Efficacy and safety of DOACs in patients with peripheral arterial disease: A systematic review and meta-analysis

Abstract

Background

The efficacy and safety of direct oral anticoagulants (DOACs) in patients with peripheral arterial disease are not completely understood. Therefore, we conducted a meta-analysis to explore the effects of DOACs in this population.

Methods

We systematically searched the PubMed, Cochrane Library, and Web of Science till April 2020 for relevant randomized controlled trials and observational studies, with no linguistic restrictions. The efficacy outcomes were cardiovascular death, stroke, myocardial infraction, major adverse cardiovascular events (MACE), acute limb ischemia, amputation, and target lesion revascularization. The safety outcome was major bleeding events. Random effects risk ratios with 95% confidence intervals were calculated.

Results

A total four randomized controlled trials were included in this meta-analysis. Among peripheral arterial disease patients, DOACs did not reduce the risk of cardiovascular death (RR = 1.02 95%CI 0.75–1.37, P = 0.92), stroke (RR = 0.73 95%CI 0.46–1.14, P = 0.16), myocardial infraction (RR = 0.85 95%CI 0.70–1.03, P = 0.10), MACE (RR = 0.73 95%CI 0.46–1.14, P = 0.16), or amputation (RR = 0.73 95%CI 0.46–1.14, P = 0.16) compared with control. However, DOACs were associated with reduction in acute limb ischemia (RR = 0.67 95%CI 0.55–0.80, P < 0.01) and target lesion revascularization (RR = 0.89 95%CI 0.81–0.99, P = 0.02) at the expense of major bleeding events (RR = 1.43 95%CI 1.16–1.77, P < 0.01) compared with control.

Conclusions

Based on current evidence, no significant difference in cardiovascular death, stroke, myocardial infraction, MACE, and amputation was found when DOACs were compared to antiplatelet monotherapy. The benefits of preventing target lesion revascularization and acute limb ischemia were balanced by amplified risk of major bleeding. Larger randomized controlled trials are needed to figure out the uncertainty around efficacy and safety of medications for peripheral arterial disease.

Keywords

Direct oral anticoagulant peripheral artery disease randomized controlled trial bleeding meta-analysis

Introduction

Peripheral arterial disease (PAD) is a chronic obstructive process that caused by atherosclerosis, which reduced blood flow to the limbs. The prevalence of PAD has markedly increased as the population ages, affecting nearly 20% of people over 60 years old.¹ Some patients remain asymptomatic, and others develop progressively worsening discomfort with claudication. Chronic limb-threatening ischemia (CLTI) is seen in end-stage PAD, associated with high risk of amputation, severe mortality, and impaired quality of life.² The typical definition of CLTI includes the presence of PAD in combination with rest pain, tissue loss, gangrene, or a lower limb ulceration >2 weeks duration. The key to PAD management is to improve clinical symptoms and reduce major adverse cardiovascular events (MACE) and major adverse limb events (MALE) over time. In addition, the risk of MALE in PAD patients after a peripheral revascularization is higher.³

At present, risk factor modification, lipid-modifying, and antiplatelet therapies are used as mainstay strategies in the patients with PAD.^4,5 Several studies have shown that antithrombotic therapy is most likely to slow down atherothrombotic progress in patients with PAD.^6–8 DOACs (rivaroxaban,⁹ dabigatran,¹⁰ edoxaban,¹¹ or apixaban¹²), new oral anticoagulant agents, are effective in the treatment of venous thromboembolism¹³ and have also been shown to reduce the risk of MACE.¹⁴ Although the use of oral anticoagulation therapy for the PAD patients has been considered in recent guideline,¹⁵ efficacy and safety optimal anticoagulation therapy in these patients remain a controversial topic due to the limited reports. In this context, we performed meta-analysis to focus on available evidence for antithrombotic therapy in PAD patients who required revascularization procedures or not that may aid clinicians in choosing the most appropriate treatment strategy.

Methods

This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA).¹⁶ This review was prospectively registered on PROSPERO #CRD42020182318.

Literature searches and study selection

Two independent investigators conducted the literature search using PubMed, Cochrane Library, and Web of Science from inception until April 2020 with no linguistic restrictions. The following algorithm was used: “direct oral anticoagulants” OR “DOAC” OR “rivaroxaban” OR “dabigatran” OR “edoxaban” OR “apixaban” AND “peripheral artery disease” OR “PAD”. In addition, we also checked the reference lists of identified articles and published reviews for potentially eligible studies. The inclusion criteria were: (1) randomized controlled trials (RCTs) of DOACs (rivaroxaban, dabigatran, edoxaban, or apixaban; any dose), (2) trials must have participants with asymptomatic or symptomatic PAD, and (3) trials must have at least follow-up of six months to provide reliable assessment. Studies that reported on irrelevant outcomes, conference abstracts, editorials, case reports, systematic reviews, and republished literatures were excluded. There were no restrictions on sample size. According to the inclusion and exclusion criteria, four randomized controlled trials were included from the electronic database (Figure 1).

Figure 1.

PRISMA search flow diagram (last search: April 2020).

Data extraction and quality assessment

For all the included studies, the following information was abstracted: details of the publication, baseline characteristics of the participants, data source, interventions, sample size, follow-up duration, efficacy outcomes, and safety outcomes. The efficacy outcomes were cardiovascular death, stroke, myocardial infraction (MI), MACE, acute limb ischemia (ALI), amputation, and target lesion revascularization (TLR). The principal safety outcome variable was major bleeding (defined by the international society on thrombosis and haemostasis (ISTH)). Any disagreements related to data between reviewers were resolved by the opinion of the third investigator. The quality of the included trials was assessed by the Cochrane Risk of Bias Tool,¹⁷ which involved selection bias, performance bias, detection bias, attrition bias, and reporting bias.

Statistical analysis

Statistical analysis was performed using Stata 16.0 (STATA Corp., College Station, TX, USA). No publication bias analysis was performed as the number of included studies was less than 10, according to the Cochrane Handbook for Systematic Reviews of Interventions (Version 6).¹⁸ Between-study heterogeneity was assessed with Cochrane Q test (P < 0.1) and I² metric, where I² < 50% is considered to represent low heterogeneity.

Results

Study selection and characteristics

Figure 1 details our retrieval process for this meta-analysis. Of 567 records, 216 were screened after removal of duplicates and 179 articles were excluded at title and abstract level as irrelevant. Ultimately, 4 RCTs^19–22 (number of patients = 11,738) were conformed to the appropriate criteria. The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies), ePAD (Edoxaban in Peripheral Arterial Disease), RIVAL–PAD (Pilot Study to Examine the Use of Rivaroxaban After Angioplasty for Critical Limb Ischemia), and VOYAGER PAD (Efficacy and Safety of Rivaroxaban in Reducing the Risk of Major Thrombotic Vascular Events in Subjects With Symptomatic Peripheral Artery Disease Undergoing Peripheral Revascularization Procedures of the Lower Extremities) trials reported data for rivaroxaban and edoxaban applications in patients with PAD, respectively. The baseline characteristics for each study were summarized in Table 1. And Table 2 reported the efficacy and safety outcomes of the included trials.

Table 1.

Baseline characteristics of included clinical trials.

Study (year)	Group (dose)	Study design	Interventions	Mean Age (years)	Females	Participants	Efficacy outcomes	Safety outcomes	Follow-up (months)
COMPASS (2018)	Rivaroxaban (2.5 mg BID) + aspirin (100 mg)	Multicentre, double blind, phase III study	Bypass surgery, PTA, amputation, non-surgery	67.9	718 (28.8%)	2492	Cardiovascular death, stroke, MI, MACE, ALI, amputation	Major bleeding	21
COMPASS (2018)	Aspirin (100 mg)	Multicentre, double blind, phase III study	Bypass surgery, PTA, amputation, non-surgery	67.8	717 (28.6%)	2504	Cardiovascular death, stroke, MI, MACE, ALI, amputation	Major bleeding	21
ePAD (2018)	Edoxaban (60 mg) + aspirin (100 mg)	Multicentre, open-label, phase II study	Endovascular treatment	68.0	34 (33.7)	101	Cardiovascular death, stroke, MI, MACE, amputation, TLR	Major bleeding	6
ePAD (2018)	Clopidogrel (75 mg) + aspirin (100 mg)	Multicentre, open-label, phase II study	Endovascular treatment	66.7	24 (23.5%)	102	Cardiovascular death, stroke, MI, MACE, amputation, TLR	Major bleeding	6
RIVAL–PAD (2018)	Rivaroxaban (2.5 mg BID) + aspirin (81 mg)	Single-center, open-label, phase II study	PTA with or without stenting	59.5	4 (36.4%)	9	Cardiovascular death, MACE, TLR	Major bleeding	12
RIVAL–PAD (2018)	Clopidogrel (75 mg) + aspirin (81 mg)	Single-center, open-label, phase II study	PTA with or without stenting	74.8	4 (44.4%)	11	Cardiovascular death, MACE, TLR	Major bleeding	12
VOYAGER PAD (2020)	Rivaroxaban (2.5 mg BID) + aspirin (100 mg)	Multicentre, double blind, phase III study	Revascularization (surgical and/or endovascular)	67.0	847 (25.8%)	3286	Cardiovascular death, stroke, MI, ALI, amputation, TLR	Major bleeding	28
VOYAGER PAD (2020)	Placebo + aspirin (100 mg)	Multicentre, double blind, phase III study	Revascularization (surgical and/or endovascular)	67.0	857 (26.1%)	3278	Cardiovascular death, stroke, MI, ALI, amputation, TLR	Major bleeding	28

PTA: percutaneous transluminal angioplasty; MI: myocardial infraction; MACE: major adverse cardiovascular events; ALI: acute limb ischemia; TLR: target lesion revascularization.

Table 2.

Efficacy and safety outcomes in clinical trials.

Study	Cardiovascular death	Stroke	MI	MACE	ALI	Amputation	TLR	Major bleeding
COMPASS (2018)
DOACs (%)	64 (2.6)	25 (1.0)	51 (1.7)	126 (5.1)	19 (0.8)	11 (0.4)	NA	64 (2.7)
Control (%)	78 (3.1)	47 (1.9)	67 (2.7)	174 (6.9)	34 (1.4)	28 (1.1)	NA	40 (1.6)
ePAD (2018)
DOACs (%)	2 (2.0)	1 (1.0)	2 (2.0)	3 (3.0)	NA	1 (1.0)	11 (11.0)	1 (1.0)
Control (%)	0	0	1 (1.0)	1 (1.0)	NA	4 (4.0)	10 (9.9)	4 (4.0)
RIVAL–PAD (2018)
DOACs (%)	0	NA	NA	0	NA	3 (33.3)	1 (11.1)	0
Control (%)	0	NA	NA	0	NA	5 (45.4)	2 (18.2)	0
VOYAGER PAD (2020)
DOACs (%)	199 (6.1)	71 (2.2)	131 (4.0)	NA	155 (4.7)	103 (3.1)	584 (17.8)	140 (4.3)
Control (%)	174 (5.3)	82 (2.5)	148 (4.5)	NA	227 (6.9)	115 (3.5)	655 (20.0)	100 (3.1)

MI: myocardial infraction; MACE: major adverse cardiovascular events; ALI: acute limb ischemia; TLR: target lesion revascularization; NA: not available.

Study quality

The included studies were evaluated by the Cochrane risk of bias tool (Figure 2). In all four studies,^19–22 patients were randomized using an interactive computer system. Two studies^19,22 were double-blinded, and an independent academic clinical events committee adjudicated the outcomes in three studies.^19,20,22 All the preconcerted outcomes were recorded in all four studies.^19–22

Figure 2.

Risk of bias assessment for included studies. + represents low risk of bias; ? represents unclear risk of bias; - represents high risk of bias.

Efficacy and safety outcomes

Table 2 reported the key outcomes of efficacy and safety. Four studies included the results of cardiovascular death, three studies included the results of stroke, three studies included the results of MI, three studies included the results of MACE, two studies included the results of ALI, four studies included the results of amputation, three studies included the results of TLR, and four studies included the results of major bleeding. Our pooled analysis indicated that in patients with PAD, DOACs did not reduce the risk of cardiovascular death (RR = 1.02 95%CI 0.75–1.37, P = 0.92; Figure 3), stroke (RR = 0.73 95%CI 0.46–1.14, P = 0.16; Figure 4), MI (RR = 0.85 95%CI 0.70–1.03, P = 0.10; Figure 5), MACE (RR = 0.73 95%CI 0.46–1.14, P = 0.16; Figure 6), or amputation (RR = 0.73 95%CI 0.46–1.14, P = 0.16; Figure 7) compared with control. However, DOACs were associated with reduction in ALI (RR = 0.67 95%CI 0.55–0.80, P < 0.01; Figure 8) and TLR (RR = 0.89 95%CI 0.81–0.99, P = 0.02; Figure 9) at the expense of major bleeding events (RR = 1.43 95%CI 1.16–1.77, P < 0.01; Figure 10) compared with control.

Figure 3.

Cardiovascular death with direct oral anticoagulant (DOAC) versus control. Tests of heterogeneity, I2 and Q statistic were included.

Figure 4.

Stroke with direct oral anticoagulant (DOAC) versus control. Tests of heterogeneity, I2 and Q statistic were included.

Figure 5.

Myocardial infraction with direct oral anticoagulant (DOAC) versus control. Tests of heterogeneity, I2 and Q statistic were included.

Figure 6.

Major adverse cardiovascular events with direct oral anticoagulant (DOAC) versus control. Tests of heterogeneity, I2 and Q statistic were included.

Figure 7.

Acute limb ischemia with direct oral anticoagulant (DOAC) versus control. Tests of heterogeneity, I2 and Q statistic were included.

Figure 8.

Amputation with direct oral anticoagulant (DOAC) versus control. Tests of heterogeneity, I2 and Q statistic were included.

Figure 9.

Target lesion revascularization with direct oral anticoagulant (DOAC) versus control. Tests of heterogeneity, I2 and Q statistic were included.

Figure 10.

Major bleeding with direct oral anticoagulant (DOAC) versus control. Tests of heterogeneity, I2 and Q statistic were included.

Discussion

Critical divergences exist in recent guideline recommendations for antithrombotic strategies in PAD, especially patients who receive revascularization. One key factor is the lack of high-quality evidence in this area which might explain the discrepancy among antithrombotic regimens in the clinical practice.²³ Current guidelines recommend antiplatelet monotherapy with clopidogrel or aspirin in symptomatic (Class I) or asymptomatic (Class IIa) PAD patients to reduce MACE.⁵ At present, dual pathway therapy with antithrombotic and antiplatelet is widely applicable to clinical practice. However, there is still no consensus regarding optimal dosage and duration of treatment due to lacking data of antithrombotic regimen in prior clinical trials.

The earlier studies have failed to detect any significant effect in the reduction of MACE and have shown an increased risk of bleeding events.^24–26 The role of antithrombotic therapy in the patients with PAD has recently been re-tested using different agents and dosing. The Warfarin Antiplatelet Vascular Evaluation trial compared Vitamin K antagonist (target international normalized ratio, 2.0–3.0) plus antiplatelet therapy to antiplatelet monotherapy in PAD patients for variation of MACE.²⁵ Warfarin therapy did not notably reduce MACE with an increase in the risk of life-threatening bleeding (RR = 3.41 95%CI 1.84–6.35, P < 0.001). Based on these prior data, full dose, systemic anticoagulation in stable PAD patients is not recommended. The recent availability of DOACs exerted its anticoagulation effect by direct inhibition of Factor Xa that did not require periodic blood testing and had fewer food and drug interactions than Vitamin K antagonist. Recently, the U.S. Food and Drug Administration had approved XARELTO® (rivaroxaban) to reduce the risk of MACE in patients with chronic coronary artery disease or PAD²⁷ based on results from the landmark of COMPASS trial.^19,28 The efficacy of anticoagulation therapy may be an alternative therapy for PAD patients.

Our analysis based on four RCT studies had shown that the use of DOACs with antiplatelet therapy was not significant and reduced cardiovascular death, stroke, myocardial infarction, or MACE in patients with PAD. Since the low event rates of mortality and limited follow-up duration of trials, which made it difficult to show a significant survival benefit of DOACs treatment,²⁹ 75% of the included trials used low dose rivaroxaban that may not grant the desired therapeutic benefits, and higher doses should be assessed in the future trials. One possible reason is that the compound beneficial effects of antiplatelet and antithrombotic therapies have plateaued. In addition, overly radical similar treatment will merely increase the risk of bleeding events without reducing MACE and MALE. Furthermore, the inherent risks of comorbidities (heart failure, MI, diabetes, and pulmonary dysfunction) could have confounded the results. In contrast, in another meta-analysis, Khan et al.³⁰ showed reduction in MACE by the use of DOACs with antiplatelet therapy at the expense of higher bleeding in patients with acute coronary syndrome. Considering the limited data regarding this issue, further study is needed to confirm the findings.

In the present meta-analysis, DOACs reduced TLR (P = 0.02, I² = 0.00%) at the cost of higher bleeding rates. Strobl et al.³¹ randomly assigned 80 patients to receive dual antiplatelet therapy (DAPT) and single antiplatelet therapy (SAPT) for six months in a double-blind trial. Similar results were observed for the TLR of DAPT versus SAPT (5% vs. 20%, P = 0.04). Second, our results showed that ALI (P < 0.01, I² = 0.00%) was reduced between DOACs and controls. It often led to amputation as the result of progression to critical limb ischemia. In addition, major amputation caused by vascular disease which seriously affect the quality of life of patients and exacerbated the burden on society. However, our finding indicated that the major amputation (P = 0.10, I² = 49.03%) was no significant difference between the DOACs and control group. The most likely explanation was that the heterogeneity of results caused by the COMPASS study included asymptomatic patients, who had the lowest risk of MALE.³² Moreover, there was the higher rates of major bleeding events in the DOACs group (P < 0.01, I² = 0.00%) with the ISTH criterion (fatal bleeding, symptomatic bleeding in a criteria area or organ, a fall in hemoglobin level of 20 g/L, or transfusion of at least two units of whole blood or red cells).³³ It was partly explained by the PAD patients who had comorbid conditions, for example, advanced age, hepatic, and renal insufficiency.^34,35 Therefore, patients with PAD who were prescribed dual pathway therapy with antithrombotic and antiplatelet should be carefully monitored for bleeding risk.

This meta-analysis has limitations. First, the baseline characteristics of participants, sample size of studies, concurrent medical treatment, and follow-up time varied remarkably among the trials. Second, since the limited available data, the control group included SAPT and DAPT simultaneously. Third, the number of participants incorporated into the comparisons was relatively small, which has affected the validity of the corresponding results. Finally, no data was available regarding the level and type of PAD in the involved studies. Hence a participant level analysis will be ideal in the further study.

Conclusion

Based on current publications, this meta-analysis demonstrates that DOACs with antiplatelet monotherapy did not reduce cardiovascular death, stroke, MI, MACE, or amputation in patients with PAD. The benefits of TLR and ALI reduction were achieved at the cost of major bleeding risk. Dual pathway therapy with antithrombotic and antiplatelet calls for a trade-off among higher bleeding and prevention of recurrent MALE. Therefore, clinicians should be carefully selected subjects having ischemic risk over their bleeding propensity. Additional RCTs are required to determine the thresholds of therapy duration or daily dose.

Footnotes

Addendum

Study concept and design: Zhang YS and Lu YM. Studies selection, extracted the data, performed the bias assessment: Chen JH and Li S. Analysis and interpretation of data: Zhang YS. Drafting of the manuscript: Zhang YS. Critical revision of the manuscript for important intellectual content: Chen JH, Li S, Mei T and Lu YM. All gave final approval and agree to the submission of the manuscript.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Yuan-Su Zhang

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