Antithrombotic Therapy for Symptomatic Peripheral Arterial Disease: A Systematic Review and Network Meta-Analysis

Abstract

Background: High-quality evidence from trials directly comparing single antiplatelet therapies in symptomatic peripheral arterial disease (PAD) to dual antiplatelet therapies or acetylsalicylic acid (ASA) plus low-dose rivaroxaban is lacking. Therefore, we conducted a network meta-analysis on the effectiveness of all antithrombotic regimens studied in PAD.

Methods: A systematic search was conducted to identify randomized controlled trials. The primary endpoints were major adverse cardiovascular events (MACE) and major bleedings. Secondary endpoints were major adverse limb events (MALE) and acute limb ischaemia (ALI). For each outcome, a frequentist network meta-analysis was used to compare relative risks (RRs) between medication and ASA. ASA was the universal comparator since a majority of studies used ASA as in the reference group.

Results: Twenty-four randomized controlled trials were identified including 48,759 patients. With regard to reducing MACE, clopidogrel [RR 0.78, 95% confidence interval (CI) 0.66-0.93], ticagrelor (RR 0.79, 95% CI 0.65-0.97), ASA plus ticagrelor (RR 0.79, 95% CI 0.64-0.97), and ASA plus low-dose rivaroxaban (RR 0.84, 95% CI 0.76-0.93) were more effective than ASA, and equally effective to one another. As compared to ASA, major bleedings occurred more frequently with vitamin K antagonists, rivaroxaban, ASA plus vitamin K antagonists, and ASA plus low-dose rivaroxaban. All regimens were similar to ASA concerning MALE, while ASA plus low-dose rivaroxaban was more effective in preventing ALI (RR 0.67, 95% CI 0.55-0.80). Subgroup analysis in patients undergoing peripheral revascularization revealed that ≥ 3 months after intervention, evidence of benefit regarding clopidogrel, ticagrelor, and ASA plus ticagrelor was lacking, while ASA plus low-dose rivaroxaban was more effective in preventing MACE (RR 0.87, 95% CI 0.78-0.97) and MALE (RR 0.89, 95% CI 0.81-0.97) compared to ASA. ASA plus clopidogrel was not superior to ASA in preventing MACE ≥ 3 months after revascularization. Evidence regarding antithrombotic treatment strategies within 3 months after a peripheral intervention was lacking.

Conclusion: Clopidogrel, ticagrelor, ASA plus ticagrelor, and ASA plus low-dose rivaroxaban are superior to ASA monotherapy and equally effective to one another in preventing MACE in PAD. Of these four therapies, only ASA plus low-dose rivaroxaban provides a higher risk of major bleedings. More than 3 months after peripheral vascular intervention, ASA plus low-dose rivaroxaban is superior in preventing MACE and MALE compared to ASA but again at the cost of a higher risk of bleeding, while other treatment regimens show non-superiority. Based on the current evidence, clopidogrel may be considered the antithrombotic therapy of choice for most PAD patients, while in patients who underwent a peripheral vascular intervention, ASA plus low-dose rivaroxaban could be considered for the long-term (> 3 months) prevention of MACE and MALE.

Fig. 1

Flow chart of study screening and selection. PAD peripheral arterial disease

Fig. 2

Network diagram of antithrombotic regimens. The line width is proportional to the sample size of each direct comparison. The number in the middle of the line represents the number of direct comparisons. The number below the antithrombotic regimen corresponds with the total number of participants on that specific antithrombotic therapy. A Network diagram of MACE. B Network diagram of major bleedings. ASA acetylsalicylic acid, bid bi-daily, INR international normalized ratio, MACE major adverse cardiovascular events, VKA vitamin K antagonist. *Patients who used no antithrombotic treatment, did receive placebo tablets

Fig. 3

Forest plots presenting estimated relative risks (RRs) and corresponding 95% confidence intervals (CIs). Results are presented for different antithrombotic strategies compared to low-dose acetylsalicylic acid (ASA). Direct comparisons are the number of studies that directly compared the treatment option to the universal comparator. Hereafter, the proportion of direct evidence is shown. The mean pathlength characterizes the degree of indirectness of an estimate. Minimal parallelism presents the minimum number of independent paths contributing to the effect estimate [22]. A All patients. B Patients who underwent a peripheral vascular intervention for peripheral arterial disease. For the patients who underwent a peripheral vascular intervention, no network meta-analysis could be performed for acute limb events, since studies had no overlapping antithrombotic regimens. ALI acute limb event, bid bi-daily, INR international normalized ratio, MACE major adverse cardiovascular events, MALE major adverse limb events, NNT number needed to treat, NNTB number needed to treat for an additional beneficial outcome, NNTH number needed to treat for an additional harmful outcome, VKA vitamin K antagonist, ∞ need to treat an infinite number of people to cause or avoid an event (i.e. no effect)