Functional Clopidogrel Resistance and CYP2C19 Genetic Determinants After Lower Limb Endovascular Intervention: A Systematic Review and Meta-analysis of Clinically Relevant Outcomes.
Aug 2026· Clinical Therapeutics· 0 citations· 22 references
Medicine
TL;DR
This is the first systematic review and meta-analysis to combine an updated quantitative synthesis of functional clopidogrel resistance with a dedicated qualitative appraisal of CYP2C19 genetic determinants, while explicitly separating analyses based on raw event data from exploratory analyses using published effect estimates and applying conservative small-sample sensitivity methods.
Abstract
Purpose
Clopidogrel is a cornerstone of antiplatelet therapy after lower-limb endovascular intervention in patients with peripheral arterial disease (PAD), yet interindividual variability in treatment response may influence clinical outcomes. To our knowledge, this is the first systematic review and meta-analysis to combine an updated quantitative synthesis of functional clopidogrel resistance with a dedicated qualitative appraisal of CYP2C19 genetic determinants, while explicitly separating analyses based on raw event data from exploratory analyses using published effect estimates and applying conservative small-sample sensitivity methods. We evaluated the association between functional clopidogrel resistance and clinically relevant limb outcomes-target lesion/target vessel revascularization (TLR/TVR) and major adverse limb events (MALE)-with all-cause mortality as a secondary exploratory outcome.
Methods
The review was conducted according to PRISMA 2020 and registered in PROSPERO (CRD42026129845). MEDLINE (PubMed), EMBASE, Web of Science, and Google Scholar were searched from inception to May 17, 2026. Functional resistance was defined as high on-treatment platelet reactivity (HTPR) assessed by platelet function testing, and genetic determinants as CYP2C19 loss-of-function alleles or metabolizer status associated with impaired clopidogrel response. Random-effects meta-analyses using restricted maximum likelihood (REML) were performed, with Hartung-Knapp-Sidik-Jonkman (HKSJ) sensitivity analyses and prediction intervals to quantify statistical uncertainty in sparse data. Genetic studies were synthesized qualitatively.
Findings
Ten studies met the inclusion criteria; 6 functional studies contributed to the quantitative analyses. In the primary analysis based on 3 studies with raw event data, HTPR was associated with an approximately 3.7-fold increase in TLR/TVR risk (odd ratios [OR] 3.68; 95% confidence interval [CI] 1.56-8.68; P = 0.003; I² = 59%). An exploratory analysis of 5 studies with published effect estimates was directionally consistent (OR 4.46; 95% CI 1.09-18.31; I² = 87%). HKSJ sensitivity analyses preserved the direction of effect but produced substantially wider confidence intervals crossing the null, indicating increased statistical uncertainty. HTPR was not significantly associated with all-cause mortality (OR 1.49; 95% CI 0.92-2.42).
IMPLICATIONS
Functional clopidogrel resistance may be associated with an approximately 3- to 4-fold higher risk of repeat revascularization after lower-limb endovascular intervention; however, the small number of studies, substantial heterogeneity, and conservative sensitivity analyses warrant cautious interpretation. Larger prospective studies and randomized trials are needed before platelet-function-guided or genotype-guided antiplatelet strategies can be recommended.
PROSPERO REGISTRATION
CRD42026129845.
OBJECTIVES
Peripheral artery disease (PAD) is a common atherosclerotic disorder characterized by progressive arterial narrowing in the limbs. This study aims to determine the efficacy and safety of rivaroxaban, focusing on major cardiovascular events, limb outcomes, and bleeding risks.
METHODS
PubMed, Cochrane, and EMBASE were searched for RCTs and non-randomized comparative studies that compared rivaroxaban, either alone or in combination with aspirin, to placebo or standard care such as antiplatelet therapy. Risk ratios and hazard ratios with 95% confidence intervals were pooled using R v4.5.1 with an appropriate random-effects model applied. Subgroup analyses were performed according to rivaroxaban plus aspirin versus rivaroxaban alone.
RESULTS
39,991 participants across six studies were included. Compared with control, use of rivaroxaban was linked to a significant reduction in composite efficacy outcomes (RR= 0.84, 95%CI 0.78-0.91, p<0.001), risk of acute limb ischemia (RR= 0.65, 95% CI 0.55-0.78, p<0.001), and thromboembolism (RR= 0.60, 95% CI 0.38-0.97, p=0.037). Although rivaroxaban plus aspirin failed to show a significant reduction in the risk of amputation, rivaroxaban alone reported a significant risk reduction (RR=0.50, 95% CI 0.30-0.85, p=0.003). However, its use was associated with a significantly higher risk of major bleeding (HR=1.54, 95% CI 1.38-1.72, p<0.001) and International Society of Thrombosis and Hemostasis-defined bleeding (RR= 1.45, 95% CI 1.19-1.76, p<0.001). No significant differences were observed for stroke, myocardial infarction, major adverse limb events, fatal bleeding, mortality, or cardiovascular mortality.
CONCLUSION
Rivaroxaban-based therapy reduced the trial-defined composite efficacy outcome, acute limb ischemia, and thromboembolism in patients with PAD, but increased the risk of major bleeding. These findings support individualized use of rivaroxaban-based therapy in carefully selected patients, balancing ischemic and limb-protective benefits against bleeding risk.
M. Shahzaib, Muhammad Roshaan, Muhammad Khan Buhadur Ali et al.· Annals of Vascular Surgery· 0 citations
BACKGROUND AND AIM
Individuals without stenotic large-artery atherosclerosis (LAA) are an important subgroup of the patients who suffer transient ischemic attack (TIA) or ischemic stroke (IS), and they are commonly treated with dual antiplatelet therapy (DAPT). Stenotic LAA is a marker of higher vascular risk, and current guideline-defining trials did not prospectively evaluate if negative LAA status modifies the effect of DAPT. Moreover, platelet activation may not contribute as much towards future stroke risk after excluding stenotic LAA, leaving uncertainty regarding the applicability of this treatment amongst populations without this marker. We aimed to evaluate the efficacy and safety of DAPT compared with monotherapy for patients who suffered a TIA or IS without stenosis of 50% or more on vessel imaging.
METHODS
We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials from inception to November 2025 for publications in English. We included randomized controlled trials comparing short-term (up to 90 days) DAPT to single antiplatelet therapy after a TIA or IS with outcome data available for the groups without 50% or more stenosis on vessel imaging. Data was pooled using random-effects for non-rare outcomes and Bayesian models for rare outcomes. The primary outcome was a new ischemic or hemorrhagic stroke. We also analyzed ischemic and hemorrhagic stroke individually, moderate and severe bleeding, any bleeding, all-cause death, functionality and a composite vascular outcome.
RESULTS
8 publications met the eligibility criteria. DAPT was associated with a reduction in new stroke, with a relative risk of 0.80 (95% CI 0.65 to 0.98; p = 0.04, I² = 25.5%). Trial sequential analysis showed a substantial risk of type I error, and a sensitivity analysis restricted to studies that included only high-risk TIA or mild IS found no significant benefit. There was an increase in moderate and severe bleeding (odds ratio of 2.70, 95% Bayesian Credible Interval 1.28 to 4.85) and no differences in functionality and mortality. Heterogeneity in trial methodology and populations may limit interpretation of our findings, but sensitivity analyses evaluating the impacts of DAPT duration and region of trial conduction on new stroke did not show significant effects, although they are hindered by the small number of studies.
CONCLUSION
In patients with TIA or IS with a negative assessment of stenotic atherosclerosis on any vessel imaging, the benefit of DAPT is unclear, particularly for individuals with high-risk TIA and mild IS, while there is an increased risk of bleeding. Further trials are required to clarify if DAPT is truly beneficial for these patients.
Mateus Kist Ibiapino, M. Ibrahim, Vanisha Kumar et al.· International Journal of Str...· 0 citations
BACKGROUND
Patients with diabetes and chronic limb-threatening ischemia (CLTI) face high risks of adverse limb and cardiovascular events. While post-revascularization dual antiplatelet therapy (DAPT) is generally recommended, the optimal regimen remains uncertain. This study aimed to compare the effectiveness of different DAPT strategies with respect to long-term clinical outcomes.
METHODS
We conducted a nationwide 90-day landmark observational analysis informed by a target trial framework based on healthcare claims data from Taiwan. The cohort included adults with type 2 diabetes who underwent lower-extremity revascularization for new-onset CLTI between 2016 and 2019. Patients were classified according to the post-procedural DAPT strategy initiated within a 90-day grace period. Inverse probability of treatment weighting (IPTW) was used to balance baseline covariates. The outcomes assessed were lower-extremity amputation (LEA), major adverse limb events (MALE), major adverse cardiovascular events (MACE), and all-cause mortality.
RESULTS
The final cohort comprised 1,849 patients (aspirin plus clopidogrel, n = 439; aspirin plus cilostazol, n = 753; clopidogrel plus cilostazol, n = 657). Median follow-up years (IQR) were 2.94 (1.97-4.11) for all-cause mortality, 2.79 (1.62-3.96) for LEA, 2.40 (0.98-3.62) for MALE, and 2.55 (1.24-3.70) for MACE. Following IPTW, baseline characteristics were well balanced. Compared with standard DAPT (aspirin plus clopidogrel), aspirin plus cilostazol was associated with a lower risk of LEA (sHR, 0.672; 95% CI, 0.460-0.981) and MACE (sHR, 0.799; 95% CI, 0.641-0.995). Clopidogrel plus cilostazol did not demonstrate significant limb-related advantages but was associated with a lower incidence of MACE (sHR, 0.790; 95% CI, 0.631-0.989). All-cause mortality was comparable across all three regimens. Notably, in stratified analyses, the clinical benefits of cilostazol-based therapies were attenuated and statistically non-significant among patients receiving dialysis.
CONCLUSIONS
Among patients with diabetes and CLTI undergoing lower-extremity revascularization, aspirin plus cilostazol was associated with lower risks of LEA and MACE compared with aspirin plus clopidogrel, whereas clopidogrel plus cilostazol was associated with lower MACE but not with significant limb-related benefit. These observational findings suggest that aspirin plus cilostazol may be a favorable DAPT strategy for long-term outcomes in this population; however, further prospective randomized trials are warranted to verify.
Cheng-Wei Lin, Pi-Hua Liu, C. Lin et al.· Cardiovascular Diabetology· 0 citations
Background Coronary artery ectasia (CAE) is characterized by abnormal coronary dilation and slow flow, predisposing patients to thrombotic complications. Optimal long-term antithrombotic strategies for CAE remain undefined. This study aimed to evaluate the efficacy and safety of low-dose rivaroxaban combined with single antiplatelet therapy in patients with CAE. Methods In this single-center retrospective cohort study, 312 patients with CAE were enrolled and followed for 36 months. Patients received either single antiplatelet therapy alone or in combination with low-dose rivaroxaban. Propensity score matching (1:1) was performed to balance baseline characteristics. The primary endpoint was major adverse cardiovascular events (MACE). Secondary analyses included changes in thrombotic, inflammatory, and myocardial injury biomarkers. Cox proportional hazards models, inverse probability weighting, competing risk models, and sensitivity analyses were conducted to assess robustness. Results After propensity score matching (124 vs. 124), combination therapy was associated with a significantly lower risk of 36-month MACE compared with antiplatelet therapy alone (8.1% vs. 21.8%; HR = 0.34, 95% CI: 0.19–0.62; P < 0.001), corresponding to an absolute risk reduction of 13.7% and a number needed to treat of 7.3. The benefit was more pronounced in patients with diffuse ectasia (Markis I/II: HR = 0.21, 95% CI: 0.09–0.49; interaction P = 0.02) and elevated baseline D-dimer (≥0.8 mg/L: HR = 0.18, 95% CI: 0.08–0.41; interaction P = 0.01). Improvements in D-dimer, inflammatory markers, and myocardial injury biomarkers were greater in the combination group. Total bleeding rates were not significantly different between groups, and no fatal bleeding occurred. Net clinical benefit favored combination therapy. Results remained consistent across multiple sensitivity analyses. A simple risk prediction model based on D-dimer, Markis classification, and treatment regimen was developed in the same cohort (C-index 0.78) but has not been externally validated. Conclusions In patients with CAE, low-dose rivaroxaban combined with single antiplatelet therapy was associated with lower long-term MACE risk without a significant increase in major bleeding. The benefit appeared particularly pronounced in patients with diffuse ectasia and higher thrombotic burden. The simple predictive model based on D-dimer, Markis classification, and treatment regimen may aid in individualized antithrombotic decision-making, but requires external validation.
Meng Feng, Yunjie Wu, Chaoqing Xie et al.· Frontiers in Cardiovascular...· 0 citations
Background: ST-segment elevation myocardial infarction (STEMI) requires primary percutaneous coronary intervention (PCI) and dual antiplatelet therapy with aspirin and a purinergic receptor Y12 inhibitor to reduce thrombotic risks. Ticagrelor, a potent purinergic receptor Y12 inhibitor, offers faster and stronger platelet inhibition than clopidogrel, but evidence on its efficacy and safety in STEMI patients post-PCI is conflicting. This study aims to compare the efficacy and safety of ticagrelor versus clopidogrel in STEMI patients undergoing primary PCI. Methods: This systematic review and meta-analysis, adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines, searched PubMed, Embase, ScienceDirect, and ClinicalTrials.gov up to July 2025. Included were randomized controlled trials and observational studies comparing ticagrelor to clopidogrel in adult STEMI patients post-PCI, reporting cardiovascular outcomes. Data were pooled using odds ratios (ORs) with 95% confidence intervals (CIs) via random-effects models. Results: Eight studies (5 randomized controlled trials, 3 observational; n = 31,729) showed ticagrelor significantly reduced all-cause mortality (OR = 0.64, 95% CI = 0.47–0.88; P = .006), cardiovascular mortality (OR = 0.68, 95% CI = 0.60–0.93; P = .01), major adverse cardiovascular events (OR = 0.71, 95% CI = 0.60–0.84; P = .01), myocardial infarction (OR = 0.71, 95% CI = 0.61–0.83; P < .00001), stent thrombosis (OR = 0.66, 95% CI = 0.55–0.79; P < .00001), and major bleeding (OR = 0.87, 95% CI = 0.78–0.97; P = .01), but increased target vessel revascularization (OR = 1.30, 95% CI = 1.05–1.61; P = .02). No significant difference was observed in stroke risk (OR = 1.16, 95% CI = 0.89–1.52; P = .28). Conclusion: Ticagrelor outperforms clopidogrel in STEMI post-PCI, reducing key adverse outcomes, though higher target vessel revascularization risk warrants caution.
Mohammad Shahid, M. Sajjad, Sanket Patel et al.· Medicine· 0 citations
Background Patients with diabetes mellitus (DM) and coronary artery disease (CAD) are at high risk of thrombotic events and exhibit reduced responsiveness to conventional antiplatelet therapy. While newer P2Y12 inhibitors such as ticagrelor and prasugrel provide more potent platelet inhibition, the optimal therapeutic strategy in this population remains uncertain. Methods A systematic review and network meta-analysis of randomized controlled trials (RCTs) was conducted in accordance with PRISMA guidelines. Electronic databases were searched through April 2026 to identify RCTs comparing clopidogrel, prasugrel, ticagrelor, and placebo in patients with DM and CAD receiving background aspirin therapy. Random-effects models were used to estimate pooled risk ratios (RRs) with 95% confidence intervals (CIs). The primary efficacy outcome was major adverse cardiovascular events (MACEs), while safety outcomes included major bleeding. Results Seventeen RCTs, including 40,919 patients, were identified, with 15 trials included in the quantitative synthesis. Compared with placebo, prasugrel and ticagrelor were associated with significant reductions in MACEs, whereas clopidogrel showed no significant benefit. No significant differences were observed in cardiovascular or all-cause mortality across treatment strategies. Prasugrel was associated with a lower risk of myocardial infarction, while ticagrelor was associated with a lower risk of stroke. Both agents increased major bleeding versus placebo, and ticagrelor was also associated with a higher risk of dyspnea. Ranking analysis suggested that prasugrel was the most effective strategy for ischemic outcomes, whereas placebo was the safest strategy overall. Conclusions In patients with DM and CAD, prasugrel and ticagrelor provide superior protection against ischemic events compared with clopidogrel but are associated with an increased bleeding risk compared with placebo. Prasugrel appears to offer the greatest overall efficacy, while ticagrelor shows a distinct benefit in stroke prevention. These findings support individualized antiplatelet strategies that balance ischemic and bleeding risks in this high-risk population.
Abdullah Aljohani, Osamah Omar Alturki, Ghaida Yahya Alahmari et al.· Cardiology Research· 0 citations