(rivaroxaban)
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Last Updated: 05/30/2023
The ROCKET-AF trial was a phase 3, double-blind, double-dummy, parallel-group, eventdriven, noninferiority study to evaluate the efficacy and safety of oral XARELTO 20 mg once daily (15 mg for patients with creatinine clearance 30-49 ml/min) and doseadjusted warfarin (target international normalized ratio: 2.0-3.0) for the prevention of stroke and systemic embolism in patients with NVAF at moderate-to-high risk for stroke.2
Baseline ASA Use | No Baseline ASA Use | P-value for Interaction of Baseline ASA and Treatment | |||||
---|---|---|---|---|---|---|---|
XARELTO | Warfarin | XARELTO vs Warfarin Adjusted HR (95% CI) | XARELTO | Warfarin | XARELTO vs Warfarin Adjusted HR (95% CI) | ||
Efficacy Endpoints | |||||||
Stroke or SE | 2.34 | 2.71 | 0.88 (0.68-1.14) | 2.00 | 2.26 | 0.89 (0.72-1.10) | 0.95 |
Stroke/SE/ vascular death | 5.15 | 5.80 | 0.90 (0.75-1.08) | 4.16 | 4.28 | 0.98 (0.84-1.14) | 0.48 |
All-cause death | 5.14 | 6.19 | 0.83 (0.70-0.99) | 4.18 | 4.21 | 0.99 (0.86-1.15) | 0.13 |
Vascular death | 3.56 | 3.95 | 0.91 (0.74-1.13) | 2.56 | 2.66 | 0.97 (0.80-1.17) | 0.67 |
Stroke | 2.23 | 2.52 | 0.89 (0.68-1.17) | 1.86 | 2.05 | 0.91 (0.73-1.14) | 0.91 |
SE | 0.15 | 0.22 | 0.73 (0.28-1.91) | 0.16 | 0.20 | 0.77 (0.37-1.59) | 0.93 |
MI | 1.37 | 1.24 | 1.14 (0.80-1.64) | 0.82 | 1.04 | 0.80 (0.58-1.10) | 0.15 |
Safety Endpoints | |||||||
Major or NMCR bleeding | 16.80 | 16.37 | 1.06 (0.95-1.19) | 13.93 | 13.56 | 1.04 (0.95-1.14) | 0.76 |
Major bleeding | 4.52 | 4.12 | 1.14 (0.92-1.42) | 3.11 | 3.11 | 1.02 (0.85-1.23) | 0.45 |
Major bleeding -ICH | 0.49 | 0.92 | 0.54 (0.31-0.95) | 0.49 | 0.65 | 0.77 (0.50-1.19) | 0.33 |
Major bleeding - fatal | 0.26 | 0.61 | 0.43 (0.20-0.89) | 0.23 | 0.42 | 0.56 (0.31-1.02) | 0.57 |
Hemorrhagic stroke | 0.29 | 0.59 | 0.49 (0.24-1.01) | 0.25 | 0.37 | 0.68 (0.38-1.24) | 0.50 |
Abbreviations: ASA, aspirin; CI, confidence interval; HR, hazard ratio; ICH; intracranial hemorrhage; MI, myocardial infarction; NMCR, nonmajor clinically relevant bleeding; SE, systemic embolism. aData presented as events per 100 patient-years. |
The EINSTEIN program consisted of 3 randomized trials:
Davidson et al (2014)6 conducted a subanalysis of the EINSTEIN-DVT and EINSTEIN-PE studies to determine the incidence of major and all clinically relevant bleeding in patients treated with XARELTO or enoxaparin-VKA and exposed to NSAIDs or ASA.
XARELTO | Enoxaparin-VKA | |||||
---|---|---|---|---|---|---|
Events | Pt-y | Event/100 Pt-y | Events | Pt-y | Events/100 Pt-y | |
ASA + | 57 | 163.5 | 34.9 | 47 | 120.1 | 39.1 |
ASA - | 331 | 2058.9 | 16.1 | 365 | 2050.2 | 17.8 |
| HR, 1.81 (95% CI, 1.36-2.41) | HR, 1.59 (95% CI, 1.17-2.17) | ||||
Abbreviations: ASA, aspirin; CI, confidence interval; HR, hazard ratio; pt-y, patient-years; VKA, vitamin K antagonist. aClinically relevant bleeding was defined as bleeding that was not major but associated with medical intervention, an unscheduled contact with a physician, temporary cessation of study treatment, or discomfort for the patient such as pain or impairment of activities of daily living. |
XARELTO | Enoxaparin-VKA | |||||
---|---|---|---|---|---|---|
Events | Pt-y | Events/100 Pt-y | Events | Pt-y | Events/100 Pt-y | |
ASA + | 6 | 179.9 | 3.3 | 9 | 129.6 | 6.9 |
ASA - | 34 | 2181.0 | 1.6 | 63 | 2172.6 | 2.9 |
| HR, 1.50 (95% CI, 0.63-3.61) | HR, 1.50 (95% CI, 0.74-3.05) | ||||
Abbreviations: ASA, aspirin; CI, confidence interval; HR, hazard ratio; pt-y, patient-years; VKA, vitamin K antagonist. aMajor bleeding was defined as bleeding that was fatal, occurred at a critical site, or were associated with a decrease in hemoglobin of more than 2 g/dL and/or the need for transfusion of 2 or more units of red blood cells. |
The RECORD clinical trial program consisted of 4 double-blind, double-dummy, multinational studies that compared efficacy and safety of oral XARELTO 10 mg once daily and subcutaneous enoxaparin 40 mg once daily (RECORD 1-3) or 30 mg twice daily (RECORD 4) for VTE prevention in patients undergoing total hip replacement or total knee replacement.14-17
Eriksson et al (2012)7 analyzed the pooled data from the RECORD 1-4 studies to evaluate the safety of concomitant use of NSAIDs and PFI, including ASA, in patients receiving either XARELTO or enoxaparin after total hip or knee arthroplasty.
COMPASS (Cardiovascular OutcoMes for People Using Anticoagulation StrategieS) was a phase 3, event-driven, double-blind, randomized, controlled study designed to evaluate whether treatment with XARELTO and ASA versus ASA alone or XARELTO alone versus ASA alone is more effective for prevention of
Outcome | XARELTO plus Aspirin (n=9152) | XARELTO Alone (n=9117) | Aspirin Alone (n=9126) | XARELTO plus Aspirin vs Aspirin Alone | XARELTO Alone vs Aspirin Alone | ||
---|---|---|---|---|---|---|---|
n (%) | HR (95% CI) | P Value | HR (95% CI) | P Value | |||
CV death, stroke or MIa | 379 (4.1) | 448 (4.9) | 496 (5.4) | 0.76 (0.66-0.86) | <0.001 | 0.90 (0.79-1.03) | 0.12 |
Abbreviations: CI, confidence interval; CV, cardiovascular; MI, myocardial infarction. aOnly P values for the primary outcome are confirmatory. |
Outcome | XARELTO plus Aspirin (n=9152) | XARELTO Alone (n=9117) | Aspirin Alone (n=9126) | XARELTO plus Aspirin vs Aspirin Alone | XARELTO Alone vs Aspirin Alone | |||
---|---|---|---|---|---|---|---|---|
n (%) | HR (95% CI) | P Value | HR (95% CI) | P Value | ||||
Major Bleeding | 288 (3.1) | 255 (2.8) | 170 (1.9) | 1.70 (1.40-2.05) | <0.001 | 1.51 (1.25-1.84) | <0.001 | |
Fatal Bleedinga | 15 (0.2) | 14 (0.2) | 10 (0.1) | 1.49 (0.67-3.33) | 0.32 | 1.40 (0.62-3.15) | 0.41 | |
Nonfatal symptomatic ICHa | 21 (0.2) | 32 (0.4) | 19 (0.2) | 1.10 (0.59-2.04) | 0.77 | 1.69 (0.96-2.98) | 0.07 | |
Other major bleedinga | 210 (2.3) | 164 (1.8) | 112 (1.2) | 1.88 (1.49-2.29) | <0.001 | 1.47 (1.16-1.87) | 0.001 | |
Fatal bleeding or symptomatic ICH | 36 (0.4) | 46 (0.5) | 29 (0.3) | 1.23 (0.76-2.01) | 0.40 | 1.59 (1.00-2.53) | 0.05 | |
Fatal bleeding or symptomatic bleeding into critical organ | 78 (0.9) | 91 (1.0) | 58 (0.6) | 1.34 (0.95-1.88) | 0.09 | 1.58 (1.13-2.19) | 0.006 | |
Major bleeding according to ISTH criteria | 206 (2.3) | 175 (1.9) | 116 (1.3) | 1.78 (1.41-2.23) | <0.001 | 1.52 (1.20-1.92) | <0.001 | |
Abbreviations: ICH, intracranial hemorrhage; ISTH, International Society on Thrombosis and Haemostasis. aIf a participant had more than one event of major bleeding, only the most serious bleeding event was counted in these analyses. |
Hori et al (2022)9 conducted a subgroup analysis to evaluate the risk of MI, stroke, or CV death and safety of XARELTO 2.5 mg twice daily + ASA 100 mg once daily compared to ASA 100 mg once daily between Asian and non-Asian patients with chronic CAD/PAD.
Results
Baseline characteristics
Efficacy
Safety
Asian | Non-Asian | ||||||||
XARELTO + ASA n (%) | ASA n (%) | ARD (95% CI) | HR (95% CI) | XARELTO +ASA n (%) | ASA n (%) | ARD (95% CI) | HR (95% CI) | P-value (het) | |
Primary Efficacy Outcomes (Asian, n= 2,848; Non-Asian, n = 15,430) | |||||||||
MI, stroke, CV death | 54 (3.72) | 81 (5.80) | -2.08 (-3.64, -0.51) | 0.64 (0.45, 0.90) | 325 (4.22) | 415 (5.37) | -1.15 (-1.82, -0.48) | 0.78 (0.67, 0.90) | 0.29 |
Safety Outcomes (Asian, n= 2,636; Non-Asian, n= 15,642) | |||||||||
Modified ISTH Major Bleeding | 57 (3.93) | 25 (1.79) | 2.14 (0.92, 3.36) | 2.24 (1.40, 3.58) | 231 (3.00) | 145 (1.88) | 1.12 (0.64,1.61) | 1.60 (1.30, 1.97) | 0.20 |
Fatal bleeding | 2 (0.14) | 2 (0.14) | −0.01 (−0.28, 0.27) | 0.96 (0.14, 6.82) | 13 (0.17) | 8 (0.10) | 0.07 (−0.05,0.18) | 1.63 (0.68, 3.94) | 0.63 |
Symptomatic bleeding into a critical organ | 21 (1.45) | 10 (0.72) | 0.73 (−0.03, 1.49) | 2.03 (0.96, 4.31) | 52 (0.68) | 43 (0.56) | 0.12 (−0.13, 0.37) | 1.21 (0.81, 1.81) | 0.23 |
Surgical site bleeding leading to reoperation | 3 (0.21) | 0 | 0.21 (−0.03, 0.44) | - | 12 (0.16) | 12 (0.16) | 0.00 (−0.12, 0.12) | 1.00 (0.45, 2.22) | 0.99 |
Bleeding leading to hospitalization | 49 (3.99) | 18 (1.29) | 2.09 (0.99, 3.19) | 2.66 (1.55, 4.57) | 210 (2.73) | 129 (1.67) | 1.06 (0.60, 1.52) | 1.63 (1.31, 2.03) | 0.10 |
GI bleeding | 27 (1.86) | 12 (0.86) | 1.00 (0.15, 1.85) | 2.19 (1.11, 4.32) | 113 (1.47) | 53 (0.69) | 0.78 (0.46, 1.11) | 2.14 (1.55, 2.97) | 0.95 |
ICH | 11 (0.76) | 3 (0.21) | 0.54 (0.04, 1.05) | 3.50 (0.98, 12.56) | 17 (0.22) | 21 (0.27) | −0.05 (−0.21, 0.11) | 0.81 (0.43, 1.53) | 0.04 |
Minor Bleeding | 227 (15.64) | 153 (10.95) | 4.69 (2.21, 7.18) | 1.52 (1.24, 1.87) | 611 (7.93) | 350 (4.53) | 3.41 (2.64, 4.17) | 1.78 (1.56, 2.03) | 0.17 |
Net clinical outcomea | 71 (4.89) | 89 (6.37) | -1.48 (-3.17, 0.22) | 0.77 (0.56, 1.05) | 360 (4.67) | 445 (5.76) | -1.08 (-1.78, -0.38) | 0.81 (0.70, 0.93) | 0.78 |
Abbreviations: ARD, absolute risk difference; ASA, aspirin; CI, confidence interval; CV, cardiovascular; GI, gastrointestinal; Het, heterogeneity; HR, hazard ratio; ICH, intracranial haemorrhage; ISTH, International Society on Thrombosis and Haemostasis; MI, myocardial infarction.aComposite of MI, stroke, or CV death, fatal bleeding, or symptomatic bleeding into a critical organ. |
VOYAGER PAD (Vascular Outcomes StudY of ASA alonG with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD) was a phase 3, multicenter, randomized, placebo-controlled, double-blind, international study designed to evaluate whether XARELTO 2.5 mg twice daily plus ASA 100 mg once daily is more effective than ASA 100 mg once daily alone for risk reduction of major atherothrombotic vascular outcomes consisting of both CV and limb events in patients with symptomatic PAD undergoing lower-extremity revascularization.
Outcome | XARELTO Plus Aspirin (n=3286) | Aspirin Alone (n=3278) | HR (95% CI) | P Value | |||
---|---|---|---|---|---|---|---|
Patients With Event, n (%) | K-M Estimate at 3 Years (%) | Patients With Event, n (%) | K-M Estimate at 3 Years (%) | ||||
ALI, major amputation for vascular causes, MI, ischemic stroke, or death from CV causes | 508 (15.5) | 17.3 | 584 (17.8) | 19.9 | 0.85 (0.76-0.96) | 0.009 | |
ALI | 155 (4.7) | 5.2 | 227 (6.9) | 7.8 | 0.67 (0.55-0.82) | - | |
Major amputation for vascular causes | 103 (3.1) | 3.4 | 115 (3.5) | 3.9 | 0.89 (0.68-1.16) | - | |
MI | 131 (4.0) | 4.6 | 148 (4.5) | 5.2 | 0.88 (0.70-1.12) | - | |
Ischemic stroke | 71 (2.2) | 2.7 | 82 (2.5) | 3.0 | 0.87 (0.63-1.19) | - | |
Death from CV causes | 199 (6.1) | 7.1 | 174 (5.3) | 6.4 | 1.14 (0.93-1.40) | - | |
Abbreviations: ALI, acute limb ischemia; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; K-M, Kaplan-Meier; MI, myocardial infarction. aAll efficacy outcomes were analyzed on an intention-to-treat basis. |
Outcome | XARELTO Plus Aspirin (n=3256) | Aspirin Alone (n=3248) | HR (95% CI) | P Value | |||
---|---|---|---|---|---|---|---|
Patients With Event, n (%) | K-M Estimate at 3 Years (%) | Patients With Event, n (%) | K-M Estimate at 3 Years (%) | ||||
Principal safety outcomes | |||||||
TIMI major bleeding | 62 (1.90) | 2.65 | 44 (1.35) | 1.87 | 1.43 (0.97-2.10) | 0.07 | |
Intracranial hemorrhage | 13 (0.40) | 0.60 | 17 (0.52) | 0.90 | 0.78 (0.38-1.61) | - | |
Fatal bleeding | 6 (0.18) | 0.21 | 6 (0.18) | 0.21 | 1.02 (0.33-3.15) | - | |
Intracranial or fatal bleeding | 17 (0.52) | 0.74 | 19 (0.58) | 0.97 | 0.91 (0.47-1.76) | - | |
Secondary safety outcomes | |||||||
BARC major bleedingb | 93 (2.86) | 3.86 | 73 (2.25) | 2.92 | 1.29 (0.95-1.76) | 0.10 | |
ISTH major bleeding | 140 (4.30) | 5.94 | 100 (3.08) | 4.06 | 1.42 (1.10-1.84) | 0.007 | |
Abbreviations: BARC, Bleeding Academic Research Consortium; CI, confidence interval; HR, hazard ratio; ISTH, International Society on Thrombosis and Haemostasis; K-M, Kaplan-Meier; TIMI aSafety analyses included all patients who underwent randomization and had received at least 1 dose of the trial medication (on-treatment). bBARC major bleeding is defined as grade 3b or higher. |
Kubitza et al (2006)11 conducted a randomized, nonblinded, 2-way crossover study to examine whether ASA influences the safety, tolerability, pharmacodynamics, and pharmacokinetics of XARELTO.
Pharmacokinetic parameters for XARELTO, including the plasma concentration profile, were not substantially altered by coadministration of ASA.
Schaefer et al12: conducted a registry-based cohort study of adult patients with NVAF or VTE who were started on a direct oral anticoagulant therapy [DOAC; apixaban, dabigatran, edoxaban or XARELTO] at 4 medical centers in Michigan between 2015-2019. The objective was to evaluate the frequency and outcomes of concomitant ASA use with DOAC therapy.
DOAC Monotherapy (n=1047) | DOAC + ASA (n=1047) | P value | |
---|---|---|---|
Number per 100 patient-years (95% CI) | |||
Any bleeding event | 26.00 (25.05-27.06) | 31.60 (30.54-32.75) | 0.009 |
Major bleeding | 3.59 (3.23-3.98) | 4.95 (4.52-5.41) | 0.09 |
Non-major bleeding | 21.70 (20.77-22.60) | 26.10 (25.14-27.15) | 0.02 |
Thrombotic events | 2.30 (1.98-2.59) | 2.50 (2.20-2.83) | 0.80 |
Hospitalization | 6.50 (6.03-7.04) | 9.10 (8.51-9.70) | 0.02 |
For bleeding | 10.40 (9.77-11.04) | 13.00 (12.31-1374) | 0.08 |
For clotting | 1.30 (1.06-1.51) | 0.90 (0.75-1.14) | 0.31 |
Emergency room visits | 11.50 (10.84-12.18) | 13.80 (13.05-14.52) | 0.14 |
For bleeding | 10.40 (9.77-11.04) | 13.00 (12.31-13.74) | .08 |
Mortality | 3.40 (3.02-3.75) | 3.80 (3.39-4.16) | 0.76 |
Abbreviations: ASA, aspirin; CI, confidence interval; DOAC, direct oral anticoagulant |
A literature search of MEDLINE®, EMBASE®, BIOSIS Previews®, DERWENT® (and/or other resources, including internal/external databases) was conducted on 18 May 2023.
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2 | Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891. |
3 | Shah R, Hellkamp A, Lokhnygina Y, et al. Use of concomitant aspirin in patients with atrial fibrillation: findings from the ROCKET AF trial. Am Heart J. 2016;179:77-86. |
4 | The EINSTEIN Investigators: Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499-2510. |
5 | The EINSTEIN, Investigators: Buller, HR, Prins MH, Lensing AWA, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:1287-1297. |
6 | Davidson BL, Verheijen S, Lensing AWA, et al. Bleeding risk of patients with acute venous thromboembolism taking nonsteroidal anti-inflammatory drugs or aspirin. JAMA Intern Med. 2014;174(6):947-953. |
7 | Eriksson BI, Rosencher N, Friedman RJ, et al. Concomitant use of medication with antiplatelet effects in patients receiving either rivaroxaban or enoxaparin after total hip or knee arthroplasty. Thromb Res. 2012;130(2):147-151. |
8 | Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med. 2017;377:1319-1330. |
9 | Hori M, Zhu J, Liang Y, et al. Rivaroxaban and aspirin vs aspirin alone in Asian compared with non-Asian patients with chronic coronary artery disease or peripheral arterial disease: the COMPASS trial. Eur Heart J. 2022;43(37):3542-3552. |
10 | Bonaca MP, Bauersachs RM, Anand SS, et al. Rivaroxaban in peripheral artery disease after revascularization. N Engl J Med. 2020;382(21):1994-2004. |
11 | Kubitza D, Becka M, Mueck W, et al. Safety, tolerability, pharmacodynamics, and pharmacokinetics of rivaroxaban - an oral, direct factor Xa inhibitor - are not affected by aspirin. J Clin Pharmacol. 2006;46(9):981-990. |
12 | Schaefer JK, Errickson J, Li Y, et al. Adverse Events Associated With the Addition of Aspirin to Direct Oral Anticoagulant Therapy Without a Clear Indication. JAMA Intern Med. 2021;181(6):817-824. |
13 | Fukaya H, Ako J, Yasuda S, et al. Aspirin versus P2Y12 inhibitors with anticoagulation therapy for atrial fibrillation. Heart. 2021;107:1731-1738. doi:1710.1136/heartjnl-2021-319321. |
14 | Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358(26):2765-2775. |
15 | Kakkar AK, Brenner B, Dahl OE, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double blind, randomized controlled trial. Lancet. 2008;372(9632):31-39. |
16 | Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358(26):2776-2786. |
17 | Turpie AGG, Lassen MR, Davidson BL, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009;373(9676):1673-1680. |
18 | Bosch J, Eikelboom JW, Connolly SJ, et al. Rationale, design and baseline characteristics of participants in the cardiovascular outcomes for people using anticoagulation strategies (COMPASS) trial. Can J Cardiol. 2017;33(8):1027-1035. |
19 | Eikelboom JW, Connolly SJ, Bosch J, et al. Protocol to: Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med. 2017;377(14):1319-1330. |