Objective Current guidelines recommend dual antiplatelet therapy (DAPT) in patients undergoing carotid artery stenting. The most common DAPT regimen is aspirin and clopidogrel, a P2Y12 receptor antagonist; however, the prevalence of clopidogrel resistance (CR) in patients undergoing percutaneous coronary interventions may exceed 60%. Few studies have investigated the prevalence and impact of CR in patients undergoing extracranial carotid artery stenting, particularly transcarotid artery revascularization (TCAR). Methods Consecutive high-risk patients ≥ 18 years who underwent TCAR for high grade (≥70%) and/or symptomatic (≥50%) carotid stenosis with preoperative P2Y12 testing between August 2019 and December 2021 were identified across five institutions. Preoperative platelet reactivity was measured with the VerifyNow P2Y12 Reaction Unit (PRU) Test (Instrumentation Laboratory, Bedford, MA), with CR defined as PRU ≥ 194 and hyper-response as PRU &lt;70. Patients without preoperative P2Y12 testing within 30 days prior to TCAR or those on a non-clopidogrel P2Y12 inhibitor preoperatively were excluded. The primary outcome of interest was prevalence of CR. Secondary outcomes of interest included the incidence of ischemic and hemorrhagic complications. Results Of 92 patients identified, the majority were male (59%) and Caucasian (75%) with a mean age of 75 years (±8, range 56 –92). Preoperatively, 93% of patients were on aspirin, 100% on clopidogrel, and 13% on therapeutic anticoagulation. At presentation, 36% were symptomatic. The mean preoperative P2Y12 was 156 PRU (±76, range 6 –349). In total, 30 (33%) patients met criteria for CR (mean PRU 240 ± 37; range 197–349), and 15 (16%) met criteria for hyper-responder (mean PRU 38 ± 20; range 6–68). There was no significant difference by clopidogrel response phenotype in terms of sex ( p = 0.246), race ( p = 0.384), or symptomatic presentation ( p = 0.956). Postoperatively, the cumulative incidence of stroke and MI was 2.1%, with no statistically significant difference in the incidence of in-hospital stroke (PRU 238, p = 0.489) or MI (PRU 168, p = 1) between clopidogrel phenotypes. Three (3.3%) patients, one CR (PRU 240) and two responders (PRU 119 and PRU 189), experienced postoperative access site hematomas that required no subsequent intervention. No other index hospitalization hemorrhagic complications occurred. Conclusions Using preoperative P2Y12 testing with a threshold PRU ≥ 194 to define CR, we identified a high prevalence of CR in patients undergoing TCAR similar to that in the pre-existing coronary literature. We found no significant differences in postoperative ischemic or hemorrhagic complications by clopidogrel response phenotype, although complication rates in the overall study cohort were low. CR may be a spectrum from responder to partial responder to complete non-responder, and this may account for the differences in our CR cohort compared to the ROADSTER 2 protocol deviation cohort. Further investigation is warranted to determine if a quantitative assessment of CR is sufficient to identify patients at risk of developing secondary cerebrovascular ischemic events in this patient population. 

Multi-institutional patterns of clopidogrel response among patients undergoing transcarotid artery revascularization

Regarding "Rapid progression of carotid stenosis is rare in a large integrated healthcare system over an eight-year period".

OBJECTIVES
Clopidogrel is effective at decreasing cardiovascular events in patients with peripheral artery disease (PAD); however, its effect on limb outcomes are less known. This study investigated the variability in response to clopidogrel and its relationship with clinical limb outcomes.


METHODS
Three hundred subjects were enrolled in the Platelet Activity and Cardiovascular Events (PACE) study prior to lower extremity revascularization, of whom 104 were on clopidogrel. Light transmission platelet aggregation was measured in response to ADP 2 μm immediately prior to revascularization. Patients were followed longitudinally for a median follow-up of 18 months. The primary endpoint was major adverse limb events (MALE) defined by major amputation or reoperation of the affected limb. Patients were stratified into groups according to percent ADP-induced aggregation. Poor response to clopidogrel was defined by >50% aggregation.


RESULTS
Overall, the median age was 70 (63, 76) and 35.6% were female. Twenty-nine (27.9%) patients experienced MALE during their follow-up. Median aggregation to ADP 2 μ m was 22.5% (Q1-Q3: 10%, 50%) and 27 subjects (26%) were clopidogrel poor responders. Baseline aggregation was higher in subjects who went on to develop a MALE than those without MALE (43% vs 20%, p = .017). Subjects with aggregation > median (22.5%) were more likely to experience MALE than aggregation < median (38.5% vs 17.3%, p = .029). After multivariable adjustment for age, sex, race/ethnicity, BMI, diabetes, coronary artery disease, and aspirin use, aggregation > median was associated with MALE (adjusted HR [aHR] 2.67, 95% CI 1.18-6.01, p = .018). When stratified by established cut-offs for responsiveness to clopidogrel (50% aggregation), poor responders were more likely to experience MALE than normal responders (44.4% vs 22.1%, aHR 2.18, 95% CI 1.00-4.78, p = .051).


CONCLUSIONS
Among patients undergoing lower extremity revascularization on clopidogrel, higher baseline percent aggregation is associated with increased risk for major adverse limb events.

Response to clopidogrel in patients undergoing lower extremity revascularization.

"Clopidogrel resistance," also defined as heightened platelet reactivity (HPR) while on clopidogrel therapy, may lead to a sub-optimal antiplatelet effect and a potential thrombotic event. There is limited literature addressing the prevalence of HPR in a large cohort of patients receiving either coronary or endovascular interventions.In a large integrated healthcare system, patients with a P2Y12 reaction units (PRU) test were identified. HPR was defined as a PRU ≥ 200 during clopidogrel therapy. Vascular and coronary interventions were identified utilizing CPT codes, HPR prevalence was calculated, and Fischer's exact test was used to determine significance.From an initial cohort of 2,405,957 patients (October 2014 to January 2020), we identified 3301 patients with PRU tests administered. Of these, 1789 tests had a PRU ≥ 200 (HPR overall prevalence, 54%). We then identified 1195 patients who underwent either an endovascular or coronary procedure and had a PRU measurement. This corresponded to 935 coronary and 260 endovascular interventions. In the coronary cohort, the HPR prevalence was 54% (503/935). In the vascular cohort, the HPR prevalence was 53% (137/260); there was no difference between cohorts in HPR prevalence (p = 0.78)."Clopidogrel resistance" or HPR was found to be present in nearly half of patients with cardiovascular disease undergoing intervention. Our data suggest HPR is more common in the cardiovascular patient population than previously appreciated. Evaluating patients for HPR is both inexpensive ($25) and rapid (< 10 min). Future randomized studies are warranted to determine whether HPR has a clinically detectable effect on revascularization outcomes. 

Thomas N. Hawken

Papers

Clopidogrel resistance is common in patients undergoing vascular and coronary interventions

Rapid progression of carotid stenosis was rare in a large integrated healthcare system during an eight-year period.