In contrast, most randomized trials do not show a benefit of genotype-guided [102-104] or platelet reactivity-guided [105-108] antiplatelet therapy. As examples: The TAILOR-PCI was a large trial of gene-guided antiplatelet therapy in the drug-eluting stent era [102]. In this trial, 5302 patients undergoing percutaneous coronary intervention (PCI; 84 percent for acute coronary syndrome [ACS]) and who were to receive 12 months of DAPT were randomly assigned to clopidogrel therapy or genotype-guided therapy. In the genotype-guided arm, CYP2C19 LoF allele carriers were given ticagrelor and wild-type allele carriers received clopidogrel; all patients in the standard-therapy arm received clopidogrel. The primary analysis only included patients with LoF alleles, which included 903 patients in the genotype-guided group and 946 patients in the standard therapy group. Genotype- guided therapy was associated with a nonsignificant 34 percent reduction in the primary endpoint of cardiovascular death, myocardial infarction (MI), stroke, stent thrombosis, or severe recurrent ischemia at 12 months (4.0 versus 5.9 percent; hazard ratio [HR] 0.66, 95% CI 0.43-1.02). The reduction in the endpoint was primarily driven by a reduction in severe recurrent ischemia (ie, ECG changes leading to urgent revascularization without a diagnosis of MI, cardiac angina). The risk of major or minor bleeding was similar in both groups. In a prespecified sensitivity analysis that assessed repeated events, genotype-guided therapy was associated with a significant 40 percent reduction in the primary endpoint compared with standard therapy (HR 0.60, 95% CI 0.41-0.89). The POPULAR GENETICS trial found that genotype-guided therapy in patients with STEMI was associated with similar rates of MACE [103]. In this trial, 1242 patients were randomly assigned to gene-guided therapy and 1246 were assigned to standard care. In the gene- guided group, LoF carriers received prasugrel or ticagrelor, while all patients in the standard therapy group received either prasugrel or ticagrelor. The rate of all-cause death, myocardial infarction, definite stent thrombosis, stroke, and bleeding were similar between https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 12/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate groups (5.1 versus 5.9 percent in the standard therapy group; absolute rate difference 0.7 percent; 95% CI 2.0 to -0.7). In the ANTARCTIC randomized trial, 877 ACS patients aged 75 years or older who underwent coronary stenting and were treated with prasugrel 5 mg were randomly assigned to platelet monitoring or no monitoring groups [107]. There was no difference between the two strategies in the primary composite end point of cardiovascular death, MI, stroke, stent thrombosis, urgent revascularization, and bleeding complications at 12 months (28 percent in both groups) or the single end point of bleeding events. The chief strength of ANTARCTIC is the randomized design, but limitations include the fact that, with low-dose prasugrel, the need to intensify therapy for high platelet reactivity was uncommon in the monitoring group (approximately 4 percent). In addition, almost all of the P2Y dose adjustments in ANTARCTIC were de-intensification from prasugrel to 12 clopidogrel in an attempt to reduce bleeding. The ARCTIC trial and subsequent ARCTIC-Monitoring study did not demonstrate a clear benefit of platelet function-guided antiplatelet therapy prior to PCI or during one year of follow-up and noted high variability in agreement between platelet function assays [105,106]. MANAGEMENT OF POSSIBLE CLOPIDOGREL FAILURE Patients who have stent thrombosis or an acute coronary syndrome (ACS) while taking clopidogrel may have clopidogrel resistance or hypo-/nonresponsiveness. As no adequately powered study has clearly demonstrated that testing for clopidogrel hyporesponsiveness improves clinically important outcomes, most of our authors and reviewers do not perform these tests. For these patients, based on studies that have shown that more potent platelet P2Y receptor 12 blockers (such as ticagrelor or prasugrel) lower on-treatment platelet reactivity, most of our experts switch to one of these drugs. However, two of our authors perform platelet function testing and point-of-care genetic testing to assess for clopidogrel hyporesponsiveness in these cases and manage the patient accordingly: the finding of platelet resistance leads to a recommendation for ticagrelor or prasugrel; the finding of adequate clopidogrel effect leads to continuation of clopidogrel therapy. None of the interventions discussed below, including the use of a more potent agent, has been shown to improve long-term clinical outcomes. https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 13/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate Acute coronary syndrome Adjusting the loading dose Achieving a platelet reactivity level below high on-treatment platelet reactivity (HPR) by selectively increasing the clopidogrel loading dose based upon laboratory evidence for clopidogrel resistance has been shown to benefit short-term outcome [109-116]. The clinical benefit of increasing the clopidogrel loading dose on reducing the incidence of subsequent adverse cardiac events was shown in a prospective randomized trial of 162 patients scheduled to undergo percutaneous coronary intervention (PCI). Clopidogrel hypo- nonresponsiveness was defined as an in vitro vasodilator-stimulated phosphoprotein phosphorylation analysis (VASP index) >50 percent after a 600 mg loading dose of clopidogrel [111]. All patients with a VASP index >50 percent were randomly assigned to a control group or VASP-guided group. In the comparison group, PCI was carried out without an additional bolus of clopidogrel, whereas in the VASP-guided group, up to three additional boluses of 600 mg of clopidogrel were given in 24-hour increments. The VASP index was then assessed 12 hours after administration until an index <50 percent was achieved, following which PCI was performed. The following findings were noted: In the VASP-guided group, 38 patients required two doses of clopidogrel to achieve a VASP index <50 percent, 14 required three doses, and 15 required four doses. Despite a total clopidogrel dose of 2400 mg, 11 patients (14 percent) remained "resistant" and received PCI. There were no major adverse cardiac events in this subgroup. The number of serious adverse cardiac events (two cardiovascular deaths, four acute or subacute stent thromboses, two recurrent ACS) during the one-month follow-up was significantly less in the VASP-guided group (0 versus 8 events). Adjusting the maintenance dose The following studies in which the maintenance dose was adjusted did not show improvement in long-term clinical outcome: In the GRAVITAS trial, 2214 subjects with high platelet reactivity on clopidogrel (as measured by the VerifyNow P2Y test) following PCI with a drug-eluting stent, were 12 assigned at random to treatment with either standard dose (no loading dose, 75 mg/day) or high dose (600 mg loading dose, 150 mg/day thereafter) clopidogrel for 60 days [6]. The primary study end point (six-month incidence of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis) was virtually identical in those receiving either standard or high dose clopidogrel (2.3 percent in each group; hazard ratio 1.01; 95% CI 0.58-1.76). In addition to being underpowered, there are other potential https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 14/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate explanations for the neutral results of GRAVITAS trial [117]. In a time-dependent analysis of GRAVITAS, <208 PRU was independently associated with the 60 days primary end point (hazard ratio [HR] 0.23, 95% CI 0.05-0.98) and tended to be an independent predictor at six months (HR 0.54, 95% CI 0.28-1.04) [118]. Only a minority of patients receiving high-dose clopidogrel achieved <208, indicating that high-dose clopidogrel regimen may have been sub-optimal and a more potent intervention that reduces HPR to a greater extent would have had greater potential to improve clinical outcomes given the very low event rate. In support of this hypothesis, the ELEVATE-TIMI (Escalating Clopidogrel by Involving a Genetic Strategy - Thrombolysis In Myocardial Infarction) 56 trial showed that up to 225 mg of clopidogrel might be necessary to overcome HPR in patients carrying one loss-of-function cytochrome 2C19 gene (see below). GRAVITAS enrolled a population at low absolute risk for ischemic events despite displaying HPR. The majority of patients had stable angina, were successfully treated with PCI, and periprocedural events were not included in the primary end point. The tested pharmacologic intervention was administered more than 12 hours after PCI and the associated acute vessel injury/stent deployment, which may have been too late to blunt a platelet-related incipient lesion. Finally, it is possible that a single platelet function test may not reliably reflect the effect of clopidogrel on adenosine diphosphate- induced platelet reactivity in all patients [117]. In the CREATIVE trial, 1078 patients undergoing PCI who had low responsiveness to clopidogrel, as assessed by thromboelastography, were randomly assigned to standard antiplatelet therapy (clopidogrel 75 mg daily plus aspirin 100 mg daily), double-dose clopidogrel (clopidogrel 150 mg daily plus aspirin 100 mg daily), or adjunctive use of cilostazol (cilostazol 100 mg twice daily plus aspirin 100 mg daily plus clopidogrel 75 mg daily) [119]. The primary end point of the incidence of major adverse cardiac and cerebrovascular events at 18 months occurred in 14.4, 10.6, and 8.5 percent of the three groups, respectively (HR 0.72, 96% CI 0.47-1.09 and 0.55, 95% CI 0.35-0.87, comparing double-dose clopidogrel or adjunctive cilostazol, respectively). There were no significant differences in the rates of major bleeding. The ELEVATE study of PCI demonstrated that 225 mg daily clopidogrel is required to reduce platelet reactivity (<50 platelet reactivity index as measured by VASP phosphorylation assay) in CYP2C19*2 heterozygotes to levels achieved with standard clopidogrel, 75 mg, in noncarriers [120]. Clinical outcomes were not assessed. Use of alternative antiplatelet agents There are no randomized trials that have tested whether the substitution (for clopidogrel) of more potent platelet P2Y receptor blockers 12 (ticagrelor and prasugrel) in patients with HPR lowers the risk of subsequent adverse cardiovascular outcomes. Since the use of these two drugs has been shown to lower on- https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 15/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate treatment platelet reactivity, it may be prudent to adopt this strategy [54,121,122] and we believe this is a reasonable approach. Practitioners and patients should be aware of the higher risk of bleeding with these agents. Further support for this approach derives from data summarized below: In a randomized, single-blind, cross-over study, prasugrel was more efficient in reducing platelet function compared to clopidogrel as measured by VerifyNow P2Y assay. The 12 prevalence of HPR was significantly lower in all patients (7.5 versus 35.8 percent), in CYP2C19*2 carriers (5.3 versus 47.4 percent), and in noncarriers (8.8 versus 29.4 percent). In another randomized, crossover study, the same authors demonstrated that 10 mg prasugrel therapy was very effective in overcoming HPR rate compared to 150 mg clopidogrel therapy in CYP2C19*2 carriers (0 versus 100 percent) [123]. In the RAPID GENE study, 200 patients undergoing PCI were randomly assigned to either rapid point-of-care genotyping for the CYP2C19*2 allele or standard treatment. Carriers were given 10 mg prasugrel daily, while noncarriers and those in the standard treatment group were given 75 mg of clopidogrel daily [122]. The primary end point was high on- treatment platelet reactivity after one week of antiplatelet therapy, which occurred in none of the 23 carriers in the genotyping group treated with prasugrel compared with 7 of the 23 carriers (30 percent) in the standard treatment group who were treated with clopidogrel. In a post-hoc subgroup analysis of data from the ONSET/OFFSET and RESPOND studies, the prevalence of high on-treatment platelet reactivity, using a number of different laboratory assays, was significantly lower for those treated with ticagrelor (0 to 8 percent) than for those treated with clopidogrel (21 to 81 percent) [121]. (See "Platelet biology", section on 'Prasugrel' and "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy".) In the TRIGER-PCI randomized trial of 212 patients with stable coronary artery disease and high on-treatment platelet reactivity undergoing PCI, a 10 mg daily dose of prasugrel was effective in reducing on-treatment platelet reactivity compared to 75 mg daily dose clopidogrel [108]. However, the study was terminated early for futility because of extremely low event rates. In a randomized trial of STEMI patients undergoing PCI, two-hour post-dose, HPR (>208 PRU) prevalence was 46.2 and 34.6 percent in patients treated with ticagrelor and prasugrel, respectively. Efficacy, defined as reducing platelet reactivity during the first 24 hours of STEMI was similar in the two groups [124]. https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 16/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate In two studies, aspirin and clopidogrel response was evaluated by VerifyNow assay in patients undergoing elective PCI. Poor responders to aspirin or clopidogrel were treated with a glycoprotein (GP) IIb/IIIa receptor inhibitor which decreased 30-day as well as one- year post-PCI ischemic events without increased bleeding rates [125,126]. Previous large scale studies of personalized antiplatelet therapy that used the VerifyNow P2Y assay mainly recruited low-risk patients undergoing PCI and mostly used the 12 suboptimal therapy of 150 mg daily clopidogrel to overcome HPR [6,106,108]. The latter studies failed to demonstrate the utility of personalization of antiplatelet therapy. In a study of 714 patients with ACS undergoing PCI, platelet function was measured by Multiplate analyzer, and patients with HPR on standard clopidogrel therapy were treated with high-dose clopidogrel or prasugrel at the discretion of the treating physician. In this study, the risk of all-cause death, myocardial infarction, stent thrombosis, or stroke at one year was higher in the high-dose clopidogrel group compared to patients without HPR (HR 2.27, 95% CI 1.45-3.55), whereas outcomes were similar between the prasugrel treated group and patients without HPR (HR 0.90, 95% CI 0.44-1.81) [127]. The latter outcomes were associated with significantly lower platelet reactivity in the prasugrel treated group compared with the high-dose clopidogrel treated group (p<0.0001). The TROPICAL ACS trial, discussed elsewhere, provides some additional evidence for switching P2Y receptor blockers in patients with an ACS. (See "Acute non-ST-elevation 12 acute coronary syndromes: Early antiplatelet therapy", section on 'Switching from ticagrelor or prasugrel to clopidogrel'.) A randomized, pharmacodynamic trial of clopidogrel 300 mg daily, ticagrelor 90 mg twice daily, or ticagrelor 60 mg twice daily in 162 aspirin-treated stable patients who underwent PCI found the following [128]: Both maintenance doses of ticagrelor achieved more potent and consistent platelet inhibition than clopidogrel at one month. There was no impact of ticagrelor on in vitro adenosine uptake or adenosine plasma levels with either ticagrelor dose compared with clopidogrel. A genotyping substudy of TROPIC ACS revealed that CYP2C19*2 and CYP2C19*17 carrier status in rapid metabolizers correlates with platelet reactivity in ACS patients on clopidogrel. Based on these results, the authors suggested that CYP2C19 genotyping can play a valuable role for preselecting patients who will and who may not be suitable for early guided deescalation of antiplatelet treatment. They also demonstrated that in https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 17/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate patients treated with platelet-function-guided deescalation strategy, genotyping may not provide added benefit in predicting ischemic or bleeding risk [129]. The CREATIVE trial presented above suggests that triple therapy with clopidogrel, aspirin, and cilostazol may be beneficial. (See 'Adjusting the maintenance dose' above.) In the HOST-REDUCE-POLYTECH-ACS trial, conducted in South Korea, 2338 ACS patients undergoing PCI were randomly assigned to the de-escalation strategy of 10 mg prasugrel for one month followed by 5 mg prasugrel versus conventional strategy of 10 mg prasugrel for one year in addition to 100 mg aspirin in both groups. The primary endpoint of net adverse clinical events (all-cause death, nonfatal MI, stent thrombosis, repeat revascularization, stroke, and bleeding events of grade 2 or higher according to Bleeding Academic Research Consortium [BARC] criteria) was similar between groups (Kaplan-Meier estimate 7.2 percent in the de- escalation group and 10.1 percent in the conventional group, a statistically significant reduction [HR 0.70, 95% CI 0.52-0.92; p equivalence = 0.012]). Ischemic risk was similar between the groups (HR 0.76, 95% CI 0.40-1.45; p = 0.40) while bleeding risk was significantly decreased in the de- escalation group (HR 0.48, 95% CI 0.32-0.73; p = 0.0007). Stent thrombosis The approach to additional antiplatelet therapy in patients with stent thrombosis taking clopidogrel is presented separately. (See "Coronary artery stent thrombosis: Clinical presentation and management", section on 'Long-term antiplatelet therapy'.) LOW PLATELET REACTIVITY AND BLEEDING While dual antiplatelet therapy (DAT) lowers the risk of ischemic events in patients undergoing percutaneous coronary intervention, the risk of bleeding is increased, particularly when more potent P2Y receptor inhibitors are used. In this setting, low platelet reactivity (LPR) is 12 associated with an increased risk of bleeding. A consensus document highlighting the above observations with a therapeutic window concept and updated cutoffs for high on-treatment platelet reactivity and LPR for P2Y receptor inhibitor therapy has been published [130]. 12 However, we do not recommend screening for low platelet reactivity, as there are insufficient data to support its use. Platelet function testing offers the possibility of discerning the optimal drug choice and dosing strategy for an individual patient. The safety and efficacy of early de-escalation of antiplatelet treatment from prasugrel to clopidogrel guided by platelet function testing was investigated in the open-label, assessor-blinded, TROPICAL-ACS trial, which is discussed elsewhere. (See "Acute ST-elevation myocardial infarction: Antiplatelet therapy", section on 'Switching from ticagrelor or prasugrel to clopidogrel'.) https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 18/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Non-ST-elevation acute coronary syndromes (non-ST-elevation myocardial infarction)" and "Society guideline links: ST- elevation myocardial infarction (STEMI)".) SUMMARY AND RECOMMENDATIONS "Resistance" or "nonresponsiveness/hyporesponsiveness" to an antiplatelet drug is a pharmacodynamic phenomenon in which there is no significant reduction in platelet function after treatment as compared to the baseline. High on-treatment platelet reactivity (HPR) is a similar concept and indicates persistent response of the P2Y receptor 12 (clopidogrel target) based on one measurement of on-treatment platelet reactivity. (See 'Definitions' above.) Most, but not all, studies have found a positive association between patients with hypo-/nonresponsiveness or HPR and subsequent thrombotic/ischemic events after percutaneous coronary intervention. (See 'HPR and thrombotic events' above.) Clopidogrel treatment failure is the occurrence of a thrombotic/ischemic event during clopidogrel therapy in patients with heightened platelet reactivity (HPR). These events are usually stent thrombosis or recurrent acute coronary syndrome (ACS). (See 'Clinical manifestations and diagnosis' above.) For patients who have been started on clopidogrel, we do not routinely test patients for clopidogrel resistance with genetic testing to detect loss of function gene carriers (eg, CYP2C19 allele testing) or with platelet function testing to detect P2Y resistance. (See 12 'Screening' above.) The optimal approach to patients taking clopidogrel for a prior ACS (without stenting) who develop a subsequent ACS is not known. For these patients, we suggest switching from clopidogrel to a more potent platelet P2Y receptor blocker rather than any other strategy 12 (Grade 2C). (See 'Management of possible clopidogrel failure' above.) Our approach to patients taking clopidogrel who develop stent thrombosis is discussed separately. (See "Coronary artery stent thrombosis: Clinical presentation and management", section on 'Long-term antiplatelet therapy'.) https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 19/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Bonello L, Tantry US, Marcucci R, et al. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 2010; 56:919. 2. Gurbel PA, Bliden KP, Hiatt BL, O'Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003; 107:2908. 3. Michelson AD, Linden MD, Furman MI, et al. 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