Dual versus single antiplatelet therapy after lower extremity revascularization in peripheral artery disease: A systematic review and meta-analysis

Abstract

BACKGROUND

Peripheral artery disease (PAD) affects millions globally, with a 5.6% prevalence in 2015 impacting 236 million adults, rising above 10% in those over 60 due to factors like diabetes and smoking. Post-revascularization, single antiplatelet therapy (SAPT) is standard, but dual antiplatelet therapy (DAPT) may improve outcomes, though duration and bleeding risks are unclear. The 2024 American College of Cardiology/American Heart Association guidelines endorse short-term DAPT, yet evidence gaps remain in comparative efficacy and safety. We hypothesized that DAPT reduces cardiovascular events and reinterventions vs SAPT without significantly elevating bleeding in PAD patients’ post-lower extremity revascularization.

AIM

To evaluate the efficacy and safety of DAPT vs SAPT in PAD patients’ post-revascularization.

METHODS

This systematic review and meta-analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, searching PubMed, EMBASE, and ScienceDirect up to July 2025. Included were randomized controlled trials (RCTs) and cohort studies from various global settings (e.g., hospitals, tertiary care) comparing DAPT (aspirin plus P2Y12 inhibitor for > 1 month) to SAPT in symptomatic PAD patients undergoing endovascular or surgical revascularization (n up to 28244 participants selected via eligibility criteria). Data were pooled using random-effects models for risk ratio (RR) with 95%CI; heterogeneity was assessed via the I² statistic. Quality appraisal used Risk of Bias in Non-randomized Studies of Interventions for cohorts and Risk of Bias 2.0 for RCTs; certainty was evaluated via Grading of Recommendations Assessment, Development and Evaluation (GRADE).

RESULTS

Twelve studies (3 RCTs, 9 cohorts, conducted 2010–2025 with follow-ups of 6 months to 5 years) were included. DAPT showed no significant difference but a trend toward reduced all-cause mortality (RR: 0.52, 95%CI: 0.27–1.01, P = 0.05, DAPT of 298/9545 events vs SAPT of 165/566 events) or stroke (RR: 0.72, 95%CI: 0.30–1.72, P = 0.46, DAPT of 16/3729 events vs SAPT of 41/7673 events) vs SAPT. DAPT significantly reduced cardiac mortality (RR: 0.46, 95%CI: 0.27–0.80, P = 0.006, DAPT of 78/2903 events vs SAPT of 171/1465 events, risk difference: -5.4%), myocardial infarction (RR: 0.82, 95%CI: 0.71–0.94, P = 0.004, DAPT of 233/7704 events vs SAPT of 262/9130 events, risk difference: -1.8%), and major reintervention (RR: 0.58, 95%CI: 0.35–0.98, P = 0.04, DAPT of 803/205 events vs SAPT of 1197/4 events, risk difference: -42%). Bleeding showed no difference (RR: 1.12, 95%CI: 0.42–3.03, P = 0.82, DAPT of 195/2775 events vs SAPT of 202/8234 events). Heterogeneity was high (I² = 59%–97%). Quality revealed moderate to serious bias in cohorts and some concerns in RCTs; GRADE certainty moderate for cardiac mortality, myocardial infarction, reintervention, low for others due to inconsistency and imprecision.

CONCLUSION

DAPT reduces cardiac mortality, myocardial infarction, and major reintervention risks compared to SAPT in PAD post-revascularization without apparent bleeding increase, though limited by heterogeneity and low certainty for some outcomes.

Key Words: Peripheral artery disease; Dual antiplatelet therapy; Single antiplatelet therapy; Lower extremity revascularization; Endovascular intervention; Surgical bypass; Cardiovascular outcomes; Bleeding risk

Core Tip: This meta-analysis synthesizes evidence from randomized controlled trials and cohort studies to compare dual antiplatelet therapy (DAPT) and single antiplatelet therapy (SAPT) following lower extremity revascularization in patients with peripheral artery disease (PAD). The findings demonstrate that DAPT is associated with reduced cardiac mortality, myocardial infarction, and major reintervention risk compared to SAPT, without a significant increase in bleeding complications. These results support the short-term use of DAPT in PAD management post-revascularization and inform current clinical guidelines.

INTRODUCTION

Peripheral artery disease (PAD) is an atherosclerotic condition that affects arteries in the lower extremities. In 2015, its global prevalence was 5.6%, affecting about 236 million adults[1]. The prevalence rises above 10% in people over 60 years old. From 2000 to 2010, PAD cases increased by 23.5%, largely due to aging populations and rising risk factors like diabetes and smoking[2]. PAD ranges from asymptomatic to severe forms, with intermittent claudication (IC) being the most common symptom[3]. As a systemic vascular disease, PAD shares risk factors with coronary artery disease (CAD) and cerebrovascular disease (CVD), notably smoking and diabetes, contributing to significant comorbidity[2,3]. The REACH registry indicates 39% of PAD patients have CAD, 10% have CVD, and 13% have all three, leading to elevated mortality, with CAD causing 40%–60% and CVD 10%–20% of deaths among PAD patients[4].

For patients with symptomatic PAD, revascularization is often recommended to relieve pain, prevent limb loss, and lower healthcare costs. Endovascular procedures are commonly preferred because they are less invasive[5]. In England from 2006 to 2015, endovascular revascularization lowered the 1-year major amputation risk from 5.7% to 3.9%, compared to a drop from 11.2% to 6.6% for surgical methods[6]. However, adverse cardiovascular and limb outcomes remain prevalent[7]. Single antiplatelet therapy (SAPT) with aspirin or clopidogrel is standard to prevent systemic atherosclerosis progression and major adverse cardiovascular and cerebrovascular events[8,9]. The 2024 American College of Cardiology/American Heart Association (ACC/AHA) guidelines now recommend dual antiplatelet therapy (DAPT) for 1–6 months post-endovascular revascularization (class IIa), a shift from the 2016 class IIb rating[8]. Meta-analyses show DAPT reduces all-cause mortality [hazard ratio (HR): 0.86], major limb events (HR: 0.60), and amputations (HR: 0.78) without significantly increasing major bleeding[4]. Dual pathway inhibition (DPI) with low-dose rivaroxaban and aspirin, as demonstrated in the COMPASS and VOYAGER PAD trials, further decreases adverse cardiovascular and limb events post-revascularization[10-12]. Viscoelastic testing, such as thromboelastography, reveals DAPT’s enhanced platelet inhibition over SAPT[9,13].

Despite these advances, important gaps remain in optimizing antiplatelet therapy for PAD after revascularization. For example, the ideal DAPT duration, ranging from 1 month to 24 months, is still uncertain, which makes standardizing treatment challenging. Outcomes comparing DAPT in endovascular vs surgical revascularization are not well explored. Similarly, translating data from mechanistic coagulation monitoring into everyday clinical practice is unclear. The relative benefits of DAPT compared to DPI are also not fully understood, as is identifying which patient subgroups would gain the most from intensified therapy with the best risk-benefit balance. This meta-analysis aims to synthesize high-quality evidence on SAPT and DAPT in PAD patients’ post-lower extremity revascularization, assessing efficacy, safety, and bleeding risks to address these gaps and inform evidence-based clinical guidelines

MATERIALS AND METHODS

This systematic review and meta-analysis were conducted in strict accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the Cochrane Handbook for Systematic Reviews of Interventions[14,15]. The protocol has been prospectively registered with PROSPERO (No. CRD420251102724)

Data sources and search strategy

A comprehensive literature search was independently performed by two reviewers across major electronic databases, including PubMed/MEDLINE, EMBASE, and ScienceDirect, from database inception through July 2025 (Supplementary material). Grey literature sources such as ClinicalTrials.gov, medRxiv, and relevant conference abstracts were also queried to capture unpublished or ongoing studies and minimize publication bias. The search strategy incorporated a combination of MeSH terms and free-text keywords to maximize sensitivity, focusing on DAPT, PAD, and revascularization procedures. Key search strings included: ("dual antiplatelet therapy" OR "DAPT") AND ("peripheral artery disease" OR "PAD") AND ("endovascular treatment" OR "percutaneous transluminal angioplasty" OR "revascularization" OR "bypass" OR "stenting"). The full search strategies tailored to each database are detailed in the Supplementary file. Additional studies were identified by hand-searching reference lists of included articles and relevant reviews.

Study selection

Retrieved citations were imported into EndNote 21 for deduplication and management. Two reviewers (Shahid MM and Das A) independently screened titles and abstracts, followed by full-text evaluation for eligibility. Disagreements were resolved through discussion or arbitration by a third reviewer (Jaffar MS). Studies drawing from overlapping datasets or registries were cross-checked and prioritized to avoid data duplication, with selection based on the largest sample size and most recent publication date.

Eligibility criteria

Inclusion criteria: (1) Randomized controlled trials (RCTs) or non-randomized studies (e.g., prospective or retrospective cohorts, observational studies) involving symptomatic PAD patients with IC or critical limb ischemia who underwent endovascular interventions (e.g., balloon angioplasty with or without stenting) or surgical bypass (e.g., venous or prosthetic graft implantation); (2) Comparisons between DAPT (aspirin plus a P2Y12 inhibitor such as clopidogrel, ticagrelor, prasugrel, or ticlopidine, administered for ≥ 1 month post-procedure) and SAPT (aspirin or clopidogrel alone); (3) Reporting of at least one dichotomous outcome related to efficacy (e.g., all-cause mortality, cardiac mortality, myocardial infarction, stroke, major reintervention) or safety (e.g., bleeding complications); and (4) English-language publications with sufficient data for meta-analysis.

Exclusion criteria included case reports, reviews, editorials, studies with fewer than 10 participants, non-comparative designs, or those lacking relevant outcomes or extractable data.

Data extraction and quality assessment

Data extraction was performed independently by two reviewers (Mukhtar A and Ejaz H) using a standardized form to collect information on study type, year of publication, country, sample size (stratified by DAPT and SAPT groups), patient population, intervention details, DAPT regimen and duration, SAPT regimen, follow-up duration, baseline characteristics (e.g., age, smoking status, diabetes, hypertension, hyperlipidemia, CAD, CVD, chronic kidney disease, ankle-brachial index), and all reported outcomes. For dichotomous outcomes, event rates and totals were extracted; if unavailable, corresponding authors were contacted for raw data.

Risk of bias was assessed by three reviewers (Mandal D, Das A, and Afzal A) using the Cochrane Risk of Bias 2 (RoB 2) tool for RCTs[16] and the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool[17] for non-randomized studies. Assessments covered domains such as randomization, deviations from intended interventions, missing outcome data, outcome measurement, and selection of reported results for RoB 2, and confounding, participant selection, intervention classification, deviations from interventions, missing data, outcome measurement, and reported result selection for ROBINS-I. Discrepancies were resolved by consensus. Results were visualized using traffic light and summary plots generated in tools like robvis.

Publication bias was evaluated using funnel plots for visual inspection and the Egger test for all outcomes, regardless of the number of studies, to assess small-study effects. The certainty of evidence for each outcome was graded using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, considering risk of bias, inconsistency, imprecision, indirectness, and publication bias.

Statistical analysis

All analyses were performed using Review Manager (RevMan) Version 5.4 (Cochrane Collaboration). A random-effects model was employed to account for anticipated clinical and methodological heterogeneity across studies, such as variations in PAD severity, intervention types, and patient characteristics. For dichotomous outcomes, pooled effect estimates were calculated as risk ratio (RR) with 95%CI using the Mantel-Haenszel method.

Heterogeneity was quantified using the Higgins I² statistic (low: 0%–25%; moderate: 25%–50%; substantial: 50%–75%; high: > 75%) and the Cochrane Q test (P < 0.10 indicating significance). Meta-regression was conducted to explore sources of heterogeneity, examining covariates such as mean patient age, prevalence of smoking, type 2 diabetes mellitus (T2DM), and hypertension from baseline characteristics, focusing on outcomes like cardiac mortality. Sensitivity analyses, including leave-one-out approaches, were performed to assess the robustness of findings by sequentially excluding individual studies. A two-sided P ≤ 0.05 was considered statistically significant.

RESULTS

Included studies

The systematic search of PubMed, ScienceDirect, and EMBASE, conducted up to July 2025, yielded 2212 records. After removing 146 duplicates, 2066 records underwent title and abstract screening, of which 1957 were excluded due to irrelevance, non-human studies, or inappropriate study designs. The full-text review was performed for 109 articles, with 97 excluded for lack of comparative bicuspid aortic valves vs tricuspid aortic valves data, insufficient outcome reporting, single-arm studies, and duplicate or overlapping data. Ultimately, 12 studies were included in the meta-analysis (Figure 1)[5,9,13,18-26].

Figure 1  Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart outlining the literature screening process, study selection, and exclusion criteria.

Study characteristics

The meta-analysis included 12 studies conducted across eight countries (United States, United Kingdom, South Korea, Netherlands, France, Sweden, Japan, and California) from 2010 to 2025, with follow-up durations ranging from 6 months to 5 years. The studies encompassed various designs, including prospective and retrospective cohorts, clinical trials, and observational studies, with sample sizes ranging from 40 patients to 28244 patients. Patient populations primarily consisted of individuals with PAD undergoing interventions such as revascularization, bypass, and endovascular therapy. DAPT regimens most frequently included aspirin combined with clopidogrel, prasugrel, or ticagrelor, administered for periods ranging from 1 month to 12 months, while SAPT typically involved aspirin or clopidogrel alone. Detailed study characteristics are presented in Table 1[5,9,13,18-26].

Table 1 Characteristics of included studies comparing dual antiplatelet therapy and single antiplatelet therapy in patients with peripheral artery disease undergoing revascularization.

Ref.	Study type	Intervention	DAPT drug name	DAPT duration	SAPT	Follow up
Rodriguez Alvarez et al[9], 2025	Prospective cohort	DAPT and SAPT	Aspirin and clopidogrel	4 weeks	Aspirin or clopidogrel	6 months
Armstrong et al[21], 2015	Retrospective cohort	N/A	Aspirin and clopidogrel, prasugrel, ticagrelor	N/A	Aspirin	3 years
Belch et al[18], 2010	RCT	Endovascular revascularization	Aspirin and clopidogrel	N/A	Aspirin	2 years
Belkini et al[26], 2020	Retrospective cohort	Bypass	Aspirin and clopidogrel, prasugrel, ticagrelor	N/A	Aspirin	1 year
Chinai et al[24], 2020	Retrospective cohort	Endovascular revascularization	Aspirin and clopidogrel	N/A	Aspirin	1.5 years
Cho et al[5], 2019	Prospective cohort	Endovascular revascularization	Aspirin plus clopidogrel	≥ 6 months	Aspirin or clopidogrel	5 years
Ipema et al[25], 2020	Retrospective cohort	Infra-inguinal endovascular treatment	Acetylsalicylic acid and clopidogrel	12 months	Acetylsalicylic acid or clopidogrel	1 year
Scheinert et al[19], 2012	RCT	Endovascular revascularization	Aspirin and clopidogrel	12 months	Aspirin	2 years
Soden et al[22], 2016	Retrospective cohort	Lower extremity revascularization	Aspirin and P2Y12 antagonist	N/A	Aspirin or P2Y12 antagonist	1 year
Strobl et al[20], 2013	RCT	Endovascular therapy	Aspirin and clopidogrel	6 months	Aspirin	12 months
Thott et al[23], 2017	Retrospective cohort	Endovascular femoropopliteal stenting	Aspirin and clopidogrel	100 days	Aspirin	2 years
Yamada et al[13], 2024	Retrospective cohort	Endovascular therapy	Aspirin and clopidogrel or aspirin and prasugrel	1 month	Any one of aspirin, clopidogrel, prasugrel	2 years

DAPT: Dual antiplatelet therapy; N/A: Not applicable; RCT: Randomized controlled trial; SAPT: Single antiplatelet therapy.

Baseline characteristics

The meta-analysis encompassed baseline characteristics from 12 studies, with mean ages ranging from 65.8 years to 78 years (overall mean approximately 69.6 years) for patients on DAPT and 65.6 years to 80 years (overall mean approximately 70.4 years) for those on SAPT, though age data were unavailable for two studies (Scheinert et al[19], 2012 and Chinai et al[24], 2020). Prevalence of current smoking varied widely, from 11 cases to 303 cases in DAPT groups and from 6 to 590 in SAPT groups across reporting studies, while T2DM was reported in all but one study (Scheinert et al[19], 2012), with rates ranging from 12 to 603 in DAPT and from 18 to 274 in SAPT. Hypertension was prevalent, with counts from 6 to 1054 in DAPT and from 8 to 488 in SAPT, and hyperlipidemia/dyslipidemia data, available in six studies, ranged from 25 to 141 in DAPT and from 25 to 163 in SAPT. CAD was noted in eight studies, with 11-195 cases in DAPT and 15-184 in SAPT; CVD in five studies, ranging from 3 to 59 in DAPT and from 4 to 169 in SAPT; and chronic kidney disease in seven studies, from 3 to 133 in DAPT and from 3.7 to 51 in SAPT. Ankle-brachial index values, reported in three studies, ranged from 0.44 to 0.61 for both groups. Detailed baseline characteristics are presented in Table 2[5,9,13,18-26].

Table 2 Baseline characteristics of patients in included studies comparing dual antiplatelet therapy and single antiplatelet therapy in peripheral artery disease.

Ref.	Age (mean ± SD)		Current smoking		Type 2 diabetes mellitus		Hypertension		Hyperlipidemia/dyslipidemia		Coronary artery disease		Cerebrovascular disease (intracranial hemorrhage)		Chronic kidney disease/dialysis		Ankle-brachial index (mean)
	DAPT	SAPT	DAPT	SAPT	DAPT	SAPT	DAPT	SAPT	DAPT	SAPT	DAPT	SAPT	DAPT	SAPT	DAPT	SAPT	DAPT	SAPT
Rodriguez Alvarez et al[9], 2025	70	66	11	6	35	24	6	8	53	32	29	19	12	7	6	6	N/A	N/A
Armstrong et al[21], 2015	67	67	265	212	187	126	299	236	N/A	N/A	195	126	N/A	N/A	N/A	N/A	0.51	0.53
Belch et al[18], 2010	66.5	65.6	38.8	36.4	37.4	38	70.1	70	50.4	48.8	38.4	31	N/A	N/A	N/A	N/A	0.44	0.46
Belkini et al[26], 2020	65.8	66.4	42.6	42	51.1	45.2	90.1	85.1	N/A	N/A	35.1	25.4	N/A	N/A	3.8	3.7	N/A	N/A
Chinai et al[24], 2020	N/A	N/A	N/A	N/A	71	222	97	303	N/A	N/A	N/A	N/A	25	55	N/A	N/A	N/A	N/A
Cho et al[5], 2019	68.6	70.5	181	198	177	274	224	309	141	163	176	184	N/A	N/A			N/A	N/A
Ipema et al[25], 2020	68.7	74.4	75	99	40	68	58	98	61	65	N/A	N/A	N/A	N/A	3	5	N/A	N/A
Scheinert et al[19], 2012	68.6	70.5	34	21	24	32	12	23	N/A	N/A	12	34	N/A	N/A	21	11	0.52	0.47
Soden et al[22], 2016	68.1	67.8	37.1	38.2	45.2	44.8	87.9	88.5	N/A	N/A	31.1	30.5	N/A	N/A	6.4	5.9	N/A	N/A
Strobl et al[20], 2013	69.8	70.2	15	17	12	18	31	31	25	25	11	15	6	9	N/A	N/A	0.61	0.61
Thott et al[23], 2017	78	80	303	590	603	242	1054	488	N/A	N/A	N/A	N/A	59	169	133	49	N/A	N/A
Yamada et al[13], 2024	73.8	75.6	30	38	96	90	136	127	104	93	13	20	3	4	44	51	N/A	N/A

DAPT: Dual antiplatelet therapy; N/A: Not applicable; RCT: Randomized controlled trial; SAPT: Single antiplatelet therapy.

Clinical outcomes

All-cause mortality: Six studies reported all-cause mortality. The pooled RR was 0.52 (95%CI: 0.27–1.01, P = 0.05), showing no significant difference in mortality risk between DAPT and SAPT patients. Heterogeneity was high (I² = 97%) and dropped significantly after removing Armstrong et al[21], 2015 and Belkini et al[26], 2020 (I² = 62%) (Figure 2A)[5,18,20-23].

Figure 2 Forest plots of pooled risk ratios for clinical outcomes comparing dual antiplatelet therapy vs single antiplatelet therapy in patients with peripheral artery disease undergoing lower extremity revascularization. A: All-cause mortality; B: Cardiac mortality; C: Myocardial infarction; D: Stroke; E: Major reintervention; F: Bleeding.

Cardiac mortality: Six studies reported cardiac mortality. The pooled RR was 0.46 (95%CI: 0.27–0.80, P = 0.006), indicating a significantly lower risk of cardiac mortality in DAPT patients compared to SAPT patients. Heterogeneity was high (I² = 94%) and dropped significantly after removing Scheinert et al[19], 2012 and Belkini et al[26], 2020 (I² = 56%) (Figure 2B)[5,13,18,21,22,24].

Myocardial infarction: Six studies reported myocardial infarction. The pooled RR was 0.82 (95%CI: 0.71–0.94, P = 0.004), demonstrating a significantly lower risk in DAPT patients compared to SAPT patients. Heterogeneity was low (I² = 0%) (Figure 2C)[5,13,18,20,21,26].

Stroke: Four studies reported stroke. The pooled RR was 0.72 (95%CI: 0.30–1.72, P = 0.46), suggesting no significant difference in stroke risk between DAPT and SAPT patients. Heterogeneity was moderate (I² = 59%) and dropped significantly after removing Scheinert et al[19], 2012 and Belkini et al[26], 2020 (I² = 54%) (Figure 2D)[5,13,21,26].

Major reintervention: Five studies reported major reintervention. The pooled RR was 0.58 (95%CI: 0.35–0.98, P = 0.04), showing a significantly lower risk in DAPT patients compared to SAPT patients. Heterogeneity was high (I² = 92%) and dropped significantly after removing Scheinert et al[19], 2012 and Thott et al[23], 2017 (I² = 60%) (Figure 2E)[5,13,18,22,23].

Bleeding complications: Five studies reported bleeding complications. The pooled RR was 1.12 (95%CI: 1.42–3.03, P = 0.82), indicating no significant difference in risk between DAPT and SAPT patients. Heterogeneity was high (I² = 92%) that dropped significantly after removing Scheinert et al[19], 2012 and Belkini et al[26], 2020 (I² = 57%) (Figure 2F)[5,18,23,24,26].

Publication bias assessment

To evaluate potential publication bias across the clinical outcomes in this meta-analysis, the Egger test was performed for each endpoint. No evidence of publication bias was detected in any of the outcomes, as all P values exceeded the significance threshold of 0.05. Specifically, the P values were as follows: (1) All-cause mortality (P = 0.12); (2) Cardiac mortality (P = 0.18); (3) Myocardial infarction (P = 0.06); (4) Stroke (P = 0.14); (5) Major reintervention (P = 0.11); and (6) Bleeding complications (P = 0.07). These results suggest that the included studies provide a balanced representation of the available evidence without systematic bias favoring publication of positive or significant findings (Supplementary Figure 1).

Quality assessment of included studies

The risk of bias in the nine cohort studies was evaluated using the ROBINS-I tool, revealing a varied profile across domains. Overall, two studies (Cho et al[5], 2019, and Rodriguez Alvarez et al[9], 2025) were rated as having moderate risk of bias, while the remaining seven (Yamada et al[13], 2024, Armstrong et al[21], 2015, Soden et al[22], 2016, Thott et al[23], 2017, Chinai et al[24], 2020, Ipema et al[25], 2020, Belkini et al[26], 2020) were assessed as having serious risk, primarily driven by concerns in confounding (D1), participant selection (D2), and missing data (D5). No studies were deemed critical or low risk overall, highlighting potential limitations in retrospective designs that could influence the reliability of pooled estimates (Supplementary Figures 2 and 3)[5,9,13,21-26].

For the three RCTs (Belch et al[18], 2010, Scheinert et al[19], 2012, and Strobl et al[20], 2013), the RoB 2.0 tool indicated an overall rating of some concerns for each, with low risk predominant in randomization (D1), deviations from interventions (D2), and selection of reported results (D5). Minor concerns were noted in missing outcome data (D3) for Belch et al[18], 2010, deviations from interventions (D2) for Scheinert et al[19], 2012, and outcome measurement (D4) for Strobl et al[20], 2013, suggesting generally robust methodology but with areas warranting caution in interpretation (Supplementary Figures 4 and 5)[18-20].

GRADE assessment

The GRADE assessment of the clinical outcomes in this meta-analysis, which included a mix of observational studies and RCTs, revealed varying levels of evidence certainty, primarily influenced by moderate risk of bias, high heterogeneity in several outcomes, and imprecision due to wide confidence intervals in non-significant findings. Certainty was rated as moderate for cardiac mortality, myocardial infarction, and major reintervention, reflecting robust effect sizes with statistical significance and no major indirectness or publication bias (Egger test P values ranging from 0.06 to 0.18 across outcomes). In contrast, all-cause mortality, stroke, and bleeding complications received low certainty ratings, downgraded mainly for serious inconsistency and imprecision, despite the absence of detected publication bias. Overall, these findings underscore the need for cautious interpretation, particularly for outcomes with high heterogeneity, while supporting moderate confidence in the benefits of DAPT for reducing cardiac mortality, myocardial infarction, and major reintervention risks compared to SAPT (Supplementary Table 1).

Meta-regression analysis

To explore potential sources of heterogeneity in the pooled estimates for key clinical outcomes, i.e., all-cause mortality (pooled RR: 0.52; 95%CI: 0.27–1.01), meta-regression analyses were conducted using study-level baseline characteristics from the DAPT groups, including mean age, prevalence of current smoking, T2DM, and hypertension. The analyses revealed no significant associations between these covariates and the log RRs. Specifically, mean age showed a coefficient of -0.023 (P = 0.069), diabetes prevalence a coefficient of -0.0004 (P = 0.072), smoking prevalence a coefficient of -0.0008 (P = 0.075), and hypertension prevalence a coefficient of -0.0002 (P = 0.095). These findings suggest that the observed heterogeneity in outcomes like cardiac mortality is unlikely to be explained by differences in these baseline factors across studies, indicating the need for further investigation into other potential moderators such as intervention type or follow-up duration.

DISCUSSION

This systematic review and meta-analysis of 12 studies involving up to 28244 patients with PAD following lower extremity revascularization found that DAPT significantly reduced cardiac mortality (RR: 0.46, 95%CI: 0.27–0.80, 54% risk reduction), myocardial infarction (RR: 0.82, 95%CI: 0.71–0.94, 18% risk reduction), and major reintervention (RR: 0.58, 95%CI: 0.35–0.98, 42% risk reduction) compared to SAPT. However, no significant differences were observed in all-cause mortality (RR: 0.52, 95%CI: 0.27–1.01), stroke (RR: 0.72, 95%CI: 0.30–1.72), or bleeding complications (RR: 1.12, 95%CI: 1.42–3.03), though high heterogeneity (I² = 59%–97%) limits confidence in these estimates. GRADE assessments indicated moderate certainty for cardiac mortality, myocardial infarction, and major reintervention, but low certainty for all-cause mortality, stroke, and bleeding. This comprehensive analysis of 12 studies encompassing up to 28244 patients represents the most extensive evaluation to date of antiplatelet strategies in this high-risk population. The meta-analysis shows that DAPT lowers the risk of dying from heart problems by 54% and the risk of heart attacks by 18% compared to SAPT, and it also leads to a 42% lower chance of needing major follow-up procedures, improving heart and leg health in patients with PAD, who are at two to three times higher risk for heart issues than the general population[27,28]. These benefits are supported by studies showing that DAPT greatly improves the ability to stop platelets from clumping together, which is important for patients at high risk of blood clots, especially right after they have had procedures to restore blood flow. These findings emerge amid a rapidly evolving landscape in PAD management, with the 2024 ACC/AHA guidelines marking a paradigm shift by recommending DAPT for 1–6 months post-endovascular revascularization (class IIa)[29], an upgrade from prior class IIb status, driven by accumulating evidence for short-term DAPT. The present meta-analysis bolsters this by showing DAPT reduces cardiac mortality and myocardial infarction without significantly elevating bleeding risk[30]. The guidelines also highlight the importance of tailored treatments, especially using DPI with low-dose rivaroxaban and aspirin, as shown in the COMPASS and VOYAGER PAD trials, which reduced major heart problems by 24% and serious leg issues by 46% compared to aspirin alone[12,31]. However, this meta-analysis looks specifically at traditional DAPT (aspirin plus P2Y12 inhibitor) compared to SAPT, providing additional information to help with clinical decisions. The results of this meta-analysis on DAPT for PAD should be considered along with earlier important studies. The CASPAR trial, the largest study on DAPT in surgical PAD patients, showed no benefit from clopidogrel plus aspirin over aspirin alone, with increased bleeding risk. However, a post-hoc analysis of the VOYAGER PAD trial using a "CASPAR-like" endpoint found rivaroxaban plus aspirin reduced composite outcomes by 24% at one year and 16% at three years, indicating that antiplatelet combinations and patient populations may affect results[32]. This meta-analysis is different from CASPAR because it includes both endovascular and surgical patients (with a predominance of endovascular procedures across studies), uses various DAPT combinations and lengths of treatment, and reflects current practices with better techniques and care during and after surgery. Although subgroup analyses stratified by revascularization type (endovascular vs surgical) were not performed, sensitivity analyses conducted to explore heterogeneity did not identify revascularization type as a clear source, but the predominance of endovascular procedures suggests potential differences in outcomes between these groups; this highlights the need for future studies to separate results by revascularization type to uncover any important distinctions and improve contextualization. A critical concern with DAPT is increased bleeding risk, yet this analysis showed no significant rise in bleeding complications compared to SAPT, contrasting some prior studies. However, this conclusion must be interpreted cautiously given the high heterogeneity (I² = 92%) in bleeding outcomes, which may arise from substantial variations in real-world bleeding definitions, reporting practices, and patient selection across studies. This is noteworthy, as bleeding in PAD patients heightens subsequent thrombotic risk and worsens outcomes[33]. The favorable bleeding profile may stem from shorter DAPT durations, better patient selection, and procedural advancements. However, high heterogeneity in bleeding outcomes indicates variability from differences in populations, techniques, and definitions, which reinforces the importance of individualized risk assessment. DAPT's efficacy in PAD likely arises from targeting multiple pathways in atherothrombosis, with aspirin inhibiting cyclooxygenase-1 and P2Y12 inhibitors blocking ADP receptors to synergistically enhance antithrombotic effects, particularly post-revascularization[34]. Overall, while the evidence supports DAPT's benefits in reducing cardiac mortality and myocardial infarction with moderate certainty per GRADE assessments, clinicians should note the low certainty for outcomes such as all-cause mortality, stroke, and bleeding, which limits definitive conclusions in these areas. Limitations We must acknowledge several limitations when interpreting these findings on DAPT in PAD. High heterogeneity across outcomes (I² = 59%-97%) indicates substantial variability in study populations, interventions, and definitions, reducing the precision of pooled estimates and suggesting that DAPT effects may differ by patient subgroups and contexts. Meta-regression showed no significant links between baseline characteristics and outcomes, implying heterogeneity stems from unmeasured factors like procedural techniques, regimens, or follow-up duration, such as variations in procedural anticoagulation protocols, patient adherence, or comorbidity burden, underscoring the need for standardized research approaches. GRADE assessments yielded moderate certainty for cardiac mortality, myocardial infarction, and major reintervention, but low certainty for all-cause mortality, stroke, and bleeding, due to challenges in high-quality PAD trials and reliance on observational studies. Additionally, the inclusion criteria required a minimum DAPT duration of one month, yet many studies employed longer durations, which may limit generalizability to shorter regimens now recommended by guidelines (e.g., 1–6 months post-endovascular procedures); this could overestimate long-term benefits or risks in real-world practice where shorter courses are preferred to balance efficacy and bleeding concerns.

Future directions

The meta-analysis findings advocate a nuanced, individualized approach to antiplatelet therapy in PAD patients. DAPT significantly reduces cardiac mortality and myocardial infarction, but its use should be tailored to patient-specific factors such as bleeding risk, cardiovascular profile, and procedural considerations. Emerging personalized strategies hold promise[34], including risk stratification tools integrating clinical, procedural, and genetic data to optimize benefits while minimizing bleeding. Platelet function testing and genetic polymorphism analysis could further refine patient selection, though validation in PAD populations is essential. The 2024 ACC/AHA guidelines recommend DAPT for 1–6 months after endovascular revascularization for PAD, individualized by risk: (1) Extended for high-risk patients (diabetes, chronic kidney disease, prior events); and (2) Shortened for bleeding-prone patients. You can use DAPT along with managing risk factors, exercise therapy, and a combination of rivaroxaban (2.5 mg twice daily) and aspirin, which helps reduce serious heart and limb problems, as another option. Large RCTs explore the best strategies based on quality-of-life and economic endpoints, develop PAD-specific risk models that incorporate clinical, biomarker, and genetic data, and compare DAPT and dual pathway approaches based on subgroups such as anatomy, symptoms, and comorbidities[8]. Additionally, future research should prioritize the harmonization of bleeding outcome definitions across PAD trials to improve the comparability of safety data, addressing the high variability in bleeding reporting that currently limits robust conclusions on DAPT’s safety profile.

CONCLUSION

This comprehensive meta-analysis suggests that DAPT may reduce cardiac mortality, myocardial infarction, and major reintervention risks compared to SAPT in PAD patients following lower extremity revascularization, with no apparent increase in bleeding complications. However, these findings are tempered by high heterogeneity (I² = 59%–97%) and variable evidence certainty, with moderate certainty for cardiac mortality, myocardial infarction, and major reintervention, but low certainty for all-cause mortality, stroke, and bleeding outcomes due to inconsistency and imprecision. These results cautiously support short-term DAPT use, aligning with the 2024 ACC/AHA guidelines for 1–6 months post-endovascular revascularization, but highlight the need for individualized treatment approaches given the limitations in evidence robustness. The findings should be interpreted within the context of evolving PAD management, which emphasizes personalized care and integration of multiple evidence-based therapies. As new antiplatelet agents and combination strategies emerge, continued research is essential to refine optimal DAPT durations, standardize bleeding definitions, and explore subgroup-specific outcomes (e.g., endovascular vs surgical revascularization) to enhance evidence certainty. Principles of individualized risk assessment and shared decision-making remain critical in optimizing outcomes for this high-risk patient population.