Can you summarize the literature supporting DOAC use in Peripheral Vascular Disease with a specific interest in apixaban use for this population?

Comment by InpharmD Researcher

The literature focuses on rivaroxaban for use in patients with peripheral artery disease (PAD) which has been associated with possibly reducing thrombotic-related events. Post-hoc analysis of the ARISTOTLE trial observed similar embolic-related outcomes. An ongoing study (AGRIPPA) will assess the use of apixaban for patients with PAD undergoing infrapopliteal angioplasty.

Background

A 2021 review article discusses the use of direct oral anticoagulants (DOACs) for patients with peripheral artery disease (PAD). The most investigated DOAC for antithrombotic therapy is rivaroxaban with robust evidence for use in PAD and is the only DOAC to date with a completed phase III clinical study for patients with acute coronary syndrome (ACS). In contrast, apixaban (plus aspirin) is currently being assessed for patients with PAD undergoing infrapopliteal angioplasty (AGRIPPA trial). Edoxaban has also observed similar outcomes in bleeding and re-occlusion compared to clopidogrel for patients with PAD. Dabigatran has shown superior risk reduction for primary outcomes consisting of thrombotic complications and vascular mortality compared to placebo in patients with myocardial injury after non-cardiac surgery. [1], [2]

A 2021 meta-analysis observed DOACs plus aspirin versus antiplatelet agents for efficacy and safety on symptomatic lower extremity (LE) PAD. Three randomized controlled trials (N= 744 major adverse limb effects [MALE]) were available for inclusion with data only for rivaroxaban and edoxaban available. Only the ongoing AGRIPPA trial was mentioned in regards to apixaban. Rivaroxaban and edoxaban were associated with significant decrease in MALE events (odds ratio [OR] 0.70; 95% confidence interval [CI] 0.61 to 0.83; p<0.001) while also observing significantly higher rates of major bleeding (OR 1.46; 95% CI 1.16 to 1.84; p=0.001). The meta-analysis is limited due to the individual differences between studies in terms of treatment strategies and outcome definitions. As a result, reported outcomes are noted to be heterogeneous when comparing the three studies. [3]

A recent 2022 meta-analysis observed the safety and efficacy of DOACs in patients with (PAD) for the primary outcomes of major adverse cardiovascular events (MACE), MALE, and bleeding. Ten studies were included for analysis (4 RCTs pooled together and 6 observational studies) that prescribed rivaroxaban or edoxaban plus aspirin versus antiplatelet therapy. The incidence of MACE was 5.5% in the DOAC group versus 6.7% in the antiplatelet group at 21 months mean follow-up, equating to a risk ratio (RR) of 1.05 (95% CI 0.43 to 2.56; p=0.917). The incidence of MALE was 7.9% in the DOAC group versus 12.4% in the antiplatelet group at the mean follow-up of 24 months (RR 1.29; 95% CI 0.96 to 1.74; p=0.093). Major bleeding events occurred in 5.4% in the DOAC group versus 4.7% in the antiplatelet group (RR 0.78; 95% CI 0.49 to 1.24; p=0.29). All-cause mortality and cardiovascular mortality were also similar between groups. Based on these results, there was not a statistical difference between DOAC and antiplatelet treatment. Two additional studies not included in the meta-analysis compared apixaban with warfarin (either alone or the results of different DOACs combined) which reported similar incidence of systemic embolism and stroke. But the results from one study suggested possible lower myocardial infarctions and lower limb amputation, but the study was observational in nature. [4]

References:

[1] Rivera-Caravaca JM, Camelo-Castillo A, Ramírez-Macías I, et al. Antithrombotic Therapy in Patients with Peripheral Artery Disease: A Focused Review on Oral Anticoagulation. Int J Mol Sci. 2021;22(13):7113. Published 2021 Jul 1. doi:10.3390/ijms22137113
[2] Biagioni RB, Lopes RD, Agati LB, et al. Rationale and design for the study Apixaban versus ClopidoGRel on a background of aspirin in patient undergoing InfraPoPliteal angioplasty for critical limb ischemia: AGRIPPA trial. Am Heart J. 2020;227:100-106. doi:10.1016/j.ahj.2020.06.010
[3] Costa G, Gonçalves L, Teixeira R. The efficacy and safety of direct oral anticoagulants plus aspirin in symptomatic lower extremity peripheral arterial disease: a systematic review and meta-analysis of randomized controlled trials. J Thromb Thrombolysis. 2021;52(3):904-913. doi:10.1007/s11239-021-02417-3
[4] Peppas S, Sagris M, Bikakis I, et al. A Systematic Review and Meta-Analysis on the Efficacy and Safety of Direct Oral Anticoagulants in Patients with Peripheral Artery Disease. Ann Vasc Surg. 2022;80:1-11. doi:10.1016/j.avsg.2021.07.028
Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

Can you summarize the literature supporting DOAC use in Peripheral Vascular Disease with a specific interest in apixaban use for this population?

Please see Table 1 for your response.

 

Efficacy and Safety of Apixaban Compared With Warfarin in Patients With Atrial Fibrillation and Peripheral Artery Disease: Insights From the ARISTOTLE Trial

Design

Post-hoc analysis of the ARISTOTLE trial

N= 884

Objective

 To evaluate the effectiveness and safety of apixaban and warfarin in patients with atrial fibrillation (AF) with and without peripheral artery disease (PAD)

Study Groups

Apixaban (n= 442)

Warfarin (n= 442)

Inclusion Criteria

 Patients with AF and at least 1 risk factor for stroke

Exclusion Criteria

Atrial Fibrillation due to reversible cause, moderate or severe mitral stenosis, conditions other than AF requiring anticoagulation, stroke within the previous 7 days, need for aspirin at a dose of > 165 mg per day or both aspirin and clopidogrel, severe renal insufficiency

Methods

Patients were randomized to receive either apixaban 5 mg or dose-adjusted warfarin. The presence of PAD was determined by site investigators and these patients were included in the cohort group for analysis. 

Duration

 N/A

Outcome Measures

Primary: ischemic/hemorrhagic stroke or systemic embolism

Secondary: death from any cause, rate of myocardial infarction (MI), major bleeding

Baseline Characteristics

  

Study participants (n= 884)

      

Age, years

 73      

Female

28.4%      

CHADS2 score

≤ 1

2

≥ 3

 

18.6%

32.1%

49.3%

      

Other medications at baseline

ACE-i or ARB

Beta-blocker

Aspirin

Clopidogrel

 

76.2%

68.8%

39.0%

3.7%

      

Results

Endpoint

Apixaban (n= 442)

Warfarin (n= 442)

Hazard ratio (95% confidence interval)

p-value

Stroke or systemic embolism, events per 100 patient-years

 1.79 2.56 0.63 (0.32 to 1.25) 0.52

All-cause death

 6.37 7.04 1.03 (0.71 to 1.51) 0.42

Cardiovascular death

 3.37 3.83 1.06 (0.63 to 1.79) 0.44

Myocardial infarction

 1.14 1.26 0.97 (0.39 to 2.38) 0.87

Major bleed

 3.04 3.81 0.81 (0.46 to 1.44) 0.58

Adverse Events

N/A

Study Author Conclusions

Patients with PAD in ARISTOTLE had a higher crude risk of stroke or systemic embolism compared with patients without PAD that was not present after adjustment. The benefits of apixaban versus warfarin for stroke and systemic embolism were similar in patients with and without PAD. These findings highlight the need to optimize the treatment of patients with atrial fibrillation and PAD.

InpharmD Researcher Critique

 Post-hoc analyses are exploratory at best and need confirmation in follow-up studies. The presence of PAD was determined based on the site investigator's reporting and not a standard protocol. Patients may have unknowingly been excluded from the analysis. Disease burden and symptom status were seldom reported in PAD patients. It is possible patients may have started or discontinued antiplatelet treatment during the course of the study which could impact the results.



References:

Hu PT, Lopes RD, Stevens SR, et al. Efficacy and Safety of Apixaban Compared With Warfarin in Patients With Atrial Fibrillation and Peripheral Artery Disease: Insights From the ARISTOTLE Trial. J Am Heart Assoc. 2017;6(1):e004699. Published 2017 Jan 17. doi:10.1161/JAHA.116.004699