Rivaroxaban plus Aspirin for Stable Cardiovascular Disease?

Akpan Anani, Mercer University College of Pharmacy

Xarelto® (rivaroxaban) is an oral anticoagulant with indications for the treatment and prevention of thromboses, but not for the secondary prevention of cardiovascular events. [1] Conversely, aspirin has been shown to lower the risk of major adverse cardiovascular events and even cardiovascular death compared to placebo. [2] As a result, low dose aspirin (≤100 mg) is recommended for all tolerant patients in need of secondary prevention. [3] Due to bleeding risks, anticoagulants have not been recommended for these same patients. [4]

Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease [5]
Design A double-blind, double-dummy, randomized trial using a 3-by-2 partial factorial design; N= 27,395
Objective To assess whether rivaroxaban alone or in combination with aspirin would be more effective than aspirin alone for secondary cardiovascular prevention
Study Groups Rivaroxaban + Aspirin; n= 9,152

Rivaroxaban alone n= 9,117

Aspirin alone; n= 9,126

Methods The Cardiovascular Outcomes for People Using Anticoagulation

Strategies (COMPASS) trial was conducted in 602 centers in 33 countries.

 

Patients were eligible if they provided written informed consent and met the criteria for coronary artery disease, peripheral arterial disease, or both.

 

Participants were randomly assigned in a 1:1:1 ratio to receive

·       rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily)

·       rivaroxaban (5 mg twice daily) with an aspirin-matched placebo once daily

·       aspirin (100 mg once daily) with a rivaroxaban matched placebo twice daily

 

After randomization, participants were seen at 1 and 6 months and then at 6-month intervals.

Duration March 2013 through May 2016
Primary Outcome Measure A composite of cardiovascular death, stroke, or myocardial infarction
Baseline Characteristics  

Characteristic Rivaroxaban + Aspirin; n= 9,152 Rivaroxaban alone n= 9,117

 

Aspirin alone; n= 9,126

 

Age—yr 68.3 68.2 68.2
Female sex—no. (%) 2059 (22.5) 1972 (21.6) 1989 (21.8)
Systolic blood pressure—mm Hg 136 136 136
Cholesterol—mmol/liter 4.2 4.2 4.2
Hypertension—no. (%) 6907 (75.5) 6848 (75.1) 6877 (75.4)
Diabetes—no. (%) 3448 (37.7) 3419 (37.5) 3474 (38.1)
Previous MI—no. (%) 5654 (61.8) 5653 (62.0) 5721 (62.7)
Medication—no. (%)      
    NSAID 531 (5.8) 466 (5.1) 473 (5.2)
    Lipid-lowering agent 8239 (90.0) 8204 (90.0) 8158 (89.4)

 

Results  

Outcome Rivaroxaban + Aspirin; n= 9,152

 

Rivaroxaban alone n= 9,117

 

Aspirin alone; n= 9,126

 

Rivaroxaban + Aspirin vs. Aspirin alone Rivaroxaban alone vs. Aspirin alone
Number (%) Hazard ratio (95% CI) p value Hazard ratio

(95% CI)

p value
Primary Outcome: CV death, stroke, or MI 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

 

 

Adverse Events Common Adverse Events:

 

Minor bleeding

R + A = 838 (9.2)

R alone = 741 (8.1)

Aspirin alone = 503 (5.5)

Serious Adverse Events:

 

Outcome Rivaroxaban + Aspirin; n= 9,152

 

Rivaroxaban alone n= 9,117

 

Aspirin alone; n= 9,126

 

Rivaroxaban + Aspirin vs. Aspirin alone Rivaroxaban alone vs. Aspirin alone
Number (%) Hazard ratio (95% CI) p value Hazard ratio

(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 bleeding 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
Percentage Discontinued due to Adverse Events: N/A
Study Author Conclusions Rivaroxaban plus aspirin had better cardiovascular outcomes than those assigned to aspirin alone; however, rivaroxaban alone did not result in better cardiovascular outcomes than aspirin alone.

A notable limitation of this study is that it was stopped early for efficacy, potentially leading to an overestimation of the treatment effect. Additionally, the rigor of pre-trial secondary prevention therapy (i.e. the intensity of statins being taken, the doses/frequencies of NSAIDS, etc.) was not accounted for. However, the homogenous baseline characteristics support the conclusion that the combination therapy intervention did cause the statistically significant benefit observed.

 

References:

[1] Xarelto® (rivaroxaban) tablets [package insert]. Titusville, NJ: Janssen Pharmaceuticals Inc.; Mar 2017.

[2] Antithrombotic Trialists’ (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomized trials. Lancet 2009;373:1849-1860

[3] Hobbs FD. Cardiovascular disease: different strategies for primary and secondary prevention?. Heart. 2004;90(10):1217-23.

[4] Anand SS, Yusuf S. Oral anticoagulants in patients with coronary artery disease. J Am Coll Cardiol 2003;41:Suppl S:62S-69S

[5] Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med. 2017.

 

 

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