Platelet function testing and clinical outcomes in peripheral arterial disease: Systematic review and narrative synthesis.

OBJECTIVE: This systematic review aims to comprehensively assess the contemporary literature on platelet function testing (PFT) in individuals undergoing revascularization therapy for peripheral arterial disease (PAD). The goal is to identify whether PFT can aid in detecting antiplatelet resistance, predicting post-procedural thrombotic complications, and informing tailored treatment strategies. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a literature review was conducted using PubMed databases. Search terms included relevant medical subject headings (MeSH) terms. Eligible articles published in English between 1990 and 2023 were analyzed. Studies that examined PFT outcomes in patients with PAD after lower extremity revascularization were included. RESULTS: Ten studies met the inclusion criteria. Various PFT methods were used, including thromboelastography with platelet mapping, multiplate analyzer, Cytochrome P450 2C19 testing, VerifyNow, corrected whole blood aggregometry, platelet function analyzer-100, and light transmission aggregometry. PFT identified individuals who were resistant or non-sensitive to antiplatelet therapy, with such patients facing increased risks of graft/stent thrombosis, amputation, and reintervention. However, substantial heterogeneity in surgical procedures, drug regimens, and testing methods was observed among the studies. CONCLUSIONS: PFTs can play a crucial role in detecting resistance and non-sensitivity to antiplatelet drugs in patients with PAD post-revascularization. However, heterogeneity of data and methods underlines the need for standardized protocols and consensus-building among PFTs. Enhancing clinical utility and reliability could help optimize antiplatelet thromboprophylaxis, minimize thrombotic complications, and improve treatment strategies in vascular surgery. Further research is necessary to solidify the role of PFTs in guiding antiplatelet therapy post-revascularization in patients with PAD.

Is Acute Carotid Artery Stent Thrombosis an Avoidable Complication?

The most serious complication of carotid artery stenting (CAS) is acute carotid artery stent thrombosis (ACAST). ACAST is a very rare complication, but it may lead to dramatic and catastrophic consequences. The most important cause is inadequate or ineffective antiaggregant therapy. It is very important to identify, before CAS, those patients who might be candidates for ACAST and to start antiplatelet therapy for them. Testing patients who are candidates for CAS for acetylsalicylic acid and clopidogrel resistance may prevent this complication.

Pathophysiologic, rather than laboratory-defined resistance drives aspirin failure in ischemic stroke.

BACKGROUND: A significant proportion of ischemic strokes occur while using aspirin and therefore can be considered as clinical aspirin resistance. Apart from this clinical description, aspirin resistance can be defined by laboratory tests of in vitro platelet reactivity. The correlation between clinical and laboratory-defined resistance, however, is far from perfect, and the heterogenous nature of stroke pathophysiology might play a role in this discrepancy. METHODS: The level of in vitro platelet inhibition by aspirin was prospectively evaluated using the VerifyNow Aspirin Assay (Accumetrics, San Diego, CA) in patients presenting with ischemic stroke while using aspirin (n = 78). Demographic and clinical features, including stroke etiology, were compared among patients with and without sufficient level of platelet inhibition and an additional set of patients suffering from stroke while not using aspirin (n = 257). Similar analyses were performed in a separate validation cohort. RESULTS: Laboratory evidence of insufficient platelet inhibition was detected in 16 of 78 patients (21%) with clinical aspirin resistance. On the other hand, 30 patients (38%) had stroke etiologies well known to be inadequately responsive to aspirin therapy. Overall, laboratory-defined resistance by itself could be considered to be accountable for the ischemic event in only 15% of these patients. The corresponding figure was 9% in validation cohort. Patients with sufficient level of platelet inhibition were more likely to harbor an anticoagulant responsive etiology compared with aspirin naive patients (odds ratio, 2.0; P = .033). CONCLUSIONS: Our findings highlight that laboratory aspirin resistance because of insufficient platelet inhibition is relatively uncommon, whereas pathophysiologic resistance, signifying the presence of etiologies that cannot be efficiently treated with aspirin treatment, is a major contributor of clinical resistance in ischemic stroke.

Antiplatelet resistance in outpatients with monitored adherence.

Antiplatelet resistance with aspirin and clopidogrel has been associated with clinical, cellular and pharmacogenetic factors; and non-adherence has been considered as a major contributor to resistance in outpatients. We aimed at assessing factors to resistance when adherence to the antiplatelet drugs and all other oral solid drugs was controlled for. In a pilot study, we tested arachidonic acid and/or ADP-induced in vitro platelet aggregation of 82 outpatients with chronic aspirin and/or clopidogrel treatment before and after a one-week period of measuring the patient's adherence with the polymedication electronic monitoring system (POEMS). Resistance was found in 20% (aspirin; n = 69) and 25% (clopidogrel; n = 32) of the patients after monitored adherence. Mean platelet aggregation was not (aspirin) or non-significantly (clopidogrel) lowered when compared to baseline. Diabetes mellitus and inflammation were consistently associated with resistance to both drugs, but CYP2C19 polymorphisms could not be confirmed as predictors of clopidogrel response. Electronically compiled multidrug dosing histories allowed the concomitant intake of high-dose lipophilic statins to be identified as a risk factor of impaired response to clopidogrel and revealed that exposure to further potential drug-drug interactions (DDIs) was too low for analysis. Multidrug adherence monitoring allowed thus dismissing non-adherence as a major contributor to resistance and inter-individual response variability in an outpatient setting. Additionally, it allowed analysing the impact of DDIs according to the actual exposure to the potentially interfering drugs. Further studies based on this methodology are essential to prevent misleading results due to incomplete adherence and gain additional insight into the impact of timing adherence on antiplatelet drug response.

Clopidogrel Resistance in Patients With Stroke Recurrence Under Single or Dual Antiplatelet Treatment.

Background: The factors associated with clopidogrel resistance in patients with stroke recurrence receiving single or dual antiplatelet treatment (SAPT or DAPT) may differ. This study compared the high on-treatment platelet reactivities (HPRs) and the factors associated with clopidogrel resistance in recurrent ischemic stroke patients receiving clopidogrel or aspirin and clopidogrel. Methods: We enrolled and allocated 275 recurrent ischemic stroke patients to the clopidogrel and DAPT groups and compared their demographics, conventional risk factors, and P2Y12 reaction units (PRUs). Clopidogrel resistance was categorized as PRU higher than 275. We performed a multivariate logistic regression analysis to determine the factors underlying clopidogrel resistance during SAPT and DAPT. Results: In total, 145 (52.7%) and 130 (47.3%) patients received clopidogrel and DAPT, respectively at recurrence. The risk factors of the two groups were not significantly different, except that coronary artery disease was more frequent in the DAPT group. The PRU was higher (255 ± 91 vs. 221 ± 84; p = 0.002) and clopidogrel resistance was more frequent (45.5 vs. 31.5%; p = 0.018) in the SAPT than in the DAPT group. Hyperlipidemia was associated with clopidogrel resistance during SAPT, and smoking (Odds ratio = 0.426, 95% confidence interval 0.210-0.861; p = 0.018) had a protective effect against clopidogrel resistance. For those receiving DAPT, old age, female, low hemoglobin A1c level, and high ARU were associated with clopidogrel resistance. Conclusions: HPR and clopidogrel resistance were more frequent in recurrent ischemic stroke patients receiving clopidogrel than in those receiving DAPT. Smoking was independently associated with less clopidogrel resistance among those receiving clopidogrel SAPT but not in those receiving DAPT.

Resistance to Antiplatelet Therapy Is Associated With Symptoms of Cerebral Ischemia in Carotid Artery Disease.

BACKGROUND: Platelet inhibitory therapy is prescribed to prevent arterial thromboembolism in patients with atherosclerotic disease. Although taken by millions of people, around 30% are resistant to the treatment they are being prescribed. AIMS: To determine whether symptoms of cerebral ischemia, or pre-operative cerebral emboli, in patients admitted for a carotid endarterectomy were associated with resistance to aspirin or clopidogrel. METHODS: Venous blood from 133 patients immediately before carotid endarterectomy (CEA) was analyzed for resistance to aspirin and clopidogrel by multiplate impedance aggregometry. The number of emboli/hour entering the ipsilateral middle cerebral artery was counted by transcranial Doppler (TCD) on the day before surgery in 33 of these patients. RESULTS: Resistance was found in 21 (26.3%) of 100 patients taking aspirin and 14 (42%) of 33 taking clopidogrel. Mean (sd) residual platelet aggregation was significantly higher at 41.9(32) Au in patients who had suffered recent symptoms of cerebral ischemia compared with 30.8(16) Au in asymptomatic patients (p = 0.012). Residual platelet aggregation also correlated significantly with the number of emboli/hour counted by TCD in the ipsilateral middle cerebral artery (r = 0.45, p = 0.009). CONCLUSION: Antiplatelet resistance was associated with the frequency of cerebral emboli and recent symptoms of cerebral ischemia in patients with carotid disease. Definitive clinical studies are needed to explore whether testing for antiplatelet resistance should be undertaken routinely in patients starting platelet inhibitory therapy for cardiovascular disease.

Aspirin and Clopidogrel Resistance in Indian Patients with Ischemic Stroke and its Associations with Gene Polymorphisms: A Pilot Study.

INTRODUCTION: Antiplatelet resistance is one of the urgent issues in current stroke care. One-third to one-half of the patients who experience a recurrent stroke is already on antiplatelet medications. We studied resistance to aspirin and clopidogrel in Indian stroke patients and its association with gene polymorphisms. METHODS: Platelet function testing by light transmission aggregometry was performed on 65 patients with ischemic stroke who were stable on dual antiplatelet therapy (clopidogrel 75 mg OD and aspirin 75 mg OD) along with 65 age-matched controls. Aspirin resistance was considered as mean platelet aggregation ≥70% with 10 µM adenosine diphosphate (ADP) and ≥20% with 0.75 mM arachidonic acid. Clopidogrel resistance was defined as <10% decrease from the baseline in platelet aggregation in response to ADP 10 µM and semi-response as <30% decrease from the baseline. Polymorphisms CYP2C19 * 2 and GPIIb/IIIa (PLA1/A2) were genotyped by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: We found 64.6% (42/65) patients with inadequate response to clopidogrel (15.4% [10/65] resistant and 49.2% [32/65] semi-responders) and 4.6% (3/65) patients with inadequate response to aspirin (3.1% [2/65] resistant and 1.5% [1/65] semi-responder). The frequency of CYP2C19*2 mutant genotype was significantly higher in clopidogrel nonresponders compared to responders (P = 0.014). Clopidogrel nonresponsiveness was much higher in small vessel stroke. CONCLUSION: Unlike aspirin, a high proportion of nonresponders to clopidogrel was identified. In an interim analysis on 65 Indian patients, a significant association was found between CYP2C19*2 and clopidogrel nonresponsiveness.

Clopidogrel Resistance in Lower Extremity Arterial Endovascular Interventions.

Antiplatelet pharmacotherapy for endovascular interventions has been widely adopted, with clopidogrel being one of the most common agents prescribed. A fraction of patients is resistant to clopidogrel resulting in decreased platelet inhibition despite adequate use. This finding is often termed high on-treatment platelet reactivity (HPR) and may lead to decreased patency in lower extremity arterial endovascular interventions. Current literature on HPR with lower extremity arterial endovascular interventions is limited to only a few studies. Resistance to clopidogrel is largely a result of CYP2C19 enzyme loss of function alleles. Several tests are available to measure clopidogrel resistance but light transmittance aggregometry remains the gold standard, yet direct genetic testing may be more reliable. One-year patency rates following lower extremity arterial endovascular interventions in patients with clopidogrel resistance (HPR) range between 35%-83% whereas those with the proper response to clopidogrel range between 73%-100%. Patients with decreased CYP2C19 activity show a significant decrease in one-year patency of endovascular femoropopliteal interventions (35% vs. 73%; p=0.006). Among patients tested for platelet function after in-stent thrombosis, up to 53% are resistant to clopidogrel. Lack of robust data limits our ability to predict patency in lower extremity arterial interventions for patients with HPR, but there is little doubt that longer patency seems to favor non-HPR patients. Large population, prospective trials are needed to guide our practice.

High on treatment platelet reactivity to aspirin and clopidogrel in ischemic stroke: A systematic review and meta-analysis.

Emerging studies highlight high on-treatment of platelet reactivity (HTPR) as a major hindrance to the secondary prevention of cardiovascular ischemic events. The aim of this systematic review and meta-analysis is to assess the prevalence of HTPR in patients with ischemic stroke (IS) or transient ischemic attack (TIA) and reveal a possible relation with a higher risk of cerebrovascular event recurrence. Studies were selected if they reported absolute numbers or percentages of HTPR with ASA or clopidogrel in IS/TIA patients at any time point after the cerebrovascular event onset and assessed with any type of platelet function tests. We included 52 full-text studies with a total of 8364 patients. Overall, the pooled prevalence of HTPR was 24% (95%CI: 20-27%). In subgroup analyses, the prevalence of HTPR on ASA was 23% (95%CI: 20-28%), on clopidogrel 27% (95%CI: 22-32%) and on dual antiplatelet treatment (DAPT) 7% (95%CI: 5-10%). The overall analysis of all studies providing data on the risk of IS/TIA recurrence, indicates that the patients with HTPR had a significantly higher risk for IS/TIA recurrence (RR=1.81, 95%CI: 1.30-2.52; p<0.001). In conclusion the present study shows a significant lower prevalence of HTPR in DAPT and an increased rate of recurrent cerebrovascular ischemic events in patients presenting HTPR.

Efficacy and safety of P2Y12 inhibitors according to diabetes, age, gender, body mass index and body weight: systematic review and meta-analyses of randomized clinical trials.

OBJECTIVE: The efficacy of antiplatelet drugs may differ in specific patient subgroups. We aimed to assess the efficacy and safety of the P2Y12 inhibitors clopidogrel, ticlopidine, prasugrel, ticagrelor, and cangrelor according to diabetes status, age, gender, body mass index, and body weight. METHODS: Randomized clinical trials (RCTs) of P2Y12 inhibitors reporting information on cardiovascular disease (defined as myocardial infarction, stroke, or cardiovascular death) and bleeding (defined as any bleeding) events among the subgroups diabetes and non-diabetes, age ≥65 and <65 year-old, men and women, body mass index ≥30 and <30 kg/m(2), and body weight ≥60 and <60 kg, were identified in Medline, Embase, Web of Science, and Cochrane Library on August 31st, 2014. For each inhibitor, random-effects meta-analyses were used to estimate the ratio of relative risks (rRR) for cardiovascular and bleeding events among patient subgroups. RESULTS: Twenty distinct RCTs (233 285 participants, 21 323 cardiovascular and 5183 bleeding events) were identified. Cardiovascular risk reduction with clopidogrel did not significantly differ according to diabetes (rRR: 1.04; 95% CI: 0.95 to 1.13; p = 0.395), age (0.98; 0.88 to 1.09; p = 0.347), gender (0.97; 0.90 to 1.04; p = 0.382), or body mass index (1.11, 0.95 to 1.31; p = 0.191). Results for other inhibitors were comparable, although available data were sparse. Limited data on bleeding events were available. CONCLUSION: Data from RCTs did not show a different cardiovascular efficacy of clopidogrel in diabetes mellitus and other clinically relevant subgroups. Limited information was available on the efficacy and safety of other P2Y12 inhibitors in specific subgroups.

State-of-the-Art: Hypo-responsiveness to oral antiplatelet therapy in patients with type 2 diabetes mellitus.

Diabetes mellitus is a global pandemic, associated with a high burden of cardiovascular disease. There are multiple platelet derangements in patients with diabetes, and antiplatelet drugs remain the first-line agents for secondary prevention as well as for high-risk primary prevention among patients with diabetes. This review provides a summary of oral antiplatelet drug hypo-responsiveness in patients with diabetes, specifically aspirin and Clopidogrel resistance. Topics discussed include antiplatelet testing, definitions used to define hypo-response and resistance, its prevalence, association with clinical outcomes and strategies to mitigate resistance. The role of prasugrel and ticagrelor, as well as investigational agents, is also discussed.

[The usefulness of platelet function evaluation in clinical practice]. / L'exploration fonctionnelle plaquettaire: intérêts en pratique clinique.

Platelets play a pivotal role in the regulation of both thrombosis and haemostasis. Functional testing of platelet response has been exclusively used in the diagnosis and management of bleeding disorders. Recent advances of light transmission aggregometry and development of more useful devices have demonstrated the clinical utility to enlarge platelet function testing in patients with cardiovascular disease. The ex vivo measurement of residual platelet response seems, with some assays, predictive of adverse clinical events. Still a debate, it represents an emerging area of interest for both the clinician and the basic scientist. Heparin-induced thrombocytopenia diagnosis is also difficult and a functional assay is now available for an easier and rapid method to rule out such a life-threatening situation. This review article will describe the available methods of measuring platelet response and will discuss both the limitations and emerging data supporting the role of platelet function studies in clinical practice.

The contribution of platelet glycoproteins (GPIa C807T and GPIba C-5T) and cyclooxygenase 2 (COX-2G-765C) polymorphisms to platelet response in patients treated with aspirin.

OBJECTIVE: Aspirin is an antiplatelet agent commonly used in treatment of patients with high risk to develop stroke and myocardial infarction. However, inter-individual variability regarding the inhibition of platelet function by aspirin is well documented. In this study, the correlation between platelet glycoproteins (GPIa C807T and GPIba C-5T) and cyclooxygenase 2 (COX-2G-765C) polymorphisms and antiplatelet response in patients treated with aspirin was investigated. METHODS: Jordanian adult patients (n=584) who are taking aspirin as an antiplatelet agent participated in the study. Platelet aggregation response was measured using Multiplate Analyzer® system. Polymerase chain reaction-restriction fragment length polymorphism assay (PCR-RFLP) was used for genotyping of the examined polymorphisms. RESULTS: Aspirin resistance was found in 15.8% of patients. Response to aspirin was significantly associated with GPIba C-5T polymorphism (P<0.05). However, the GPIa C807T and COX-2G-765C polymorphisms were not related to aspirin resistance (P>0.05). CONCLUSION: A considerable fraction of the Jordanian population is resistant to the antiplatelet effect of aspirin, which might be related to GPIba C-5T polymorphism.

Antiplatelet resistance and thromboembolic complications in neurointerventional procedures.

Antiplatelet resistance is emerging as a significant factor in effective secondary stroke prevention. Prevalence of aspirin and clopidogrel resistance is dependent upon laboratory test and remains contentious. Large studies in cardiovascular disease populations have demonstrated worse ischemic outcomes in patients with antiplatelet resistance, particularly in patients with coronary stents. Thromboembolism is a complication of neurointerventional procedures that leads to stroke. Stroke rates related to aneurysm coiling range from 2 to 10% and may be higher when considering silent ischemia. Stroke associated with carotid stenting is a major cause of morbidity. Antiplatelet use in the periprocedure setting varies among different centers. No guidelines exist for use of antiplatelet regimens in neurointerventional procedures. Incidence of stroke in patients post procedure may be partly explained by resistance to antiplatelet agents. Further research is required to establish the incidence of stroke in patients with antiplatelet resistance undergoing neurointerventional procedures.