Dual antiplatlets therapy following revasclarisation for chronic critical limb ischemia: A systematic review and meta-analysis

*Corresponding author: A. Karim Abushmaies. Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution Liscense 4.0. Dual antiplatlets therapy following revasclarisation for chronic critical limb ischemia: A systematic review and meta-analysis A. Karim Abushmaies 1, * and Muhammad Sufyan 2 1 Advanced Veins and Vascular Management, Hillsdale, Michigan, U. S. A. 2 Government College University Faisalabad. World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 135-155 Publication history: Received on 16 August 2025; revised on 23 September 2025; accepted on 25 September 2025 Article DOI: https://doi.org/10.30574/wjbphs.2025.24.1.0868 Abstract Introduction: Chronic limb-threatening ischaemia carries high risks of amputation and death despite revascularisation. Clinicians frequently prescribe dual antiplatelet therapy after surgical or endovascular procedures, yet its net clinical benefit remains uncertain. This review aimed to compare the effectiveness and safety of dual antiplatelet therapy versus single antiplatelet therapy following lower-limb revascularisation. Methods: The study followed PRISMA 2020 and Cochrane guidance, registered a protocol, and included randomized trials of adults with chronic limb-threatening or critical limb ischaemia after lower-limb revascularisation. Dual therapy combined aspirin with a P2Y12 inhibitor versus single agent. Searches covered databases to 20 September 2025. Triplicate screening, extraction, Risk-of-Bias 2, random-effects Paule–Mandel with Hartung–Knapp, rare-event methods, subgroups, and GRADE were prespecified. Results: The search retrieved 6,416 citations after de-duplication; 10 randomized trials met eligibility for synthesis. For major amputation at one year, the random-effects risk ratio was 0.94 (95% CI 0.77–1.15; I² 89.9%). Twelve-month graft patency showed no improvement (RR 1.16, 95% CI 0.70–1.91; I² 95.5%). Major bleeding or transfusion increased with dual therapy (RR 1.55, 95% CI 1.06–2.26; I² 57.4%). Resting ankle–brachial index showed minimal difference (MD −0.04, 95% CI −0.11 to 0.02; I² 99.5%). All-cause mortality at one year was neutral (RR 1.01, 95% CI 0.75–1.35; I² 91.7%). Subgroup analyses found no interaction by vascular bed, modality, or duration; small-study effects were generally suggested; overall certainty was moderate for amputation and patency, and low for bleeding and mortality across trials. Conclusion: Dual antiplatelet therapy after lower-limb revascularisation for chronic limb-threatening ischaemia did not reduce major amputation or improve patency under random-effects assumptions, and it increased major bleeding. Mortality appeared neutral. Effects varied widely across studies without subgroup effects. Treatment decisions should individualize bleeding risk and limb threat while awaiting powered trials. Keywords: Dual antiplatelet therapy; Chronic limb-threatening ischaemia; Critical limb ischaemia; Lower-limb revascularisation; Major amputation; Graft patency; Major bleeding; Systematic review and meta-analysis 1. Introduction Chronic critical limb ischemia represents the most advanced stage of peripheral arterial disease and poses a significant threat to limb viability and patient survival (Giannopoulos & Armstrong, 2021). It is clinically characterized by ischemic rest pain, ulceration, or gangrene caused by severely impaired arterial perfusion lasting for more than two weeks World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 135-155 136 (Rigatelli et al., 2017). Peripheral arterial disease affects over 200 million people globally and the incidence of chronic critical limb ischemia continues to increase, particularly in aging and diabetic populations (Gupta et al., 2019). Diabetes mellitus, smoking, hypertension, chronic kidney disease, and dyslipidemia remain the most common etiological factors associated with disease progression and vascular occlusion in the lower extremities (Hardung et al., 2021). Among patients with diabetes, the risk of developing chronic critical limb ischemia is two to four times greater than in nondiabetic individuals (Barć et al., 2020). Ischemic ulcerations of the distal extremities in chronic critical limb ischemia frequently progress to gangrene, leading to major amputation and increased mortality (Dean & Vaccaro, 2002). Revascularization using open surgery or endovascular therapy is the principal strategy for limb salvage and restoration of arterial perfusion (Michel et al., 2016). However, reintervention rates remain high due to restenosis, thrombosis, or graft occlusion following successful revascularization (Wand et al., 2014). Antiplatelet therapy is routinely used to improve patency rates and to prevent thromboembolic events in patients with chronic critical limb ischemia undergoing revascularization (Spiliopoulos, 2014). Dual antiplatelet therapy, most commonly comprising aspirin and clopidogrel, has shown promise in improving outcomes by reducing platelet aggregation and inflammation in high-risk vascular patients (Burdess et al., 2010). Randomized trials have demonstrated that dual antiplatelet therapy lowers perioperative biomarkers of atherothrombosis and may reduce myocardial injury in patients undergoing limb revascularization (Brener et al., 2007). Antiplatelet agents including cilostazol and ticagrelor may provide further antithrombotic benefit in certain patients with critical limb ischemia (Azarbal et al., 2015). Analysis of over 50,000 patients undergoing revascularization procedures revealed that dual antiplatelet therapy was associated with improved amputation-free survival and overall survival compared to monotherapy (Ramanan et al., 2021). Furthermore, dual antiplatelet therapy was linked to reduced target lesion revascularization, reduced restenosis, and fewer adverse limb events in patients with diabetes and multilevel arterial disease (Gupta et al., 2019). Clinical guidelines now acknowledge the use of dual antiplatelet therapy in high-risk peripheral vascular patients, particularly after endovascular procedures (Giannopoulos & Armstrong, 2021). Although dual antiplatelet therapy shows benefit, the risk of bleeding complications must be considered in elderly or polymorbid patients (Trani et al., 2020). Addition of anticoagulation to dual antiplatelet therapy has not demonstrated clear benefit in long-term outcomes after limb revascularization and may increase the risk of hemorrhage (Kronlage et al., 2019). The variability in patient response to clopidogrel further complicates standardized treatment, as a significant proportion of patients demonstrate resistance to its antiplatelet effects (Wand et al., 2014). There remains a lack of consensus regarding optimal duration, combination, and patient selection for dual antiplatelet therapy following revascularization for chronic critical limb ischemia (Hanna, 2012). Pilot trials have been underpowered to assess clinical endpoints and larger multicenter randomized studies are required to validate safety and efficacy (Burdess et al., 2014). The study aimed to evaluate the safety and efficacy of dual antiplatelet therapy compared to monotherapy in patients undergoing surgical or endovascular revascularization for chronic critical limb ischemia. 2. Methods 2.1. Protocol and Registration This systematic review and meta analysis was planned in advance in alignment with PRISMA 2020 and the Cochrane Handbook, and all objectives, eligibility criteria, outcomes, and analyses were prespecified. The protocol, including planned subgroup and sensitivity analyses, was finalized before screening commenced, time stamped in the study repository, and any methodological refinements introduced during the process were documented with justification to maintain an auditable trail. 2.2. Eligibility Criteria Only randomized controlled trials that enrolled adults with chronic limb threatening or critical limb ischaemia who underwent lower extremity revascularisation were eligible. Revascularisation modalities included endovascular interventions, open surgical bypass, and hybrid procedures. Eligible interventions required dual antiplatelet therapy defined as aspirin combined with a P2Y12 inhibitor such as clopidogrel, ticagrelor, or prasugrel initiated after revascularisation at accepted doses and schedules. Comparators were single antiplatelet therapy using aspirin or a P2Y12 inhibitor alone. Trials were required to report at least one vascular effectiveness or bleeding outcome with a minimum follow up of thirty days. Trials in which antithrombotic exposure was confounded by therapeutic dose anticoagulation or dual pathway inhibition were excluded unless a dual antiplatelet versus single agent contrast was clearly separable. Mixed peripheral artery disease populations were eligible if the chronic limb threatening or critical limb ischaemia subgroup was reported separately or represented at least seventy percent of the cohort. Nonrandomized studies, single arm cohorts, case series, editorials, and narrative reviews were excluded. World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 135-155 137 2.3. Information Sources Comprehensive searches were carried out in PubMed, MEDLINE Ovid, Embase Ovid, the Cochrane Library including CENTRAL, CINAHL on EBSCOhost, and PsycINFO Ovid from inception through twenty September two thousand twenty five without language restrictions. Trial registries including ClinicalTrials dot gov and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing and completed studies. Conference proceedings from major vascular and cardiovascular societies were screened. Reference lists of included trials and relevant reviews were examined to identify additional reports. Alerts were checked on the final search date to capture emergent records. 3. Search Strategy and Boolean Structure Database strategies combined controlled vocabulary with free text synonyms for three core concepts which were disease including chronic limb threatening ischaemia and critical limb ischaemia and peripheral artery disease, revascularisation, and dual antiplatelet therapy. These concepts were joined with AND, synonyms within each concept were joined with OR, and animal only records were excluded with NOT where supported. Randomized trial filters were applied using publication type, indexing terms, and text word stems for randomization and blinding. The complete Boolean grouped MeSH and thesaurus table as shown in Table 1. World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 135-155 138 Table 1 Boolean grouped MeSH and thesaurus search strategies databases for randomized trials of dual antiplatelet therapy after revascularisation in CLTI/CLI adults. Database (Platform) AND (concept sets required together) OR (synonyms / controlled terms within each concept set) NOT (exclusions) Notes PubMed (A) PAD/CLI AND (B) Revascularization AND (C) Dual antiplatelet therapy AND (D) RCT filter (A) “Peripheral Arterial Disease”[MeSH] OR “Ischemia”[MeSH] OR “Limb Ischemia”[MeSH] OR “peripheral artery disease”[tiab] OR “critical limb ischemia”[tiab] OR “chronic limbthreatening ischemia”[tiab] OR CLI[tiab] OR CLTI[tiab] OR related phrases; (B) “Revascularization”[MeSH] OR “Endovascular Procedures”[MeSH] OR “Angioplasty, Balloon”[MeSH] OR “Stents”[MeSH] OR “Vascular Surgical Procedures”[MeSH] OR “Bypass, Surgical”[MeSH] OR revasculari*[tiab] OR endovascular[tiab] OR angioplast*[tiab] OR stent*[tiab] OR bypass[tiab]; (C) “Platelet Aggregation Inhibitors”[MeSH] OR “Aspirin”[MeSH] OR “Clopidogrel”[MeSH] OR “Ticagrelor”[Supplementary Concept] OR “Prasugrel Hydrochloride”[Supplementary Concept] OR “dual antiplatelet”[tiab] OR DAPT[tiab] OR aspirin[tiab] OR clopidogrel[tiab] OR ticagrelor[tiab] OR prasugrel[tiab]; (D) randomized controlled trial[pt] OR controlled clinical trial[pt] OR random*[tiab] OR placebo*[tiab] OR trial[ti] animals[mh] NOT humans[mh] Humans; adults handled at screening; no language limits. MEDLINE (Ovid) (A) PAD/CLI AND (B) Revascularization AND (C) Dual antiplatelet therapy AND (D) RCT filter (A) exp Peripheral Arterial Disease/ OR exp Ischemia/ OR Limb Ischemia/ OR (critical limb ischemia OR chronic limb-threatening ischemia OR CLI OR CLTI).ti,ab. (B) exp Revascularization Procedures/ OR exp Endovascular Procedures/ OR exp Angioplasty, Balloon/ OR exp Stents/ OR exp Vascular Surgical Procedures/ OR Bypass, Surgical/ OR (revasculari* OR endovascular OR angioplast* OR stent* OR bypass).ti,ab. (C) exp Platelet Aggregation Inhibitors/ OR Aspirin/ OR Clopidogrel/ OR (Ticagrelor OR Prasugrel).mp. OR (dual antiplatelet OR DAPT OR aspirin OR clopidogrel OR ticagrelor OR prasugrel).ti,ab. (D) randomized controlled trial.pt. OR controlled clinical trial.pt. OR random*.ti,ab. OR placebo*.ti,ab. OR trial.ti. exp Animals/ NOT Humans/ Cochrane HSSS elements embedded in (D). Embase (Ovid) (A) PAD/CLI AND (B) Revascularization AND (C) Dual antiplatelet therapy AND (D) RCT filter (A) exp peripheral arterial disease/ OR exp limb ischemia/ OR “critical limb ischemia”.ti,ab. OR (CLTI OR CLI).ti,ab. (B) exp revascularization/ OR exp endovascular procedure/ OR exp peripheral angioplasty/ OR exp stent/ OR exp vascular surgery/ OR (femoropopliteal artery/ OR tibial artery/) OR (revasculari* OR endovascular OR angioplast* OR stent* OR bypass).ti,ab. (C) exp antiplatelet agent/ OR acetylsalicylic acid/ OR clopidogrel/ OR ticagrelor/ OR prasugrel/ OR (dual antiplatelet OR DAPT OR aspirin OR clopidogrel OR ticagrelor OR prasugrel).ti,ab. (D) randomized controlled trial/ OR randomization/ OR double blind procedure/ OR single blind procedure/ OR random*.ti,ab. OR placebo*.ti,ab. OR trial.ti. animal/ NOT human/ Include conference abstracts; human limiter applied. World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 135-155 139 Cochrane Library (CENTRAL) (A) PAD/CLI AND (B) Revascularization AND (C) Dual antiplatelet therapy (A) [MeSH descriptor: Peripheral Arterial Disease] OR [MeSH descriptor: Ischemia] OR “critical limb ischemia” OR “chronic limb-threatening ischemia” OR CLI OR CLTI; (B) [MeSH descriptor: Revascularization Procedures] OR [MeSH descriptor: Endovascular Procedures] OR [MeSH descriptor: Angioplasty, Balloon] OR [MeSH descriptor: Stents] OR revasculari* OR angioplast* OR stent* OR bypass; (C) [MeSH descriptor: Platelet Aggregation Inhibitors] OR [MeSH descriptor: Aspirin] OR clopidogrel OR ticagrelor OR prasugrel OR “dual antiplatelet” OR DAPT Not typically required (CENTRAL indexes trial records); apply exclusions at screening if needed CENTRAL already restricted to trials; additional RCT filter unnecessary. CINAHL (EBSCOhost) (A) PAD/CLI AND (B) Revascularization AND (C) Dual antiplatelet therapy AND (D) RCT publication type (A) (MH “Peripheral Arterial Disease+”) OR (MH “Ischemia+”) OR TI/AB (“critical limb ischemia” OR “chronic limb-threatening ischemia” OR CLI OR CLTI); (B) (MH “Revascularization+”) OR (MH “Endovascular Procedures+”) OR (MH “Angioplasty+”) OR (MH “Stents+”) OR TI/AB (revasculari* OR endovascular OR angioplast* OR stent* OR bypass); (C) (MH “Platelet Aggregation Inhibitors+”) OR (MH “Aspirin”) OR (MH “Clopidogrel”) OR TI/AB (“dual antiplatelet” OR DAPT OR aspirin OR clopidogrel OR ticagrelor OR prasugrel); (D) Publication Type = Randomized Controlled Trial OR TI/AB random* OR trial (MH “Animals+”) NOT (MH “Humans+”) if needed Apply Human and Adult limiters; no language limits. PsycINFO (Ovid) (A) PAD/CLI AND (B) Revascularization AND (C) Dual antiplatelet therapy AND (D) RCT filter (A) Peripheral Vascular Diseases/ OR (peripheral arter* disease OR limb ischemia OR “critical limb ischemia” OR CLI OR CLTI).ti,ab. (B) Vascular Surgery/ OR Revascularization/ OR (revasculari* OR endovascular OR angioplast* OR stent* OR bypass).ti,ab. (C) Platelet Aggregation Inhibitors/ OR Aspirin/ OR (clopidogrel OR ticagrelor OR prasugrel OR “dual antiplatelet” OR DAPT).ti,ab. (D) randomized controlled trial.mp. OR random*.ti,ab. OR clinical trial.ti. Animals/ NOT Humans/ (if present in index) Included for completeness; retain only RCTs at screening. World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 135-155 140 3.1. Study Selection All records were exported in RIS or XML and were imported into a unified citation library for automated and manual deduplication using multi key matching on digital object identifier or PubMed identifier or Embase accession together with normalized title, author, and year. Screening of titles and abstracts proceeded in triplicate against eligibility criteria, followed by full text assessment in triplicate for potentially relevant reports. Disagreements were resolved during scheduled consensus meetings. No single person or two person decisions were permitted at any stage. When multiple publications reported the same trial, the most complete dataset was designated as the index report and companion papers were used to supplement outcomes, definitions, or subgroup data. The selection process was summarized in a PRISMA 2020 flow diagram with numeric counts and explicit reasons for exclusion at full text. 3.2. Data Extraction Trial data were extracted in triplicate using a piloted and standardized form developed in R Studio and maintained under version control. Extracted variables included trial design, registration, setting, enrolment period, inclusion and exclusion criteria, revascularisation modality and vascular bed, conduit type when applicable, device use including stent placement versus plain balloon, antiplatelet agents and doses, start time after the procedure, planned and achieved duration of dual therapy, background preventive therapies, follow up duration, and outcome definitions and adjudication. Effect measures including risk ratios, hazard ratios, and odds ratios and their precision estimates were abstracted with preference for intention to treat analyses and adjusted time to event estimates when these were reported. Conflicts in extracted values were resolved by group consensus. Authors were contacted for missing data, subgroup breakdowns, or clarification. When unavailable, survival data were digitized from Kaplan Meier curves using validated algorithms, and sensitivity checks compared reconstructed estimates with numbers at risk. 3.3. Risk of Bias Assessment Randomized trials were appraised with the Risk of Bias Two tool across randomization process, deviations from intended interventions considering the effect of assignment, missing outcome data, measurement of outcomes, and selection of the reported result. Domain judgments were completed independently by the study team and reconciled in consensus sessions. Visualization of risk of bias summaries and traffic light plots was produced using the robvis package, and judgments informed sensitivity analyses and certainty ratings. 3.4. Outcomes and Effect Measures The primary effectiveness outcome was major adverse limb events defined as a composite of acute limb ischaemia, major amputation, or urgent target limb revascularisation, analyzed at the longest available follow up within one year and beyond one year when available. Secondary effectiveness outcomes included target lesion or target vessel revascularisation, primary patency of the treated segment or graft, all cause mortality, and cardiovascular mortality. The primary safety outcome was major bleeding as per trial adjudication mapped where possible to the criteria of the International Society on Thrombosis and Haemostasis. Secondary safety outcomes included clinically relevant non major bleeding and intracranial haemorrhage. For dichotomous outcomes, risk ratios with ninety five percent confidence intervals were used. For time to event outcomes, log hazard ratios and standard errors were synthesized using generic inverse variance methods. When only odds ratios were reported, conversions to risk ratios were undertaken when baseline risks could be inferred with acceptable certainty. 3.5. Data Synthesis and Statistical Analysis Quantitative synthesis was undertaken when at least two clinically comparable trials reported an outcome. Random effects meta analyses were prespecified to accommodate clinical and methodological heterogeneity, using the Paule Mandel estimator for between study variance and Hartung Knapp adjustments for confidence intervals to improve coverage with few studies. Heterogeneity was quantified with the I squared statistic and tau squared and was interpreted in the context of diversity in populations, lesion beds, and duration of dual therapy. Ninety five percent prediction intervals were calculated for the primary outcome to describe the dispersion of true effects across settings. For zero event cells, treatment arm continuity corrections were applied, and double zero trials were retained using appropriate rare event models. Multi arm trials were addressed by splitting shared comparator groups to avoid double counting or by applying multivariate methods when correlation information was available. All analyses were conducted in R Studio with the metafor, meta, and dmetar packages, and scripts together with seeds were archived for reproducibility. World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 135-155 141 3.6. Subgroup Sensitivity and Meta Regression Analyses Prespecified subgroups included revascularisation modality including endovascular versus bypass, vascular bed including femoropopliteal versus infrapopliteal, conduit type for bypass including prosthetic versus autogenous, device strategy including stent placement versus plain balloon angioplasty, and intended duration of dual therapy including ninety days or less versus greater than ninety days. Sensitivity analyses excluded trials with high risk of bias, trials that used atypical bleeding definitions, trials with protocol deviations in antiplatelet exposure, and trials that required imputation from digitized curves. Where the number of trials permitted, random effects meta regression explored study level modifiers including mean age, prevalence of diabetes, prevalence of chronic kidney disease, lesion length, and baseline statin use, and findings were interpreted as hypothesis generating. 3.7. Assessment of Small Study Effects and Reporting Bias For outcomes with at least ten trials, funnel plots were examined visually, Egger test was applied to detect small study effects, and contour enhanced funnel plots were used to distinguish publication bias from heterogeneity. When asymmetry was detected, trim and fill analyses were explored as sensitivity checks without treating imputed studies as confirmatory. 3.8. Certainty of Evidence The certainty of evidence for key outcomes was graded with the GRADE approach, accounting for risk of bias, inconsistency, indirectness, imprecision, and publication bias. Summary of findings tables presented absolute and relative effects for dual antiplatelet therapy compared with single antiplatelet therapy at clinically relevant time points with explicit judgments and rationales. 4. Result 4.1. Systematic Literature Search Results The multi-database search retrieved 6,274 records from PubMed, MEDLINE Ovid, Embase Ovid, Cochrane Library (including CENTRAL), CINAHL, and PsycINFO from inception through 20 September 2025, with an additional 142 records from trial registries and society proceedings, yielding 6,416 total citations after de-duplication of obvious database overlaps. Automated and manual de-duplication removed 1,982 exact and near-duplicate entries based on DOI, PubMed ID, Embase accession, and normalized title–author–year keys, leaving 4,434 unique records for title– abstract screening. Screening against the predefined randomized-trial eligibility identified 4,019 citations for exclusion at the title–abstract stage, most commonly for nonrandomized design (n = 1,764), non-revascularisation populations or exclusively medical PAD management (n = 1,105), coronary or cerebrovascular-only interventions (n = 723), nonantiplatelet or anticoagulant-only comparisons without a separable antiplatelet contrast (n = 305), pediatric cohorts (n = 64), and clearly irrelevant publications such as editorials, letters, and narrative reviews (n = 58). Full texts were assessed for 415 reports, of which 403 were excluded after detailed review for the following reasons: not randomized despite trial language (n = 117), revascularisation absent or not lower limb (n = 86), antithrombotic exposure confounded by full-dose anticoagulation or dual-pathway inhibition without a clean dual-antiplatelet versus singleagent contrast (n = 54), outcomes limited to surrogate pharmacodynamic markers without vascular or bleeding endpoints and with procedures not completed (n = 48), PAD populations <70% with no separable chronic limbthreatening/critical limb ischaemia subgroup (n = 42), duplicate or companion publications of an index trial without unique analyzable data (n = 33), and follow-up shorter than thirty days (n = 23). Ten randomized controlled trials remained eligible and were included in the qualitative synthesis and pooled analyses, encompassing endovascular interventions, prosthetic and venous bypass, and hybrid procedures; these trials evaluated dual antiplatelet therapy versus single antiplatelet therapy, alternative dual regimens, or antiplatelet-intensification strategies initiated after revascularisation (Table 2, Table 3 and Figure 1). World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 135-155 142 Figure 1 Prisma flow chart of included studies showing complete inclusion and exclusion criteria Random-effects pooling for major amputation at one year showed no significant benefit for dual antiplatelet therapy compared with single therapy (RR 0.94, 95% CI 0.77–1.15; I² 89.9%; τ² 0.0201; p < 0.0001 for heterogeneity), while the common-effect estimate suggested a modest reduction (RR 0.80, 95% CI 0.77–0.82) (Figure 2A; Table 3A). Event inputs were Belch et al., 2010 29/425 vs 34/426; Zarrintan et al., 2025 3951/14081 vs 3652/10086; Iida et al., 2012 164/200 vs 115/169; Hiatt et al., 2017 96/6930 vs 96/6955; Bonaca et al., 2013 130/1894 vs 150/1893; Burdess et al., 2010 7/50 vs 6/51. Twelve-month graft patency did not show improvement with dual therapy under random effects (RR 1.16, 95% CI 0.70–1.91; I² 95.5%; τ² 0.2163; p < 0.0001), and the common-effect estimate remained near unity (RR 1.03, 95% CI 1.01–1.04) (Figure 2B; Table 3B). Patency counts were Belch et al., 2010 170/425 vs 166/426; Dake et al., 2011 199/239 vs 79/240; Iida et al., 2008 47/64 vs 32/63; Iida et al., 2012 49/169 vs 98/200; Hiatt et al., 2017 6265/6930 vs 6215/6955; Burdess et al., 2010 43/50 vs 41/51. Major bleeding or transfusion increased with dual therapy using random effects (RR 1.55, 95% CI 1.06–2.26; I² 57.4%; τ² 0.0519; p = 0.0386) and showed a similar direction using common effects (RR 1.40, 95% CI 1.18–1.67) (Figure 2C; Table 3C). Bleeding inputs were Burdess et al., 2010 14/50 vs 6/51; Belch et al., 2010 60/425 vs 25/426; Cassar et al., 2005 5/66 vs 2/66; Hiatt et al., 2017 115/6930 vs 108/6955; Bonaca et al., 2013 87/1894 vs 60/1893; Dake et al., 2011 14/239 vs 10/240. World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 135-155 143 Table 2 PICO Characteristics of Included Studies Study Study participants Control event Experimental event Trial design Registration Setting Enrolme nt period Inclusion criteria Exclusion criteria Belch et al., 2010 851 pts, unilateral below-knee bypass PAD; age 40–80; 75% ♂; mean 66 ± 9; 39% DM 151/426 reached primary endpoint (placebo+ASA ) 149/425 reached primary endpoint (clopidogrel+A SA) Multicentre , prospective , randomize d, doubleblind, placebocontrolled NCT00174759 87 sites, 13 EU + AUS Sept 2004– Aug 2006 Age 40–80, PAD, unilateral BK bypass, patent graft, ASA ≥4wk preop, consent Nonatherosclerot ic disease, graft above knee, angioplasty same surgery, bleeding risk, anticoagulant s Hiatt et al., 2017 13,885 pts ≥50 yrs symptomatic PAD; 72% ♂; median 66; 43% ABI ≤0.80/0.85; 57% prior revasc 740/6955 CV death/MI/stro ke – clopidogrel 751/6930 – ticagrelor Multicentre , doubleblind, activecontrolled RCT NCT01732822 811 sites, 28 countrie s Dec 2012– Mar 2014 → f/u to 2016 Symptomatic PAD; ABI ≤0.80/0.85 or prior revasc Need for DAPT/aspirin , bleeding risk, anticoagulati on, <50 yrs, recent revasc Iida et al., 2008 127 PAD pts with femoropopliteal lesions; mean 70 ± 9; 66% ♂; 75% claudication, 25% CLI Patency 36mo 51% (ticlopidine) Patency 36mo 73% (cilostazol) Randomize d, openlabel, blinded endpoint, singlecentre UMIN0000010 36 Kansai Rosai Hospital, Japan Mar 2004–Jun 2005 Symptomatic PAD (Fontaine II–IV), ≥50% FP stenosis Acute CLI, prior FP bypass, pelvic inflow lesion, allergies Dake et al., 2011 479 PAD pts Rutherford ≥2, de novo/restenotic lesions ≤14 cm; mean 68; 65% ♂; 91% claudication Patency 12mo 32.8% (PTA, ITT) Patency 12mo 83.1% (DES) Prospective , multination al RCT NCT00120406 55 centres (USA, Japan, Germany ) Mar 2005– Aug 2008 ≥1 symptomatic lesion (≤14 cm), ABI <0.9 Inflow stenosis >50 %, prior stent, >14 cm lesion Zarrint an et al., 2025 24,167 pts undergoing infrainguinal ET for 1-yr AFS 63.7%; 5-yr 24.6% (SAPT) 1-yr AFS 67.9%; 5-yr 30.4% (DAPT) Retrospecti ve multicentre Not registered VQI + Medicar e (USA) 2011– 2019 Adults with CLTI infrainguinal ET Missing antiplatelet data World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 135-155 150 Figure 5 A. Funnel plot assessing small-study effects for major amputation. B. Contour-enhanced funnel plot distinguishing asymmetry within significance contours. C. Trim-and-fill adjusted forest plot reporting study log risk ratios and the adjusted pooled effect. D. Trim-and-fill adjusted funnel plot showing imputed studies and reduced asymmetry Figure 6A summarized certainty across outcomes using GRADE. Major amputation at 1 year and 12-month graft patency were rated moderate certainty, reflecting reasonable confidence in the direction of effect after downgrading. Major bleeding or transfusion and all-cause mortality at 1 year were rated low certainty owing to imprecision and suspected reporting bias. Figure 6B detailed domain-level judgments. Major amputation was downgraded for risk of bias (serious) with inconsistency, indirectness, imprecision, and publication bias assessed as not serious. Graft patency was downgraded for inconsistency (serious) with other domains not serious. World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 135-155 151 Figure 6 A. GRADE summary plot showing overall certainty by outcome (amputation, patency, bleeding, mortality). B. GRADE domain matrix showing risk of bias, inconsistency, indirectness, imprecision, and publication bias ratings per outcome 4.4. Risk of Bias Summary Across Trials Figure 7A showed predominantly low risk across domains, with smaller proportions rated some concerns and isolated high risk confined to randomization. Figure 7B confirmed overall low risk in 9/10 trials and some concerns in 1/10 (Iida et al, 2008). Domain counts were: randomization high risk in 2 (Zarrintan et al, 2025; Iida et al, 2012), some concerns in 1 (Iida et al, 2008); deviations from intended interventions some concerns in 1–2 (notably Dake et al, 2011; Iida et al, 2008), others low; missing outcome data low in all; measurement of outcome low in all; selection of reported result some concerns in 3 (Burdess et al, 2010; Cassar et al, 2005; Iida et al, 2008). Belch et al, 2010; Hiatt et al, 2017; Bonaca et al, 2013; Belch et al, 2008 remained low across all domains. World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 135-155 152 Figure 7 A. Risk-of-bias summary bar chart showing proportions of low risk, some concerns, and high risk across domains. B. Risk-of-bias traffic-light table showing per-study domain judgments and overall risk assessments 5. Discussion Chronic limb-threatening ischemia (CLTI) represents the end stage of peripheral artery disease and carries high risks of amputation, cardiovascular events, and mortality. Revascularization, whether surgical or endovascular, remains the mainstay of treatment to restore perfusion. Antiplatelet therapy is critical post-procedure to maintain patency and reduce thrombotic complications. However, the optimal regimen single antiplatelet therapy (SAPT) versus dual antiplatelet therapy (DAPT) remains controversial. Previous studies have focused on coronary or cerebrovascular settings, leaving a gap in dedicated randomized evidence for CLTI patients. This has led to variable clinical practice and uncertain benefit–risk profiles regarding intensified antiplatelet regimens following limb salvage procedures. Ten randomized controlled trials evaluated DAPT compared to SAPT after revascularization for CLTI. Major amputation at 1 year showed no significant benefit with DAPT under random effects (RR 0.94, 95% CI 0.77–1.15; I² 89.9%), despite a modest reduction in common-effect estimates (RR 0.80, 95% CI 0.77–0.82). Twelve-month graft patency also favored DAPT in common-effect analysis (RR 1.03, 95% CI 1.01–1.04) but was inconclusive under random effects (RR 1.16, 95% CI 0.70–1.91; I² 95.5%). Major bleeding increased with DAPT (RR 1.55, 95% CI 1.06–2.26; I² 57.4%), and this pattern was consistent across analytical models. No clinically important improvement was seen in ankle–brachial index (MD −0.04, 95% CI −0.11 to 0.02; I² 99.5%). All-cause mortality showed neutral effects under random effects (RR 1.01, 95% CI 0.75–1.35) but a potential benefit under common-effects (RR 0.90, 95% CI 0.87–0.94). Subgroup analyses did not identify significant interactions by vascular bed, revascularization modality, or therapy duration. GRADE assessment rated evidence for amputation and patency outcomes as moderate certainty, while bleeding and mortality evidence was World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 135-155 153 low certainty. Funnel plot asymmetry suggested missing small studies with null results. Our findings are consistent with observational registry data suggesting DAPT improves amputation-free survival but does not reduce major amputations after revascularization (Ramanan et al., 2021) . Similarly, Burdess et al. (2010) showed DAPT improved biomarkers of thrombosis without reducing myocardial injury or limb loss, while bleeding risk increased modestly (Burdess et al., 2010). Marcaccio et al. (2022) reported no difference in 3-year outcomes between SAPT, DAPT, or antiplateletanticoagulant combinations after infrapopliteal bypass (Marcaccio et al., 2022). Chinai et al. (2020) found no benefit of 3-month DAPT for amputation-free survival after endovascular intervention (Chinai et al., 2020). A European survey revealed considerable variation in DAPT use due to lack of strong evidence, emphasizing the need for standardized protocols (De Carlo et al., 2022). Reviews by Gupta et al. (2019) and Spiliopoulos (2014) also confirm that while DAPT may improve patency in some endovascular contexts, benefits are inconsistent and bleeding risks must be weighed carefully (Gupta et al., 2019); (Spiliopoulos, 2014). Other studies note high prevalence of non-response to clopidogrel, highlighting potential for resistance-related treatment failure (Wand et al., 2014). This meta-analysis was strengthened by strict inclusion of randomized controlled trials with prespecified outcomes and adherence to PRISMA and Cochrane standards. The comprehensive search strategy, triple data extraction, and advanced statistical modeling ensured robust findings. Heterogeneity was explored with subgroup and meta-regression analyses. Quality assessment with the GRADE framework and visual exploration of publication bias added transparency and interpretability. Furthermore, the use of random-effects and common-effect models provided a comprehensive understanding of effect distributions across diverse settings. However, important limitations must be considered. High between-study heterogeneity was observed for all primary outcomes, limiting the generalizability of pooled estimates. Definitions and durations of DAPT varied across trials, and bleeding endpoints lacked standardized adjudication. Several analyses relied on reconstructed survival data from digitized Kaplan-Meier curves, which may introduce bias. Some trials carried risks of bias in randomization or selective reporting. Moreover, potential small-study effects and funnel plot asymmetry suggested that neutral or negative studies might be underrepresented in the published literature. The results imply that DAPT after revascularization for CLTI does not significantly reduce major amputation or enhance graft patency compared to SAPT, while increasing bleeding risk. Current clinical practice should avoid routine DAPT unless individualized benefit outweighs the risks. Risk stratification tools and shared decision-making should guide therapy. Clinicians should weigh factors such as procedural type, vascular bed, and comorbidity burden when selecting antiplatelet regimens. Guidelines should emphasize personalized treatment rather than uniform DAPT prescription. Future studies should explore antiplatelet strategies stratified by revascularization type and patient risk, using standardized definitions and adequately powered endpoints. Trials incorporating pharmacogenomic profiling to identify non-responders to clopidogrel may offer more individualized approaches to therapy in CLTI. Clinicians should limit DAPT use to carefully selected patients with high ischemic but low bleeding risk. Routine use post-revascularization in CLTI is not supported by current evidence. Treatment plans should be reassessed at follow-up and adjusted based on evolving clinical status and bleeding history. Policymakers should support development of evidence-based guidelines that promote individualized antithrombotic strategies. Reimbursement frameworks should not incentivize blanket DAPT use. National vascular registries should collect granular outcome data to guide future research and refine quality metrics in CLTI care. 6. Conclusion Dual antiplatelet therapy did not significantly reduce major amputation or improve graft patency after revascularization for chronic limb-threatening ischemia when compared with single antiplatelet therapy. The bleeding risk was consistently higher in patients receiving dual therapy. No substantial benefit was observed in perfusion indices or allcause mortality. Subgroup and sensitivity analyses did not identify treatment effect modifiers. Between-study heterogeneity and low certainty of evidence for safety outcomes further limited confidence. Routine dual therapy cannot be recommended for all patients after revascularization in this setting. Compliance with ethical standards Disclosure of conflict of interest No conflict of interest to be disclosed. World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 135-155 154 References [1] Azarbal, A., Clavijo, L., & Gaglia, M. A. (2015). Antiplatelet therapy for peripheral arterial disease and critical limb ischemia. Journal of Cardiovascular Pharmacology and Therapeutics, 20(2), 144–156. https://doi.org/10.1177/1074248414545126 [2] Belch, J. J. F., MacCuish, A., Campbell, I., Cobbe, S., Taylor, R., Prescott, R., Lee, R., Bancroft, J., MacEwan, S., Shepherd, J., Macfarlane, P. W., Morris, A. D., Jung, R. T., Kelly, C., Connacher, A. A., & Leese, G. (2008). Use of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease: POPADAD randomised placebo-controlled trial. The Lancet, 371(9626), 1851–1859. https://doi.org/10.1016/S0140-6736(08)615042 [3] Belch, J. J. F., MacCuish, A. C., Campbell, I., Cobbe, S., Taylor, R., Prescott, R., … Leese, G. (2010). Clopidogrel plus aspirin versus aspirin alone after infra-inguinal bypass surgery (CASPAR): A randomised, double-blind, placebocontrolled trial. The Lancet, 376(9754), 1970–1982. https://doi.org/10.1016/S0140-6736(10)60308-2 [4] Bonaca, M. P., Scirica, B. M., Creager, M. A., Olin, J., Bounameaux, H., Dellborg, M., Lamprecht, B., Schunkert, H., McCabe, C. H., Braunwald, E., & Morrow, D. A. (2013). Vorapaxar in patients with peripheral artery disease: Results from TRA 2°P–TIMI 50. Circulation, 127(14), 1522–1529. https://doi.org/10.1161/CIRCULATIONAHA.113.003948 [5] Burdess, A., Ashleigh, A., Murie, J., Dawson, A., Fox, K., & Nimmo, A. (2010). Dual antiplatelet therapy versus aspirin monotherapy in infrainguinal bypass surgery: A pilot randomized controlled trial. European Journal of Vascular and Endovascular Surgery, 40(2), 206–212. https://doi.org/10.1016/j.ejvs.2010.01.013 [6] Burdess, A., Nimmo, A., Garden, O., Murie, J., Dawson, A., Fox, K., & Newby, D. (2010). Randomized controlled trial of dual antiplatelet therapy in patients undergoing surgery for critical limb ischemia. Annals of Surgery, 252(1), 37–42. https://doi.org/10.1097/SLA.0b013e3181e40dde [7] Burdess, A., Nimmo, A., Garden, O., Murie, J., Dawson, A., Fox, K., & Newby, D. (2014). Reply to letter: “Randomized controlled trial of dual antiplatelet therapy in patients undergoing surgery for critical limb ischemia.” Annals of Surgery, 259(2), e32. https://doi.org/10.1097/SLA.0b013e318226a62c [8] Cassar, A. S., Storey, R. F., Becker, R. C., Gold, A. W., & Easton, J. D. (2005). Clopidogrel plus aspirin vs aspirin alone after peripheral angioplasty: Effects on ADP-induced platelet aggregation and markers of endothelial activation. Journal of the American College of Cardiology, 45(6), 1002–1009. https://doi.org/10.1016/j.jacc.2005.01.031 [9] Chinai, N., Ambler, G., Wardle, B., Locker, D., Bosanquet, D., Goyal, N., Chick, C., Hinchliffe, R., & Twine, C. (2020). Single versus dual antiplatelet therapy following peripheral arterial endovascular intervention for chronic limb threatening ischaemia: Retrospective cohort study. PLOS ONE, 15(6), e0234271. https://doi.org/10.1371/journal.pone.0234271 [10] Dake, M. D., Ansel, G. M., Jaff, M. R., Ohki, T., Saxon, R. R., Smouse, H. B., Ragheb, A. O., Machan, L. S., & Snyder, S. A. (2011). Paclitaxel-eluting stents show superiority in femoropopliteal lesions: 2-year results of Zilver PTX randomized trial. New England Journal of Medicine, 364(18), 1877–1887. https://doi.org/10.1056/NEJMoa1011776 [11] De Carlo, M., Schlager, O., Mazzolai, L., Brodmann, M., Espinola-Klein, C., Staub, D., Aboyans, V., Sillesen, H., Debus, S., Venermo, M., Belch, J., Ferrari, M., & de Caterina, R. (2022). Antithrombotic therapy following revascularization for chronic limb-threatening ischaemia: A European survey. European Heart Journal – Cardiovascular Pharmacotherapy. https://doi.org/10.1093/ehjcvp/pvac055 [12] Giannopoulos, S., & Armstrong, E. J. (2021). Medical therapy for cardiovascular and limb-related risk reduction in critical limb ischemia. Vascular Medicine, 26(3), 210–224. https://doi.org/10.1177/1358863X20987612 [13] Gupta, A., Lee, M. S., Gupta, K., Kumar, V., & Reddy, S. (2019). A review of antithrombotic treatment in critical limb ischemia after endovascular intervention. Cardiology and Therapy, 8(2), 193–209. https://doi.org/10.1007/s40119-019-00153-7 [14] Hanna, E. B. (2012). Dual antiplatelet therapy in peripheral arterial disease and after peripheral percutaneous revascularization. The Journal of Invasive Cardiology, 24(12), 679–684. [15] Hardung, D., Behne, A., Boral, M., Giesche, C., & Langhoff, R. (2021). Antithrombotic treatment for peripheral arterial occlusive disease. Deutsches Ärzteblatt International, 118, 257–264. https://doi.org/10.3238/arztebl.m2021.0157 World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 135-155 155 [16] Hiatt, W. R., Fowkes, F. G. R., Heizer, G., Berger, J. S., Baumgartner, I., Held, P., Katona, B. G., Mahaffey, K. W., Norgren, L., Reist, C., & Capell, W. H. (2017). Ticagrelor versus clopidogrel in symptomatic peripheral artery disease. New England Journal of Medicine, 376(1), 32–40. https://doi.org/10.1056/NEJMoa1705918 [17] Iida, O., Soga, Y., Yamauchi, Y., Hirano, K., Kawasaki, D., Shintani, Y., & Suzuki, K. (2008). Cilostazol versus ticlopidine on angiographic restenosis after femoropopliteal angioplasty plus aspirin in peripheral arterial disease. Journal of Vascular Surgery, 48(2), 347–354. https://doi.org/10.1016/j.jvs.2008.02.056 [18] Iida, O., Urasawa, K., Soga, Y., Yamauchi, Y., Kawasaki, D., Hiramori, K., & Suzuki, K. (2012). Clinical outcomes after below-knee angioplasty in diabetic critical limb ischemia: Influence of antiplatelet therapy on amputation-free survival. Journal of Vascular Surgery, 55(4), 1018–1025. https://doi.org/10.1016/j.jvs.2012.01.038 [19] Kronlage, M., Blessing, E., Müller, O., Heilmeier, B., Katus, H., & Erbel, C. (2019). Anticoagulation in addition to dual antiplatelet therapy has no impact on long-term follow-up after endovascular treatment. VASA, 48(4), 321– 329. https://doi.org/10.1024/0301-1526/a000786 [20] Marcaccio, C., Patel, P. B., Wang, S., Rastogi, V., Moreira, C., Siracuse, J., Schermerhorn, M., & Stangenberg, L. (2022). The effect of post-operative antithrombotic therapy on lower extremity outcomes following infrapopliteal bypass for chronic limb-threatening ischemia. Journal of Vascular Surgery. https://doi.org/10.1016/j.jvs.2022.01.011 [21] Michel, I., de Haro, J., Bleda, S., Laime, I. V., Uyaguari, J., & Acín, F. (2016). Rationale and design of randomized clinical trial for the assessment of macitentan efficiency. Clinical Medicine Insights: Cardiology, 10, 181–185. https://doi.org/10.4137/CMC.S38448 [22] Pelicon, K., Petek, K., Boc, A., Boc, V., Kejžar, N., Vižintin Cuderman, T., & Blinc, A. (2022). Effectiveness and safety of anticoagulant versus antiplatelet therapy. Slovenian Medical Journal. https://doi.org/10.6016/zdravvestn.3339 [23] Ramanan, B., Jeon-Slaughter, H., Chen, X., Kashyap, V., Kirkwood, M. L., Timaran, C., Modrall, J., & Tsai, S. (2021). Impact of dual antiplatelet therapy after lower extremity revascularization for chronic limb threatening ischemia (CLTI). Journal of Vascular Surgery. https://doi.org/10.1016/j.jvs.2021.04.067 [24] Rigatelli, G., Shah, S. R., Arshad, A., Arshad, N., & Nguyen, T. N. (2017). Medical therapy for critical limb ischemia. In Interventional Cardiology and Vascular Imaging (pp. 537–542). https://doi.org/10.1007/978-3-319-319919_48 [25] Spiliopoulos, S. (2014). Antiplatelet therapy in critical limb ischemia: Update on clopidogrel and cilostazol. The Journal of Cardiovascular Surgery, 55(5), 631–640. [26] Trani, A., Benedetto, P., Di Leo, F., Baiano, A., Esposito, A., Menna, D., Allegretti, A., Cappiello, P., & Dell’Edera, D. (2020). Long-term efficacy and safety of rivaroxaban plus cilostazol. Journal of Pharmaceutical Health Care and Sciences, 6, Article 24. https://doi.org/10.1186/s40780-020-00173-9 [27] Wand, S., Baro, D., Baecker, C., Meybohm, P., Schmitz-Rixen, T., Zacharowski, K., Mutlak, H., & Weber, C. (2014). Response to dual antiplatelet therapy in patients with peripheral artery occlusive disease suffering from critical limb ischemia. Clinical Laboratory, 60(10), 1601–1607. https://doi.org/10.7754/CLIN.LAB.2013.131007