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Efficacy and safety of rivaroxaban compared with warfarin in patients with peripheral artery disease and non-valvular atrial fibrillation: insights from ROCKET AF

William Schuyler Jones , Anne S. Hellkamp , Jonathan Halperin , Jonathan P. Piccini , Gunter Breithardt , Daniel E. Singer , Keith A.A. Fox , Graeme J. Hankey , Kenneth W. Mahaffey , Robert M. Califf , Manesh R. Patel
DOI: http://dx.doi.org/10.1093/eurheartj/eht492 242-249 First published online: 3 December 2013

Abstract

Aims Vascular disease is included in a risk scoring system to predict stroke in patients with non-valvular atrial fibrillation (AF). This post hoc analysis of ROCKET AF aimed to determine the absolute rates of stroke and bleeding, and the relative effectiveness and safety of rivaroxaban vs. warfarin in patients with and without peripheral artery disease (PAD). Peripheral artery disease was defined on the case-report form as the presences of intermittent claudication, amputation for arterial insufficiency, vascular reconstruction, bypass surgery, or percutaneous intervention to the extremities, or previously documented abdominal aortic aneurysm.

Methods and results ROCKET AF was a double-blind, double-dummy, randomized-controlled trial comparing rivaroxaban and warfarin for the prevention of stroke or systemic embolism. A total of 839 (5.9%) patients in ROCKET AF had PAD. Patients with and without PAD had similar rates of stroke or systemic embolism [HR: 1.04, 95% CI (0.72, 1.50), P = 0.84] and major or non-major clinically relevant (NMCR) bleeding [HR: 1.11, 95% CI (0.96, 1.28), P = 0.17], respectively. The efficacy of rivaroxaban when compared with warfarin for the prevention of stroke or systemic embolism was similar in patients with PAD (HR: 1.19, 95% CI: 0.63–2.22) and without PAD (HR: 0.86, 95% CI: 0.73–1.02; interaction P = 0.34). There was a significant interaction for major or NMCR bleeding in patients with PAD treated with rivaroxaban compared with warfarin (HR: 1.40, 95% CI: 1.06–1.86) compared with those without PAD (HR: 1.03, 95% CI: 0.95–1.11; interaction P = 0.037).

Conclusion Patients with PAD in ROCKET AF did not have a statistically significant higher risk of stroke or systemic embolism than patients without PAD, and there were similar efficacy outcomes in patients treated with rivaroxaban and warfarin. In PAD patients, there was a higher risk of major bleeding or NMCR bleeding with rivaroxaban when compared with warfarin (interaction P = 0.037). Further investigation is warranted to validate this subgroup analysis and determine the optimal treatment in this high-risk cohort of AF patients with PAD.

  • Peripheral artery disease
  • Atrial fibrillation
  • Rivaroxaban
  • Stroke
  • Systemic embolism
  • Bleeding

Introduction

Vascular disease as defined by prior myocardial infarction (MI), peripheral artery disease (PAD), or aortic atherosclerotic plaque was recently incorporated into an updated risk score (CHA2DS2-VASc risk score) for stroke in patients with non-valvular atrial fibrillation (AF).15 The incorporation of vascular disease into the risk stratification of AF patients has some limitations. First, fewer than 6% of the 1000 patients in the CHA2DS2-VASc validation cohort actually had PAD.1 Secondly, few reports have evaluated the prognostic significance of PAD independently and in these studies, patients were not treated with oral anticoagulation at baseline.1,5 Thirdly, the use of anti-platelet therapy is generally accepted in patients with PAD, especially if patients are symptomatic (intermittent claudication or critical limb ischaemia).68 Owing to these factors, an evidence gap exists surrounding the prognostic significance of PAD in patients with AF and the efficacy and safety of concomitant anti-platelet and anticoagulant medications in PAD patients with AF, and the optimal combination of antithrombotic medications is unknown.3,4,9

In the 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) study, rivaroxaban was non-inferior to warfarin for the prevention of stroke and systemic embolization and similar to warfarin in rates of major or non-major clinically relevant (NMCR) bleeding.10 In this substudy of ROCKET AF, we sought to describe the rate of efficacy and safety outcomes in patients with and without PAD, and evaluate the relative effectiveness and safety of rivaroxaban vs. warfarin in patients with and without PAD.

Methods

The design and methods of the ROCKET AF trial have been previously described.10,11 In brief, ROCKET AF was an international, multi-centre, double-blind, double-dummy randomized-controlled trial in patients with non-valvular AF and a moderate-to-high risk of stroke based on the CHADS2 risk score of at least 2.9 Patients were randomly assigned to rivaroxaban 20 mg daily (15 mg daily in patients with creatinine clearance 30–49 mL/min) or dose-adjusted warfarin [target international normalized ratio (INR) 2.5, range 2.0–3.0].

Patients were excluded from ROCKET AF if they had prosthetic heart valves, haemodynamically significant mitral stenosis, creatinine clearance <30 mL/min, or a recent stroke or systemic embolic event, or were at risk of bleeding.11 The study protocol was reviewed and approved by the institutional review board or ethics committee at each participating site and by the coordinating centre's institutional review board. All the patients were required to provide written, informed consent before randomization.

Definition of peripheral artery disease

Patients with a history of PAD as determined by the site investigator and documented on the case-report form were included in the PAD cohort. On the case-report form instructions, PAD included intermittent claudication, amputation for arterial insufficiency, vascular reconstruction, bypass surgery, or percutaneous intervention to the extremities, or previously documented abdominal aortic aneurysm. If patients did not have a diagnosis of PAD, they were included in the no-PAD cohort. The presence of carotid artery stenosis was captured separately and was not counted as PAD.

Outcomes

The primary efficacy outcome was stroke or systemic embolism. The secondary efficacy outcomes included all-cause death, MI, and the composite (and individual components) of stroke, systemic embolism, or vascular death. Efficacy endpoints were measured until the time of site notification of study termination. The primary safety endpoint was a combination of major or NMCR bleeding. Bleeding events involving the central nervous system that met the definition of stroke were designated as haemorrhagic strokes and included in both the primary efficacy and safety endpoints. All events were adjudicated using pre-defined endpoint definitions by an independent clinical events committee that was blinded to treatment assignment.

Statistical analysis

The current analysis was not a pre-specified subgroup analysis. The intention-to-treat (ITT) study population was used for all efficacy outcome analyses. Safety endpoints were analysed using the on-treatment population (patients who were randomized and received at least one dose of the study drug).

We used Cox proportional hazard models to assess the association with risk of outcomes for (i) patients with PAD vs. patients without PAD and (ii) rivaroxaban vs. warfarin within subgroups of patients with and without PAD. All models included a term for the interaction between randomized treatment and PAD, as well as covariates identified as predictive of outcomes by modelling in the full ROCKET AF cohort. For efficacy outcomes, these covariates were age, gender, BMI, geographic region, diabetes mellitus, prior stroke/TIA, prior MI, carotid occlusive disease, CHF, hypertension, chronic obstructive pulmonary disease, paroxysmal AF, diastolic BP, creatinine clearance (Cockcroft–Gault equation), heart rate, and abstinence from alcohol use. For safety outcomes, these covariates were age, gender, geographic region, prior stroke/TIA, anaemia, prior GI bleed, chronic obstructive pulmonary disease, diastolic BP, creatinine clearance, platelet count, albumin, prior aspirin (ASA), vitamin K antagonist, or thienopyridine use.

Categorical variables are summarized as percentages (counts), and differences were tested with the Pearson χ2 test; continuous variables are summarized as median (25th and 75th percentiles); and differences were tested with the Wilcoxon rank-sum test. Outcomes are presented as events per 100 patient-years. Risk relationships are presented as adjusted hazard ratios (HR) with 95% confidence intervals (CI) derived from the adjusted Cox models. The time to event for each group was assessed by the Kaplan–Meier method.

A level of significance of P < 0.05 was pre-specified. All analyses were performed with SAS version 9.2 (SAS Institute, Inc., Cary, NC, USA). ROCKET AF is registered with ClinicalTrials.gov, number NCT00403767.

Results

Study population

A total of 14 264 patients with AF from 1178 centres in 45 countries were randomly assigned to treatment in ROCKET AF between 18 December 2006 and 17 June 2009. From the total trial population, 839 patients (5.9%) carried a diagnosis of PAD at study entry. Of these patients, 17% had previously undergone surgical revascularization for PAD and 14% had previously undergone peripheral angioplasty without stenting. Baseline demographic and clinical characteristics of study participants with and without PAD are shown in Table 1. Subjects with PAD were older, more likely to be male, have a higher CHADS2 score, and more likely to have a prior diagnosis of diabetes mellitus, MI, heart failure, or chronic obstructive pulmonary disease. In terms of prior medication use, subjects with PAD had a higher use of vitamin K antagonist, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, beta-blocker, and diuretic at baseline. Baseline ASA, clopidogrel, and any anti-platelet agent (ASA, clopidogrel, or dipyridamole) use was observed in a higher proportion of PAD patients but was not statistically different between groups. At 1 year and at the time of study medication discontinuation, more patients with PAD when compared with no PAD were taking daily ASA, clopidogrel, and any anti-platelet agent (ASA, clopidogrel, or dipyridamole) (Table 2).

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Table 1

Baseline demographic and clinical characteristics of patients with and without peripheral artery disease

VariableAll ITT patients (n = 14 264)PAD (n = 839)No PAD (n = 13 425)P-value
Age73 (65, 78)74 (67, 79)73 (65, 78)0.0002
Female40% (5660)28% (233)40% (5427)<0.0001
Atrial fibrillation0.95
 Persistent81% (11 548)81% (678)81% (10 870)
 Paroxysmal18% (2514)18% (150)18% (2364)
 New onset1% (202)1% (11)1% (191)
CHADS2 score [mean (SD)]3.5 (0.9)3.7 (1.0)3.5 (0.9)<0.0001
CHADS2 score
 1<1% (3)0<1% (3)
 213% (1859)8% (68)13% (1791)
 344% (6216)38% (322)44% (5894)
 429% (4091)29% (242)29% (3849)
 513% (1813)21% (177)12% (1636)
 62% (282)4% (30)2% (252)
HAS-BLED score [mean(SD)]2.8 (0.9)2.9 (1.0)2.8 (0.9)<0.0001
HAS-BLED score
 01% (91)<1% (2)1% (89)
 17% (984)5% (45)7% (939)
 230% (4275)26% (217)30% (4058)
 342% (5934)41% (343)42% (5591)
 418% (2585)24% (201)18% (2384)
 53% (362)3% (27)2% (335)
 6<1% (18)<1% (4)<1% (14)
Presenting characteristics
 Body mass index, kg/m228 (25, 32)28 (25, 32)28 (25, 32)0.44
 Systolic blood pressure, mmHg130 (120, 140)130 (120, 140)130 (120, 140)0.68
 Diastolic blood pressure, mmHg80 (70, 85)80 (70, 85)80 (70, 85)<0.0001
 Heart rate, b.p.m.76 (67, 86)74 (65, 84)76 (68, 86)0.0018
 Creatinine clearance (C&G)67 (52, 87)63 (49, 82)68 (52, 87)<0.0001
Baseline comorbidities
 Prior stroke, TIA, or non-CNS embolism55% (7811)57% (480)55% (7331)0.14
 Carotid occlusive disease4% (593)18% (155)3% (438)<0.0001
 Hypertension91% (12 910)92% (768)90% (12 142)0.29
 Diabetes40% (5695)48% (400)39% (5295)<0.0001
 Prior myocardial infarction17% (2468)34% (289)16% (2179)<0.0001
 Congestive heart failure62% (8908)71% (594)62% (8314)<0.0001
  Chronic obstructive pulmonary disease10% (1497)20% (166)10% (1331)<0.0001
Medications
 Prior vitamin K antagonist use62% (8904)71% (593)62% (8311)<0.0001
 Prior chronic ASA use36% (5205)39% (330)36% (4875)0.079
 ACE-inhibitor/ARB at baseline74% (10 583)78% (653)74% (9930)0.012
 Beta-blocker at baseline65% (9250)68% (574)65% (8676)0.025
 Digitalis at baseline38% (5468)39% (324)38% (5144)0.86
 Diuretic at baseline60% (8490)68% (570)59% (7920)<0.0001
  • Categorical variables are shown as % (number). Continuous variables are shown as median (25th and 75th percentiles) unless otherwise noted.

  • SD, standard deviation; PAD, peripheral artery disease; kg, kilogram; m, meter; mmHg, millimetres of mercury; min, minute; C&G, Cockcroft–Gault; TIA, transient ischaemic attack; CNS, central nervous system; ASA, aspirin; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; ITT, intention to treat; CHADS2, Cardiac failure, Hypertension, Age, Diabetes, Stroke (doubled); HAS-BLED, Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65 years), Drugs/alcohol concomitantly.

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Table 2

Anti-platelet use at baseline and during the follow-up

Time point anti-plateletPAD (all)No PAD (all)PAD rivaroxabanPAD warfarinNo PAD rivaroxabanNo PAD warfarin
Baseline
 No. patients83913 42540143867306695
 ASA39.3% (330)36.3% (4875)39.7% (159)39.0% (171)36.1% (2427)36.6% (2448)
 Clopidogrel2.5% (21)1.2% (164)2.2% (9)2.7% (12)1.1% (77)1.3% (87)
 ASA, clopidogrel, or dipyridamole41.2% (346)37.3% (5013)41.9% (168)40.6% (178)37.0% (2488)37.7% (2525)
At 1 year
 No. patients62110 50729033152455262
 ASA25.6% (159)17.6% (1851)23.4% (68)27.5% (91)17.1% (899)18.1% (952)
 Clopidogrel2.9% (18)1.2% (123)3.1% (9)2.7% (9)1.2% (62)1.2% (61)
 ASA, clopidogrel, or dipyridamole28.0% (174)18.7% (1962)26.6% (77)29.3% (97)18.3% (959)19.1% (1003)
At time of study drug discontinuationa
 No. patients83913 42540143867306695
 ASA26.6% (223)19.0% (2546)23.4% (94)29.5% (129)18.6% (1253)19.3% (1293)
 Clopidogrel3.2% (27)1.4% (191)3.0% (12)3.4% (15)1.3% (90)1.5% (101)
 ASA, clopidogrel, or dipyridamole28.7% (241)20.1% (2698)26.4% (106)30.8% (135)19.7% (1325)20.5% (1373)
  • aFor ITT patients who did not receive study drug, this is the time of last contact.

The median exposure to study drug was 564 days (25th–75th percentiles 356–785) in patients with PAD and 592 days (25th–75th percentiles 401–808) in patients without PAD. The median duration of follow-up was 730 days (25th–75th percentiles 575–897) in patients with PAD and 718 days (25th–75th percentiles 551–884) in patients without PAD. Complete follow-up for vital status was achieved in 14 232 patients (99.8%). Among patients with PAD who were assigned to warfarin, the median proportion of time in the therapeutic INR range (including periods after initiation and temporary discontinuation of therapy) was 59% (25th–75th percentiles 45–72%) compared with 58% (25th–75th percentiles 43–70%) for patients without PAD.

Outcomes in patients with and without peripheral artery disease

The overall rate of stroke or non-CNS systemic embolism was not statistically significantly different among patients with PAD compared with those without PAD (2.41 vs. 2.09 events/100 patient-years; adjusted HR: 1.04, 95% CI: 0.72–1.50; P = 0.84, Table 3). The overall rate of major or NMCR bleeding was also not statistically significantly different among patients with PAD compared with those without PAD (17.81 vs. 14.54; HR: 1.11, 95% CI: 0.96–1.28; P = 0.17, Table 3).

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Table 3

Adjusted hazards for efficacy and safety endpoints in patients with and without peripheral artery disease

OutcomesPAD-events/100 patient-years (total events)No PAD-events/100 patient-years (total events)PAD vs. no PAD hazard ratio (95% CI)P-value
Efficacy outcomes
 Stroke or systemic embolization2.41 (39)2.09 (536)1.04 (0.72, 1.50)0.84
 Stroke, systemic embolization, or vascular death6.81 (106)4.29 (1075)1.02 (0.82, 1.28)0.84
 Stroke2.03 (33)1.95 (501)0.98 (0.66, 1.46)0.93
 Systemic embolization0.36 (6)0.16 (41)1.06 (0.39, 2.86)0.91
 All-cause death7.97 (123)4.34 (1091)1.15 (0.93, 1.43)0.19
 Vascular death5.18 (82)2.72 (694)1.05 (0.81, 1.36)0.69
 Myocardial infarction2.02 (33)0.92 (239)0.86 (0.58, 1.27)0.45
Safety outcomes
 Major or NMCR bleeding17.81 (195)14.54 (2729)1.11 (0.96, 1.28)0.17
 Major bleeding4.74 (59)3.45 (722)1.16 (0.88, 1.53)0.29
 Major bleeding by type
  Decrease in haemoglobin ≥2 g/dL3.67 (46)2.44 (513)1.16 (0.84, 1.60)0.36
  Transfusion ≥2 units1.90 (24)1.46 (308)0.95 (0.62, 1.47)0.82
  Critical bleeding0.79 (10)1.01 (214)0.79 (0.41, 1.52)0.49
  Fatal bleeding0.16 (2)0.38 (80)0.37 (0.09, 1.52)0.17
 Major bleeding by site
  Intracranial0.39 (5)0.61 (130)0.64 (0.26, 1.61)0.35
  Mucosal3.10 (39)2.04 (428)1.09 (0.76, 1.58)0.63
  Other site1.19 (15)0.78 (164)1.29 (0.71, 2.35)0.40
 Intracranial haemorrhage0.39 (5)0.63 (134)0.63 (0.25, 1.58)0.33
 Haemorrhagic stroke0.08 (1)0.37 (78)0.23 (0.03, 1.66)0.14
  • PAD, peripheral artery disease; CI, confidence intervals; NMCR, non-major clinically relevant; g, grams; dL, decilitre.

  • aAdjusted estimates for hazard ratios (95% CI) are derived from the main ROCKET AF model.

Rivaroxaban vs. warfarin in patients with and without peripheral artery disease

The relative effect of rivaroxaban compared with warfarin on the primary efficacy outcome was similar in patients with PAD (HR: 1.19, 95% CI: 0.63–2.22) and without PAD (HR: 0.86, 95% CI: 0.73–1.02) (P = 0.34 for interaction, Table 4 and Figures 1 and 2) . No differences in treatment effect were detected between patients with and without PAD for any of the secondary efficacy endpoints.

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Table 4

Treatment comparisons for efficacy and safety endpoints in patients with and without peripheral artery disease

OutcomesPADNo PADP-value for interaction of PAD and treatment
Rivaroxaban events/100 patient-years (total events)Warfarin events/100 patient-years (total events)Rivaroxaban vs. Warfarin hazard ratio (95% CI)Rivaroxaban events/100 patient-years (total events)Warfarin events/100 patient-years (total events)Rivaroxaban vs. Warfarin hazard ratio (95% CI)
Efficacy outcomes
 Stroke or systemic embolization2.61 (20)2.23 (19)1.19 (0.63, 2.22)1.93 (249)2.25 (287)0.86 (0.73, 1.02)0.34
 Stroke, systemic embolization, or vascular death6.30 (47)7.28 (59)0.86 (0.59, 1.26)4.17 (525)4.41 (550)0.95 (0.85, 1.07)0.61
 Stroke2.34 (18)1.75 (15)1.35 (0.68, 2.69)1.82 (235)2.08 (266)0.88 (0.74, 1.05)0.23
 Systemic embolization0.25 (2)0.46 (4)0.58 (0.11, 3.18)0.14 (18)0.18 (23)0.79 (0.43, 1.46)0.74
 All-cause death7.29 (54)8.61 (69)0.82 (0.57, 1.17)4.19 (528)4.50 (563)0.93 (0.83, 1.05)0.50
 Vascular death4.47 (34)5.84 (48)0.74 (0.48, 1.15)2.67 (341)2.78 (353)0.97 (0.84, 1.13)0.26
 Myocardial infarction2.19 (17)1.87 (16)1.18 (0.59, 2.33)0.87 (113)0.97 (126)0.91 (0.70, 1.17)0.49
Safety outcomes
 Major or NMCR bleeding21.02 (105)15.12 (90)1.40 (1.06, 1.86)14.59 (1370)14.48 (1359)1.03 (0.95, 1.11)0.037
 Major bleeding6.11 (35)3.58 (24)1.76 (1.04, 2.95)3.46 (360)3.45 (362)1.03 (0.89, 1.19)0.053
 Major bleeding by type
  Decrease in haemoglobin ≥2 g/dL5.21 (30)2.36 (16)2.29 (1.25, 4.21)2.63 (275)2.26 (238)1.20 (1.01, 1.43)0.045
  Transfusion ≥2 units2.58 (15)1.32 (9)2.19 (0.95, 5.00)1.60 (168)1.32 (140)1.27 (1.02, 1.60)0.22
  Critical bleeding0.68 (4)0.89 (6)0.76 (0.21, 2.68)0.82 (87)1.19 (127)0.70 (0.53, 0.92)0.90
  Fatal bleeding0.00 (0)0.29 (2)0.25 (27)0.50 (53)0.52 (0.33, 0.83)
 Major bleeding by site
  Intracranial0.51 (3)0.29 (2)1.74 (0.29, 10.4)0.48 (51)0.74 (79)0.66 (0.47, 0.94)0.30
  Mucosal4.86 (28)1.62 (11)3.22 (1.60, 6.48)2.32 (243)1.75 (185)1.38 (1.14, 1.67)0.021
  Other site0.68 (4)1.63 (11)0.42 (0.13, 1.31)0.63 (66)0.92 (98)0.69 (0.50, 0.94)0.41
 Intracranial haemorrhage0.51 (3)0.29 (2)1.74 (0.29, 10.4)0.49 (52)0.77 (82)0.65 (0.46, 0.92)0.29
 Haemorrhagic stroke0.00 (0)0.15 (1)0.27 (29)0.46 (49)0.60 (0.38, 0.96)
  • PAD, peripheral artery disease; CI, confidence interval; NMCR, non-major clinically relevant; g, grams; dL, decilitre.

  • aAdjusted estimates for hazard ratios (95% CI) are derived from the main ROCKET AF model.

Figure 1

Cumulative rate of stroke or systemic embolism in patients classified by peripheral artery disease and treatment assignment.

Figure 2

Efficacy and safety endpoints classified by peripheral artery disease status and treatment assignment.

The relative risk of rivaroxaban compared with warfarin for the primary safety endpoint of major or NMCR bleeding was significantly higher in patients with PAD (HR: 1.40, 95% CI: 1.06–1.86) than without PAD (HR: 1.03, 95% CI: 0.95–1.11; interaction P = 0.037). There was a non-statistically significant trend towards a higher risk of major bleeding with rivaroxaban compared with warfarin in patients with PAD (HR: 1.76, 95% CI: 1.04–2.95) than without PAD (HR: 1.03, 95% CI: 0.89–1.19; interaction P = 0.053) (Table 4). This was the result of bleeding events adjudicated as major because of drops in haemoglobin levels or transfusions of packed red blood cells. There were only two fatal and five intracranial bleeding events in PAD patients.

Discussion

This subgroup analysis of patients with PAD in the ROCKET AF study identifies three major findings. First, subjects with PAD and AF did not have a significantly higher risk of stroke or systemic embolism when compared with AF subjects without PAD. Secondly, the treatment efficacy of rivaroxaban when compared with warfarin in patients with PAD was consistent with that in patients without PAD. Thirdly, patients with PAD treated with rivaroxaban had a higher relative hazard of major or NMCR bleeding than patients with PAD treated with dose-adjusted warfarin, a finding that was not consistent with the main trial findings. This result was driven by bleeding events that led to drops in haemoglobin of ≥2 g/dL or transfusions of ≥2 units. There were very few fatal or intracranial haemorrhage events among patients with PAD.

Vascular disease, including PAD, is now included as a risk factor for stroke or systemic embolism in certain practice guidelines.1,5,12 We observed that PAD patients in the ROCKET AF trial had a virtually identical-adjusted risk of stroke and systemic embolism as patients without PAD (adjusted HR: 1.04, 95% CI: 0.72–1.50, P = 0.84). Further, the risk of major or NMCR bleeding was very similar among patients with vs. without PAD (adjusted HR: 1.11, 95% CI: 0.96–1.28, P = 0.17).

Our second major finding, no difference in treatment efficacy based on the presence or absence of PAD, is of note. Rivaroxaban was found to be non-inferior to dose-adjusted warfarin in the entire ROCKET AF study population,10 findings that were similar in the current subgroup analysis. The consistency of the current findings with the overall trial results should provide a measure of confidence to clinicians that rivaroxaban can be used to prevent stroke and systemic embolism in patients who prefer not to take warfarin or are poor candidates for long-term warfarin therapy.

A cause for concern is the finding that there was a treatment interaction in PAD patients for the primary safety endpoint of major or NMCR bleeding. This suggests that patients with PAD assigned to rivaroxaban may have more bleeding than those PAD patients assigned to warfarin. However, these results are derived from post hoc subgroup analysis and should be interpreted as hypothesis-generating rather than definitive. Importantly, there were no fatal bleeds among rivaroxaban-treated patients with PAD. Excess bleeding events on rivaroxaban were the result of non-fatal mucosal bleeding (i.e. epistaxis and gastrointestinal), a pattern seen among all patients in the ROCKET AF trial.

Limitations

There are multiple limitations of this subgroup analysis of a large, randomized-controlled trial. First, this is a post hoc analysis and the findings are not confirmatory, rather hypothesis-generating. Secondly, the percentage of patients with PAD (5.9%) and the total number of patients with PAD in ROCKET AF (n = 839) limited our power to reliably detect differences and similarities. Furthermore, designation of the presence or absence of PAD on the case-report form rather than by symptomatic status (asymptomatic, intermittent claudication, and critical limb ischaemia) or haemodynamic abnormality (ankle brachial index value) could lead to inaccurate or inconsistent findings across a broad population of PAD patients. Additionally, the inclusion of patients with abdominal aortic aneurysm in ROCKET AF, while consistent with ACC/AHA guidelines at the time of study design, would be considered non-uniform in a contemporary definition of PAD. Our analyses comparing patients with and without PAD were not randomized and thus subject to residual confounding, despite multivariable risk adjustment. Finally, the ROCKET AF study enrolled patients at a high baseline risk for stroke and systemic embolism with >93% of patients having a CHADS2 score ≥3, and the results may not be generalizable to the entire population of AF patients.

Conclusions

In this large randomized-controlled trial, the risk of stroke/systemic embolism and major bleeding/NMCR bleeding was similar between patients with and without PAD. Furthermore, there was no difference in the treatment efficacy of rivaroxaban or warfarin in patients with or without PAD. There was a treatment interaction for the primary safety endpoint (major or NMCR bleeding), suggesting that PAD patients treated with rivaroxaban may have a higher risk of bleeding when compared with warfarin that was not observed in non-PAD patients. However, risk of fatal and intracranial bleeding was very low among rivaroxaban-treated patients whether with or without PAD.

Funding

Johnson and Johnson Pharmaceutical Research and Development and Bayer HealthCare sponsored the ROCKET AF trial. The Duke Clinical Research Institute coordinated the trial, managed the database, and undertook the primary analysis independent of the sponsors. The authors had complete access to the data and were responsible for writing and submitting the manuscript for publication.

Conflict of interest: W.S.J.: Research funding from AstraZeneca and Bristol-Myers Squibb. A.S.H.: None. J.H.: Consulting fees from Astellas Pharma, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Pfizer, and Sanofi-Aventis; serves as chair of the data safety monitoring committee for the EUCLID trial, sponsored by AstraZeneca. J.P.P.: Research funding from Janssen Pharmaceuticals, GE Healthcare; consulting fees from Forest Laboratories, Janssen Pharmaceuticals, Medtronic, Pfizer-BMS, Spectranetics. G.B.: Scientific advisory board member for Bayer HealthCare, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Sanofi-Aventis, and MSD; lectures fees from Boehringer Ingelheim, Bayer Health Care, Bristol-Myers Squibb, and Sanofi-Aventis. D.E.S.: Consulting fees from Bayer Healthcare, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, Pfizer, CSL Behring; research grant from Johnson & Johnson. K.A.A.F. Grant support and lecture fees from Eli Lilly; lecture fees from Sanofi-Aventis and AstraZeneca. G.J.H.: Consulting and advisory board fees from Bayer Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer; honoraria from Bayer Pharmaceuticals and theHeart.org. K.W.M.: Consulting fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Merck, Ortho/McNeill, Pfizer, PolyMedix; grant support from AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Merck, Portola, Regado Biotechnologies, Sanofi, The Medicines Company. R.M.C.: Consulting fees from Kowa, Nile, Orexigen, Sanofi-Aventis, Novartis, and Xoma; grant support from Novartis, Merck, and Amilyn/Lilly; equity interest in Nitrox. M.R.P.: Research grant from Astra Zeneca; consulting fees from Ortho McNeil. Janssen and Bayer HealthCare; advisory board for Genzyme.

Acknowledgements

Johnson and Johnson Pharmaceutical Research and Development and Bayer HealthCare.

References

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