The main findings of our analysis are as follows: (1) in real-world practice, there was significant variability in the duration of antiplatelet therapy after endovascular revascularization for LEAD; 2) DAPT ≥ 6 months was associated with significantly lower rates of MACE than DAPT < 6 months or MAPT, without evidence of increased bleeding events; and 3) DAPT ≥ 6 months was an independent predictor of a reduced risk for MACE, with its benefit appearing consistently across multiple subgroups.
In the 2016 AHA/ACC lower-extremity PAD guideline, aspirin alone or clopidogrel alone was recommended in patients with symptomatic PAD. However, the effectiveness of DAPT in reducing the risk of cardiovascular ischemic events in patients with symptomatic PAD has not been well established. There are limited data suggesting that DAPT may be reasonable to reduce the risk of limb-related events after lower-extremity revascularization among patients with symptomatic PAD.(9) According to the 2017 ESC guidelines on the diagnosis and treatment of peripheral arterial diseases, which were developed in collaboration with the European Society for Vascular Surgery (ESVC), single antiplatelet agent therapy is indicated for patients with symptomatic LEAD and dual-antiplatelet agent therapy may be considered in LEAD patients with coronary artery disease. Dual-antiplatelet therapy for at least 1 month after percutaneous revascularization should be considered among patients with LEAD.(8) The post-hoc analysis of CHARISMA trial(16) demonstrated that among patients with PAD, the primary endpoints, which were MI, stroke of any cause, or death from cardiovascular causes including hemorrhage, occurred less frequently in the clopidogrel plus aspirin group than in the placebo plus aspirin group (HR, 0.85; P = 0.18). Among these patients, the rate of MI and the rate of hospitalization for ischemic events were lower in the dual-antiplatelet arm than the aspirin-alone arm (HR, 0.63; P = 0.029), at the cost of an increase in minor bleeding. As a randomized trial, the MIRROR study(17) demonstrated that DAPT reduced peri-interventional platelet activation more than aspirin alone and improved functional outcomes without causing higher bleeding complications in patients with PAD treated with endovascular therapy.
Soden et al.(18) studied DAPT at time of discharge and found that in comparison with aspirin alone, DAPT was associated with prolonged survival for patients with CLI undergoing lower-extremity revascularization but not for those showing claudication. However, they did not evaluate bleeding complications. Cho et al.(19) evaluated the optimal duration for antiplatelet therapy after endovascular revascularization in patients with lower-extremity peripheral artery disease. In their study, MACE occurred less frequently in the DAPT ≥ 6 months group than the DAPT < 6 months or MAPT group (hazard ratio: 0.44; p < 0.001), and MALE also occurred less frequently in the DAPT ≥ 6 months group than in the DAPT < 6 months or MAPT group (hazard ratio: 0.42; p < 0.001) without increasing major bleeding events. However, procedures using atherectomy devices were not included in their study.
According to our study, the DAPT ≥ 6 months group showed less frequent major adverse cardiovascular events than the DAPT < 6 months or MAPT group without increasing the risk of bleeding in IPTW matched analysis, although the incidence of MALE showed no significant difference. Patients with PAD who underwent the endovascular revascularization procedure were patients with advanced atherosclerosis, which is more likely to result in cardiovascular events. Moreover, during the endovascular revascularization procedure, the blood vessels are damaged by the wire, balloon angioplasty, stent deployment, and atherectomy device. This endothelial damage promoted the adhesion of platelets, platelet activation, and increased expression of adhesion molecules, results in the aggravation of atherosclerosis and ischemic events. Thus, antiplatelet therapy is much more important for patients who have undergone endovascular procedures than for those who have not. Prolonged use of dual antiplatelet agents could be more effective in controlling platelet activation than short-term use of dual antiplatelet agents and mono-antiplatelet therapy.
Soden et al.(18) showed that dual antiplatelet therapy after lower-extremity revascularization is associated with prolonged survival in patients with CLI. They suggested that DAPT and discharge on statin are favorable predictors for long-term mortality and reported the following unfavorable predictors for long-term mortality: age, white ethnicity, current smoker, diabetes, coronary artery disease, congestive heart failure, renal dysfunction, hemodialysis, prior major amputation, urgent procedure, and perioperative anticoagulation. Gaurav et al.(15) reported that statin use in patients receiving PAD with interventions was associated with improved limb salvage and survival.
Armstrong et al.(20) investigated the effectiveness of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) for patients with CLI who underwent diagnostic angiography or endovascular intervention. After a 3-year follow up, patients prescribed ACEIs or ARBs had lower rates of MACE (HR: 0.76, 95% CI 0.58–0.99, p = 0.04) and overall mortality (HR: 0.71, 95% CI 0.53–0.95, p = 0.02), but the medications had no effect on limb-related outcomes.
In our study, DAPT ≥ 6 months was an independent predictor of reduced MACE in multivariate Cox analysis. Its benefit was consistent across multiple subgroups. Moreover, age, heart failure, chronic kidney disease, statin administration, use of an RAAS blocker, and CLI were predictors of MACE. The use of statins is a predictor of MALE. Thus, for patients with LEAD after endovascular revascularization, prolonged DAPT beyond 6 months may be reasonable to possibly prevent adverse cardiovascular events, and statin use may be considered to prevent limb events. Further prospective studies are needed to show whether the use of DAPT for periods longer than 6 months improves clinical outcomes.
Study Limitations
This study had several limitations. First, we reported the outcomes from a single center. Therefore, our findings are not generalizable. In addition, this was a retrospective, non-randomized study, and the study design may have introduced selection biases and unmeasured data. However, we reduced this bias by performing multivariate Cox and IPTW analyses. Third, in our study, the use of medication was at the physicians’ discretion. Last, the outcomes were clinical events or revascularization, since angiography and CT were not performed routinely. Thus, there was a high possibility that the vascular outcome was overestimated.