ALI (associated with death, amputation, or prolonged hospitalization and intensive care unit stay, HR, 0.58 [95% CI, 0.40–0.83]; P =0.003) and regardless of LER type (surgical versus endovascular revascularization, P interaction=0.42) or clopidogrel use ( P interaction=0.59). Conclusions: After LER for symptomatic PAD, ALI is frequent, particularly early after LER, and is associated with poor prognosis. Low-dose rivaroxaban plus aspirin reduces ALI after LER, including ALI events associated with the most severe outcomes. The benefit of rivaroxaban for ALI appears early, continues over time, and is consistent regardless of revascularization approach or clopidogrel use.

Background: The VOYAGER PAD trial (Vascular Outcomes Study of ASA Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease) demonstrated superiority of rivaroxaban plus aspirin versus aspirin to reduce major cardiac and ischemic limb events after lower extremity revascularization. Clopidogrel is commonly used as a short-term adjunct to aspirin after endovascular revascularization. Whether clopidogrel modifies the efficacy and safety of rivaroxaban has not been described. Methods: VOYAGER PAD was a phase 3, international, double-blind, placebo-controlled trial in patients with symptomatic PAD undergoing lower extremity revascularization randomized to rivaroxaban 2.5 mg twice daily plus 100 mg aspirin daily or rivaroxaban placebo plus aspirin. The primary efficacy outcome was a composite of acute limb ischemia, major amputation of a vascular cause, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety end point was TIMI (Thrombolysis in Myocardial Infarction) major bleeding, with International Society on Thrombosis and Haemostasis major bleeding a secondary safety outcome. Clopidogrel use was allowed at the discretion of the investigator for up to 6 months after the qualifying revascularization. Results: Of the randomized patients, 3313 (50.6%) received clopidogrel for a median duration of 29.0 days. Over 3 years, the hazard ratio for the primary outcome of rivaroxaban versus placebo was 0.85 (95% CI, 0.71–1.01) with clopidogrel and 0.86 (95% CI, 0.73–1.01) without clopidogrel without statistical heterogeneity ( P for interaction=0.92). Rivaroxaban resulted in an early apparent reduction in acute limb ischemia within 30 days (hazard ratio, 0.45 [95% CI, 0.14–1.46] with clopidogrel; hazard ratio, 0.48 [95% CI, 0.22–1.01] without clopidogrel; P for interaction=0.93). Compared with aspirin, rivaroxaban increased TIMI major bleeding similarly regardless of clopidogrel use ( P for interaction=0.71). With clopidogrel use >30 days, rivaroxaban was associated with more International Society on Thrombosis and Haemostasis major bleeding within 365 days (hazard ratio, 3.20 [95% CI, 1.44–7.13]) compared with shorter durations of clopidogrel ( P for trend=0.06). Conclusions: In the VOYAGER PAD trial, rivaroxaban plus aspirin reduced the risk of adverse cardiovascular and limb events with an early benefit for acute limb ischemia regardless of clopidogrel use. The safety of rivaroxaban was consistent regardless of clopidogrel use but with a trend for more International Society on Thrombosis and Haemostasis major bleeding with clopidogrel use >30 days than with a shorter duration. These data support the addition of rivaroxaban to aspirin after lower extremity revascularization regardless of concomitant clopidogrel, with a short course (≤30 days) associated with less bleeding. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02504216.

Background: Patients with established coronary artery disease or peripheral artery disease often have diabetes mellitus. These patients are at high risk of future vascular events. Methods: In a prespecified analysis of the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies), we compared the effects of rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg daily) versus placebo plus aspirin in patients with diabetes mellitus versus without diabetes mellitus in preventing major vascular events. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included all-cause mortality and all major vascular events (cardiovascular death, myocardial infarction, stroke, or major adverse limb events, including amputation). The primary safety end point was a modification of the International Society on Thrombosis and Haemostasis criteria for major bleeding. Results: There were 10 341 patients with diabetes mellitus and 17 054 without diabetes mellitus in the overall trial. A consistent and similar relative risk reduction was seen for benefit of rivaroxaban plus aspirin (n=9152) versus placebo plus aspirin (n=9126) in patients both with (n=6922) and without (n=11 356) diabetes mellitus for the primary efficacy end point (hazard ratio, 0.74, P =0.002; and hazard ratio, 0.77, P =0.005, respectively, P interaction =0.77) and all-cause mortality (hazard ratio, 0.81, P =0.05; and hazard ratio, 0.84, P =0.09, respectively; P interaction =0.82). However, although the absolute risk reductions appeared numerically larger in patients with versus without diabetes mellitus, both subgroups derived similar benefit (2.3% versus 1.4% for the primary efficacy end point at 3 years, Gail-Simon qualitative P interaction P interaction =0.02; 2.7% versus 1.7% for major vascular events, P interaction P interaction =0.001). Conclusions: In stable atherosclerosis, the combination of aspirin plus rivaroxaban 2.5 mg twice daily provided a similar relative degree of benefit on coronary, cerebrovascular, and peripheral end points in patients with and without diabetes mellitus. Given their higher baseline risk, the absolute benefits appeared larger in those with diabetes mellitus, including a 3-fold greater reduction in all-cause mortality. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01776424.

Background: The COMPASS trial (Cardiovascular Outcomes for People using Anticoagulation Strategies) demonstrated that dual pathway inhibition (DPI) with rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily versus aspirin 100 mg once daily reduced the primary major adverse cardiovascular event (MACE) outcome of cardiovascular death, myocardial infarction, or stroke, as well as, mortality, in patients with chronic coronary syndromes or peripheral arterial disease. Whether this remains true in patients with a history of percutaneous coronary intervention (PCI) is unknown. Methods: In a prespecified subgroup analysis from COMPASS, we examined the outcomes of patients with a chronic coronary syndrome with or without a previous PCI treated with DPI versus aspirin alone. Among patients with a previous PCI, we studied the effects of treatment according to the timing of the previous PCI. Results: Of the 27 395 patients in COMPASS, 16 560 patients with a chronic coronary syndrome were randomly assigned to DPI or aspirin, and, of these, 9862 (59.6%) had previous PCI (mean age 68.2±7.8, female 19.4%, diabetes mellitus 35.7%, previous myocardial infarction 74.8%, multivessel PCI 38.0%). Average time from PCI to randomization was 5.4 years (SD, 4.4) and follow-up was 1.98 (SD, 0.72) years. Regardless of previous PCI, DPI versus aspirin produced consistent reductions in MACE (PCI: 4.0% versus 5.5%; hazard ratio [HR], 0.74 [95% CI, 0.61–0.88]; no PCI: 4.4% versus 5.7%; HR, 0.76 [95% CI, 0.61–0.94], P -interaction=0.85) and mortality (PCI: 2.5% versus 3.5%; HR, 0.73 [95% CI, 0.58–0.92]; no PCI: 4.1% versus 5.0%; HR, 0.80 [95% CI, 0.64–1.00], P -interaction=0.59), but increased major bleeding (PCI: 3.3% versus 2.0%; HR, 1.72 [95% CI, 1.34–2.21]; no PCI: 2.9% versus 1.8%; HR, 1.58 [95% CI, 1.15–2.17], P -interaction=0.68). In those with previous PCI, DPI compared with aspirin produced consistent (robust) reductions in MACE irrespective of time since previous PCI (as early as 1 year and as far as 10 years; P -interaction=0.65), irrespective of having a previous myocardial infarction ( P -interaction=0.64). Conclusions: DPI compared with aspirin produced consistent reductions in MACE and mortality but with increased major bleeding with or without previous PCI. Among those with previous PCI 1 year and beyond, the effects on MACE and mortality were consistent irrespective of time since last PCI. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01776424.

Background: Patients with peripheral artery disease requiring lower extremity revascularization (LER) are at high risk of adverse limb and cardiovascular events. The VOYAGER PAD trial (Vascular Outcomes Study of ASA [Acetylsalicylic Acid] Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD) demonstrated that rivaroxaban significantly reduced this risk. The efficacy and safety of rivaroxaban has not been described in patients who underwent surgical LER. Methods: The VOYAGER PAD trial randomized patients with peripheral artery disease after surgical and endovascular LER to rivaroxaban 2.5 mg twice daily plus aspirin or matching placebo plus aspirin and followed for a median of 28 months. The primary end point was a composite of acute limb ischemia, major vascular amputation, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety outcome was Thrombolysis in Myocardial Infarction major bleeding. International Society on Thrombosis and Haemostasis bleeding was a secondary safety outcome. All efficacy and safety outcomes were adjudicated by a blinded independent committee. Results: Of the 6564 randomized, 2185 (33%) underwent surgical LER and 4379 (67%) endovascular. Compared with placebo, rivaroxaban reduced the primary end point consistently regardless of LER method ( P -interaction, 0.43). After surgical LER, the primary efficacy outcome occurred in 199 (18.4%) patients in the rivaroxaban group and 242 (22.0%) patients in the placebo group with a cumulative incidence at 3 years of 19.7% and 23.9%, respectively (hazard ratio, 0.81 [95% CI, 0.67–0.98]; P =0.026). In the overall trial, Thrombolysis in Myocardial Infarction major bleeding and International Society on Thrombosis and Haemostasis major bleeding were increased with rivaroxaban. There was no heterogeneity for Thrombolysis in Myocardial Infarction major bleeding ( P -interaction, 0.17) or International Society on Thrombosis and Haemostasis major bleeding ( P -interaction, 0.73) on the basis of the LER approach. After surgical LER, the principal safety outcome occurred in 11 (1.0%) patients in the rivaroxaban group and 13 (1.2%) patients in the placebo group; 3-year cumulative incidence was 1.3% and 1.4%, respectively (hazard ratio, 0.88 [95% CI, 0.39–1.95]; P =0.75) Among surgical patients, the composite of fatal bleeding or intracranial hemorrhage ( P =0.95) and postprocedural bleeding requiring intervention ( P =0.93) was not significantly increased. Conclusions: The efficacy of rivaroxaban is associated with a benefit in patients who underwent surgical LER. Although bleeding was increased with rivaroxaban plus aspirin, the incidence was low, with no significant increase in fatal bleeding, intracranial hemorrhage, or postprocedural bleeds requiring intervention. Registration: URL: http://www.clinicaltrials.gov ; Unique Identifier: NCT02504216.

Background: Strokes were significantly reduced by the combination of rivaroxaban plus aspirin in comparison with aspirin in the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies). We present detailed analyses of stroke by type, predictors, and antithrombotic effects in key subgroups. Methods: Participants had stable coronary artery or peripheral artery disease and were randomly assigned to receive aspirin 100 mg once daily (n=9126), rivaroxaban 5 mg twice daily (n=9117), or rivaroxaban 2.5 mg twice daily plus aspirin (n=9152). Patients who required anticoagulation or had a stroke within 1 month, previous lacunar stroke, or intracerebral hemorrhage were excluded. Results: During a mean follow-up of 23 months, fewer patients had strokes in the rivaroxaban plus aspirin group than in the aspirin group (83 [0.9% per year] versus 142 [1.6% per year]; hazard ratio [HR], 0.58; 95% CI, 0.44–0.76; P P P =0.01). Independent predictors of stroke were prior stroke, hypertension, systolic blood pressure at baseline, age, diabetes mellitus, and Asian ethnicity. Prior stroke was the strongest predictor of incident stroke (HR, 3.63; 95% CI, 2.65–4.97; P Conclusions: Low-dose rivaroxaban plus aspirin is an important new antithrombotic option for primary and secondary stroke prevention in patients with clinical atherosclerosis. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01776424.

Introduction: Chronic kidney disease (CKD) is common among patients undergoing lower extremity revascularization (LER) for peripheral artery disease (PAD) and identifies a population at high risk for adverse outcomes. The VOYAGER PAD trial demonstrated the efficacy of rivaroxaban in PAD patients after LER on a composite of cardiovascular (CV) and limb ischemic events (HR 0.85 vs placebo, 95% CI 0.76-0.96; p=0.009); this analysis examines the prespecified subgroup of patients with CKD. Methods: VOYAGER PAD (NCT02504216) was a double-blind, placebo-controlled trial which randomized PAD patients with recent LER to rivaroxaban 2.5 mg twice daily or placebo on a background of aspirin 100 mg daily. The primary endpoint was a composite of acute limb ischemia, major amputation for vascular cause, myocardial infarction, ischemic stroke or CV death. The primary safety endpoint was TIMI major bleeding. Analysis of the intention-to-treat population utilized Kaplan Meier estimates and Cox proportional-hazards models. Results: Among 6319 VOYAGER patients with baseline estimated glomerular filtration rate (eGFR), 21% were 2 . During 28-month (median) follow up, patients with CKD had a higher rate of major CV and limb events: placebo group 10.0 events/100 patient-years (95% CI 8.5, 11.8) for eGFR Conclusions: Rivaroxaban reduced major CV and limb events in patients with PAD undergoing LER, including those with CKD, a particularly high-risk population.

Background: Prior studies suggest that atherosclerotic vascular disease may be associated with risk of venous thromboembolism (VTE), though the relationship remains uncertain and has not been well-studied in peripheral artery disease (PAD) after lower extremity revascularization (LER). Hypothesis: We hypothesized that patients with PAD undergoing LER are at risk for VTE and that this risk may be reduced by low-dose rivaroxaban plus aspirin versus aspirin alone. Methods: VOYAGER PAD randomized 6,564 PAD patients undergoing LER to rivaroxaban 2.5 mg twice daily or placebo on a background of aspirin 100 mg daily. Clopidogrel was allowed for up to 6 months. Patients could not be enrolled if they had an indication for therapeutic anticoagulation, including secondary prevention of VTE. Symptomatic VTE was a prespecified secondary endpoint. Results: Over a median of 28 months, there were 66 patients with VTE. In patients randomized to placebo, risk for VTE accrued steadily after randomization at a rate of ~0.5% per year resulting in a 3-year rate of 1.66%. Compared with placebo, rivaroxaban reduced the risk of VTE by 39% (HR 0.61, 95% CI 0.37-1.00, p=0.047), with benefit apparent early and sustained over time (Figure). The efficacy of rivaroxaban was not modified by use of clopidogrel at randomization (without clopidogrel HR 0.55, 95% CI 0.29, 1.07; with clopidogrel HR 0.69, 95% CI 0.32, 1.48; p-interaction = 0.67). Conclusions: PAD is associated with continuous and linearly increasing risk for VTE after LER. A strategy of low-dose rivaroxaban plus aspirin versus aspirin alone reduced this risk by 39% with benefits apparent early and continued over time. The addition of clopidogrel does not modify this benefit. VTE, along with arterial thrombotic events, is part of the adverse thrombotic risk profile in PAD patients, and low-dose rivaroxaban plus aspirin provides protection against venous and arterial thrombosis.

Background: Patients treated with antithrombotic drugs are at risk of bleeding. Bleeding may be the first manifestation of underlying cancer. Methods: We examined new cancers diagnosed in relation to gastrointestinal or genitourinary bleeding among patients enrolled in the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies) and determined the hazard of new cancer diagnosis after bleeding at these sites. Results: Of 27 395 patients enrolled (mean age, 68 years; women, 21%), 2678 (9.8%) experienced any (major or minor) bleeding, 713 (2.6%) experienced major bleeding, and 1084 (4.0%) were diagnosed with cancer during a mean follow-up of 23 months. Among 2678 who experienced bleeding, 257 (9.9%) were subsequently diagnosed with cancer. Gastrointestinal bleeding was associated with a 20-fold higher hazard of new gastrointestinal cancer diagnosis (7.4% versus 0.5%; hazard ratio [HR], 20.6 [95% CI, 15.2–27.8]) and 1.7-fold higher hazard of new nongastrointestinal cancer diagnosis (3.8% versus 3.1%; HR, 1.70 [95% CI, 1.20–2.40]). Genitourinary bleeding was associated with a 32-fold higher hazard of new genitourinary cancer diagnosis (15.8% versus 0.8%; HR, 32.5 [95% CI, 24.7–42.9]), and urinary bleeding was associated with a 98-fold higher hazard of new urinary cancer diagnosis (14.2% versus 0.2%; HR, 98.5; 95% CI, 68.0–142.7). Nongastrointestinal, nongenitourinary bleeding was associated with a 3-fold higher hazard of nongastrointestinal, nongenitourinary cancers (4.4% versus 1.9%; HR, 3.02 [95% CI, 2.32–3.91]). Conclusions: In patients with atherosclerosis treated with antithrombotic drugs, any gastrointestinal or genitourinary bleeding was associated with higher rates of new cancer diagnosis. Any gastrointestinal or genitourinary bleeding should prompt investigation for cancers at these sites. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01776424.

Patients with impaired renal function have higher rates of bleeding and thromboembolism.1 Our group recently described the impact of worsening renal function on patients in the ROCKET AF study (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) (ClinicalTrials.gov. Unique identifier: NCT00403767).2 In the process of publishing these findings, questions arose from reviewers regarding the influence of baseline creatinine clearance (CrCl) on trial outcomes in ROCKET AF.3 Bohula et al4 demonstrated higher relative rates of thromboembolism in those with CrCl >95 mL/min treated with edoxaban in the ENGAGE TIMI-AF 48 trial (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation -Thrombolysis in Myocardial Infarction 48). We present the findings of an analysis using data from ROCKET AF3 to evaluate the consistency of treatment effect of rivaroxaban versus warfarin across the full range of baseline CrCl included in the trial. ROCKET AF included 14 264 patients with nonvalvular atrial fibrillation (AF). Patients were randomly assigned to 20 mg rivaroxaban once daily (15 mg once daily in patients with a CrCl of 30–49 mL/min) or dose-adjusted warfarin (target international normalized ratio 2.5, range 2.0–3.0). Further description of the ROCKET AF results and design has been published previously.3,5 All patients provided written informed consent, and approval by appropriate ethics committees was obtained at all sites. We included 14 221 patients with CrCl data who received the study drug. We examined the primary efficacy end point of stroke or systemic embolism (SE); the principal safety end point of major or nonmajor clinically relevant bleeding; the secondary efficacy outcomes of ischemic stroke, hemorrhagic stroke, …

Background: Despite rapid clinical adoption of novel anticoagulants, it is unknown whether outcomes differ among patients with worsening renal function (WRF) taking these new drugs compared with warfarin. We aimed to determine whether the primary efficacy (stroke or systemic embolism) and safety (major bleeding and nonmajor clinically relevant bleeding) end points from the ROCKET AF trial (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation trial) differed among participants with WRF taking rivaroxaban and those taking warfarin. Methods: After excluding patients without at least 1 follow-up creatinine measurement (n=1624), we included all remaining patients (n=12 612) randomly assigned to either rivaroxaban or dose-adjusted warfarin. On-treatment WRF (a decrease of >20% from screening creatinine clearance measurement at any time point during the study) was evaluated as a time-dependent covariate in Cox proportional hazards models. Results: Baseline characteristics were generally similar between patients with stable renal function (n=9292) and WRF (n=3320). Rates of stroke or systemic embolism, myocardial infarction, and bleeding were also similar, but WRF patients experienced a higher incidence of vascular death versus stable renal function (2.21 versus 1.41 events per 100 patient-years; P =0.026). WRF patients who were randomized to receive rivaroxaban had a reduction in stroke or systemic embolism compared with those taking warfarin (1.54 versus 3.25 events per 100 patient-years) that was not seen in patients with stable renal function who were randomized to receive rivaroxaban ( P =0.050 for interaction). There was no difference in major or nonmajor clinically relevant bleeding among WRF patients randomized to warfarin versus rivaroxaban. Conclusions: Among patients with on-treatment WRF, rivaroxaban was associated with lower rates of stroke and systemic embolism compared with warfarin, without an increase in the composite bleeding end point. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00403767.

Background: Non-dihydropyridine calcium channel blockers (non-DHP CCBs) are agents commonly used for ventricular rate control in patients with atrial fibrillation (AF). The agents have the property of combined cytochrome 3A4 and P-glycoprotein (P-gp) inhibition which may lead to increased drug exposure for oral anticoagulants that are substrates for these pathways. We investigated the safety and efficacy of rivaroxaban versus warfarin according to use of these agents. Objectives: This post-hoc analysis examined patient characteristics and compared outcomes between rivaroxaban and warfarin using Cox proportional hazards modeling according to the use of non-DHP CCBs at baseline in ROCKET AF (n=14,264). Methods and Results: At the time of randomization, 1308 patients (9.2%) were taking a non-DHP CCBs. Patients taking a non-DHP CCB were more likely to be female (45% vs. 39%), have diabetes (43% vs. 40%), and have a medical history of COPD (21% vs. 9%) while they were less likely to have a medical history of heart failure (49% vs. 64%), myocardial infarction (14% vs.18%) and had a lower mean CHADS 2 score (3.3 vs. 3.5). Non-DHP CCB use was not associated with an increased risk of stroke or non-CNS embolism (P=0.11) or the composite outcome of non-major clinically relevant or major bleeding (P=0.087). No significant difference was observed in the primary efficacy (stroke or non-CNS embolism; adjusted interaction P value=0.38) or primary safety outcome (non-major clinically relevant bleeding or major bleeding; adjusted interaction P value=0.14) between rivaroxaban and warfarin with non-DHP CCB use (Table). Conclusion: Non-DHP CCBs are commonly used medications for rate control in patients with AF. In spite of having the properties of combined P-gp and moderate CYP3A4 inhibition, use of these agents was not associated with a significant change in the efficacy or safety of rivaroxaban compared with warfarin in the ROCKET AF trial.

Introduction: ROCKET AF demonstrated the noninferiority of rivaroxaban vs. warfarin in preventing stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (AF). It is unknown whether outcomes differ among patients with worsening renal function (WRF) on rivaroxaban compared with warfarin. Methods: After excluding patients with insufficient data to calculate creatinine clearance (CrCl, Cockcroft-Gault; n=1624), we included all remaining patients (n=12,612) randomly assigned to either rivaroxaban or dose-adjusted warfarin. The primary efficacy endpoint was the composite of stroke or SE; the primary safety endpoint was the composite of major bleeding and clinically relevant non-major bleeding. On-treatment WRF, as defined in recent cardiovascular studies as a decrease of ≥20% from screening CrCl, was evaluated as a time-dependent covariate in Cox proportional hazards models. Results: Baseline characteristics were generally similar between patients who maintained stable renal function (SRF) (n=9292) and patients with WRF (n=3320). Overall rates of stroke or SE, myocardial infarction, and bleeding were also similar, but WRF patients had an increase in vascular death (1.41 events/100 pt-years for SRF to 2.21 for WRF p=0.026). WRF patients on rivaroxaban had a reduction in stroke or SE compared with WRF patients on warfarin (1.54 events/100 pt-years for rivaroxaban to 3.25 for warfarin) that was not seen in SRF patients (p=0.050 for interaction; Figure). WRF patients on rivaroxaban had a greater incidence of hemoglobin fall ≥2 g/dL (3.56 events/100 pt-years for rivaroxaban to 1.85 for warfarin), that was not seen in SRF patients (p=0.047 for interaction). However, there was no difference in major or clinically relevant non-major bleeding. Conclusions: Among patients with on-treatment WRF, rivaroxaban was associated with lower rates of stroke and SE compared with warfarin without an increase in the composite bleeding endpoint.

Background: Hypertension (HTN) is a risk factor for stroke and bleeding in atrial fibrillation (AF). Yet, the association between HTN stage and stroke and bleeding risk in AF is unknown. Methods: The study population included 14,256 of the patients randomized in the ROCKET AF trial. Baseline systolic blood pressure (SBP) and history of HTN were determined and categorized as follows: (1) no history of HTN, (2) controlled HTN (SBP Results: Of the 90.5% of patients in ROCKET AF with HTN, 55.9% were controlled and 34.6% had stage 1 or 2 HTN. Compared with those with HTN, those without HTN had lower mean CHADS 2 scores (2.8 vs. 3.5), lower rates of prior myocardial infarction (11% vs. 18%), and lower mean age (69 vs. 73 years). Compared with those with no history of HTN, there was a trend towards an increased adjusted risk of stroke or SE in patients with controlled HTN (HR 1.22, 95% CI 0.89-1.66) and stage 1 or 2 HTN (HR 1.42, 95% CI 1.03-1.95) (p=0.06). A similar trend in adjusted risk of hemorrhagic stroke (controlled HTN: HR 2.50, 95% CI 0.89-7.05; stage 1 or 2 HTN: HR 3.04, 95% CI 1.06-8.71) (p=0.11) was observed. The effect of HTN stage on stroke risk did not vary by baseline CHADS 2 score (p interaction=0.70). The adjusted risk of major bleeding was not different between groups (HR 0.96, 95% CI 0.74-1.23; HR 1.00, 95% CI 0.77-1.30) (p=0.84). The benefit of rivaroxaban versus warfarin in preventing stroke or SE was consistent among patients regardless of baseline SBP (p interaction=0.69). Conclusion: One-third of patients in a clinical trial of AF had uncontrolled SBP at baseline. Uncontrolled SBP showed a trend towards a higher risk of stroke or SE, but not bleeding. Uncontrolled SBP may be an important factor in reducing the overall risk of stroke, and specifically hemorrhagic stroke, in patients with AF.

Background —The significance of thrombocytopenia in patients experiencing an acute coronary syndrome (ACS) has not been examined systematically. We evaluated this condition in a large non–ST-elevation ACS clinical trial, with particular interest paid to its correlation with clinical outcomes. Methods and Results —Patients presenting without persistent ST elevation during an ACS were randomized to receive a double-blind infusion of the platelet glycoprotein (GP) IIb/IIIa inhibitor eptifibatide or placebo in addition to other standard therapies including heparin and aspirin. The primary end point was death/nonfatal myocardial infarction (MI) at 30 days, whereas bleeding and stroke were the main safety outcomes. Thrombocytopenia (nadir platelet count 9 /L or P Conclusions —Although causality between thrombocytopenia and adverse clinical events could not be established definitively, thrombocytopenia was highly correlated with both bleeding and ischemic events, and the presence of this condition identified a more-at-risk patient population.

Background —In the ESSENCE trial, subcutaneous low-molecular-weight heparin (enoxaparin) reduced the 30-day incidence of death, myocardial infarction, and recurrent angina relative to intravenous unfractionated heparin in 3171 patients with acute coronary syndrome (unstable angina or non–Q-wave myocardial infarction). No increase in major bleeding was seen. Methods and Results —Of the 936 ESSENCE patients randomized in the United States, 655 had hospital billing data collected. For the remainder, hospital costs were imputed with a multivariable linear regression model ( R 2 =.86). Physician fees were estimated from the Medicare Fee Schedule. During the initial hospitalization, major resource use was reduced for enoxaparin patients, with the largest effect seen with coronary angioplasty (15% versus 20% for heparin, P =.04). At 30 days, these effects persisted, with the largest reductions seen in diagnostic catheterization (57% versus 63% for heparin, P =.04) and coronary angioplasty (18% versus 22%, P =.08). All resource use trends seen in the US cohort were also evident in the overall ESSENCE study population. In the United States, the mean cost of a course of enoxaparin therapy was $155, whereas that for heparin was $80. The total medical costs (hospital, physician, drug) for the initial hospitalization were $11 857 for enoxaparin and $12 620 for heparin, a cost advantage for the enoxaparin arm of $763 ( P =.18). At the end of 30 days, the cumulative cost savings associated with enoxaparin was $1172 ( P =.04). In 200 bootstrap samples of the 30-day data, 94% of the samples showed a cost advantage for enoxaparin. Conclusions —In patients with acute coronary syndrome, low-molecular-weight heparin (enoxaparin) both improves important clinical outcomes and saves money relative to therapy with standard unfractionated heparin.

Background Although the benefit of thrombolytic therapy in reducing mortality in acute myocardial infarction is well established, the types of bleeding and risk factors for bleeding are less well described in large trials. Methods and Results We analyzed the baseline characteristics, outcomes, and incidence of bleeding by location, severity, and treatment assignment among 41 021 patients in the GUSTO-I trial of thrombolysis for acute myocardial infarction. Of the 40 903 patients for whom there were complete data, 1.2% suffered severe bleeding and 11.4% experienced moderate hemorrhage at a variety of sites. The most common sources of bleeding were procedure related. The thrombolytic regimen was strongly related to the incidence of bleeding; comparatively more bleeding was seen with the therapies of streptokinase plus intravenous heparin and the streptokinase and tissue plasminogen activator plus intravenous heparin combination. In multivariate analysis, the four most powerful independent predictors of hemorrhage were older age, lighter body weight, female sex, and African ancestry; they remained the most important predictors of bleeding when multivariate analysis was performed on patients who did not undergo invasive procedures. The presence of serious hemorrhage was associated with other undesirable outcomes (recurrent events, left ventricular dysfunction, arrhythmia, or stroke). Conclusions Important predictors of bleeding in this population are increased age, lighter weight, female sex, African ancestry, and experiencing invasive procedures. Other nonhemorrhagic adverse clinical outcomes were associated with moderate and severe bleeding, which was in turn associated with increased length of hospital stay and mortality at 30 days.

Background Platelets play a crucial role in the ischemic complications of percutaneous coronary procedures. The recent availability of c7E3 Fab (abciximab; ReoPro), a chimeric monoclonal antibody Fab fragment directed against the platelet glycoprotein IIb/IIIa receptor, has reduced abrupt closure and other adverse clinical events and lessened the need for revascularization procedures. As experience accrues, rare cases of acute profound thrombocytopenia have been revealed. Methods and Results From November 1991 to July 1996, patients at Duke University Medical Center who underwent percutaneous coronary revascularization and received their first exposure to c7E3 Fab were evaluated for the development of acute profound thrombocytopenia, defined as a platelet count 9 /L occurring within 24 hours of initial treatment. Four patients (0.5%) developed acute profound thrombocytopenia within 11 to 21 hours of receiving the c7E3 Fab bolus. Nadir platelet counts ranged from 1 to 16×10 9 /L and occurred within 11 to 26 hours. No patient developed a significant hemorrhagic complication, and each patient's platelet count responded to platelet transfusion. Platelet counts remained depressed for at least 3 days but returned to baseline within 2 weeks. Conclusions Acute profound thrombocytopenia can occur after c7E3 Fab administration. Its development was not predictable, and it requires consideration in every patient treated. A platelet count 2 to 4 hours after the bolus would likely have detected these four cases. When indicated, platelet transfusion will raise the platelet count to safer levels without adverse effects. The differential diagnosis (including heparin-induced thrombocytopenia), a plan for management, and postulates as to the mechanism are discussed.

Background —Heparin-induced thrombocytopenia (HIT) is an immune-mediated syndrome caused by heparin. Complications range from thrombocytopenia to thrombocytopenia with thrombosis. We report a prospective, historical- controlled study evaluating the efficacy and safety of argatroban, a direct thrombin inhibitor, as anticoagulant therapy in patients with HIT or HIT with thrombosis syndrome (HITTS). Methods and Results —Patients with HIT (isolated thrombocytopenia, n=160) or HITTS (n=144) received 2 μg · kg −1 · min −1 IV argatroban, adjusted to maintain the activated partial thromboplastin time 1.5 to 3.0 times baseline value. Treatment was maintained for 6 days, on average. Clinical outcomes over 37 days were compared with those of 193 historical control subjects with HIT (n=147) or HITTS (n=46). The incidence of the primary efficacy end point, a composite of all-cause death, all-cause amputation, or new thrombosis, was reduced significantly in argatroban-treated patients versus control subjects with HIT (25.6% versus 38.8%, P =0.014). In HITTS, the composite incidence in argatroban-treated patients was 43.8% versus 56.5% in control subjects ( P =0.13). Significant between-group differences by time-to-event analysis of the composite end point favored argatroban treatment in HIT ( P =0.010) and HITTS ( P =0.014). Argatroban therapy, relative to control subjects, also significantly reduced new thrombosis and death caused by thrombosis ( P P =0.0001). Bleeding events were similar between groups. Conclusions —Argatroban anticoagulation, compared with historical control subjects, improves clinical outcomes in patients who have heparin-induced thrombocytopenia, without increasing bleeding risk.

Glycoprotein IIb/IIIa Integrin Blockade Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1998 American Heart Association, Inc. All rights reserved. is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Circulation doi: 10.1161/01.CIR.98.23.2629 1998;98:2629-2635 Circulation. http://circ.ahajournals.org/content/98/23/2629 World Wide Web at: The online version of this article, along with updated information and services, is located on the