Cost analysis of CYP2C19 genetic testing in percutaneous coronary intervention patients.

CYP2C19 loss of function (LOF) carriers undergoing percutaneous coronary intervention (PCI) have an increased risk of ischemic events when treated with clopidogrel. PCI patients in TAILOR-PCI were randomized to clopidogrel or genotype-guided (GG) therapy in which LOF carriers received ticagrelor and non-carriers clopidogrel. Direct medical costs associated with a GG approach have not been described before. TAILOR-PCI participants for whom direct medical costs were available for the duration from the date of PCI to one-year post PCI were included. Primary cost estimates were obtained from the Mayo Clinic Cost Data Warehouse. There were no differences in direct medical costs between the GG and clopidogrel groups (mean $20,682 versus $19,747, p = 0.11) however total costs were greater in the GG group (mean $21,245 versus $19,891, p = 0.02) which was primarily driven by ticagrelor costs. In conclusion the increased expense of a GG strategy post PCI as compared to clopidogrel for all is primarily driven by the cost of ticagrelor.

Impact of continued clopidogrel use on outcomes of patients undergoing carotid endarterectomy.

OBJECTIVE: The aim of this study was to evaluate the use of clopidogrel at the time of carotid endarterectomy (CEA) and its association with postoperative complications. METHODS: Single-institution, retrospective review of a prospective database. RESULTS: From 2010 to 2017, CEA was performed in 1066 consecutive patients (median age, 73 years; 66% men). The indications for operation included ≥70% asymptomatic stenosis (458; 43%), prior stroke (314; 29%), and transient cerebral or retinal ischemia (294; 28%). At the time of operation, 509 (48%) patients were taking aspirin alone, 441 (41%) were taking clopidogrel (374 in combination with aspirin, 67 as sole therapy), 83 (8%) were on no documented antiplatelet medication, and 33 (3%) were taking warfarin (with therapeutic international normalized ratio). The likelihood of clopidogrel use at the time of operation was higher for patients with a history of symptomatic carotid disease (P = .002). Over the study period, clopidogrel use increased from 31.9% in 2010 to 56.8% in 2017, which corresponds to an 11% (95% confidence interval, 6%-15%) increase annually. Postoperative strokes occurred in 15 patients (overall incidence, 1.4%), the majority of which were minor (12/15; 80%). Six strokes occurred in patients taking aspirin alone (6/509; 1.2%), two in patients on clopidogrel and aspirin (2/441; 0.5%), two in patients taking clopidogrel alone (2/67; 2.9%), three in patients on no documented antiplatelet medication (3/83; 3.6%), and two in those taking warfarin (one of which was secondary to a fatal intracranial hemorrhage within 30 days of discharge [2/33; 6.1%]). The 30-day mortality rate was 0.03% (3/1066); the risk for the combined endpoint of any stroke, death, or myocardial infarction (MI) was 2.3% (25/1066), and the risk for major stroke, death, or MI was 1.2%. There was no apparent association between clopidogrel use and the incidence of postoperative bleeding (P = .59) or any other postoperative complication (stroke, death, MI, cranial nerve injury; P = .15). CONCLUSIONS: Clopidogrel use in our CEA practice has increased over time and has not been associated with an increased risk of postoperative complications, including bleeding. These data suggest that clopidogrel should not be discontinued prior to CEA and should be considered as part of 'optimal medical therapy' in patients undergoing CEA.

Impact of Pancreatic ß-Cell Function on Clopidogrel Responsiveness and Outcomes in Chinese Nondiabetic Patients Undergoing Elective Percutaneous Coronary Intervention.

PURPOSE: Insulin resistance and ß-cell dysfunction are fundamental defects contributing to type 2 diabetes development. Prior studies indicated that insulin resistance may be correlated with low responsiveness to clopidogrel. This study aimed to investigate the effects of ß-cell function on clopidogrel-induced platelet P2Y12 inhibition and the clinical outcomes of nondiabetic patients undergoing elective percutaneous coronary intervention (PCI). METHODS: Patients scheduled to undergo elective PCI and receive clopidogrel in addition to aspirin were recruited for this study. Homeostatic model assessment 2 of ß-cell function (HOMA2-ß%) was used to classify participants into quartiles. Thromboelastography (TEG) was used to calculate the quantitative platelet inhibition rate to assess clopidogrel-induced antiplatelet reactivity. The clinical outcome was major adverse cardiovascular and cerebrovascular events (MACCEs). RESULTS: Of the 784 participants evaluated, 21.3% of them (169 of 784) had low responsiveness to clopidogrel. According to multivariate linear regression analysis, the first quartile of HOMA2-ß% (19.9-78.1), indicating greater ß-cell dysfunction, was independently associated with low responsiveness to clopidogrel compared with the fourth quartile (126.8-326.2) after adjustment for potential covariates [odds ratio 2.140, 95% confidence interval (CI) (1.336 to 3.570), P = 0.038]. In addition, at one year, the first quartile of HOMA2-ß% was associated with an increased risk of 1-year MACCE occurrence compared with the fourth quartile [adjusted hazard ratio 4.989, 95% CI (1.571 to 15.845), P = 0.006]. CONCLUSION: Increased ß-cell dysfunction, indicated by a low HOMA2-ß%, was associated with low responsiveness to clopidogrel and an increased risk of one-year MACCEs in nondiabetic patients undergoing elective PCI.

A Systematic Review of Clopidogrel Resistance in Vascular Surgery: Current Perspectives and Future Directions.

BACKGROUND: Clopidogrel resistance is a well-described phenomenon that has been linked to adverse cardiovascular events in patients with coronary artery disease. The impact of clopidogrel resistance in patient outcomes after vascular and endovascular surgery is not well-established. METHODS: Using preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, a literature review with the medical subject headings (MeSH) terms "(clopidogrel resistance) and (vascular)", "(clopidogrel resistance) and (vascular surgery)", "(clopidogrel resistance) and (endovascular)", and "(clopidogrel resistance) and (endovascular surgery)" was performed in PubMed and Cochrane databases, to identify all peer-reviewed studies performed on clopidogrel resistance in vascular and endovascular surgery. Studies written in the English language from inception to 2022 were included. Case reports, studies with limited information, nonhuman studies, and studies not pertaining to vascular or endovascular surgery were excluded from analysis. Each study was independently reviewed by 2 qualified researchers to assess eligibility. RESULTS: Of the 691 studies identified through the MeSH strategy, 16 studies met the inclusion criteria and were reviewed and summarized. These studies focused on extracranial cerebrovascular disease (n = 5) and peripheral arterial disease (PAD, n = 11), encompassing a total of 1,716 patients. The prevalence of clopidogrel resistance ranged from 0% to 83.3%, depending on the diagnostic assay and cutoff values used. In cerebrovascular disease, clopidogrel resistance may be associated with cerebral embolization, ischemic neurologic events, and vascular-related mortality. In PAD, clopidogrel resistance has been linked to recurrent stent thrombosis, target lesion revascularization, amputation-free survival, and all-cause mortality. CONCLUSIONS: This systematic review provides an up-to-date summary of clopidogrel resistance in vascular and endovascular surgery. The impact of clopidogrel resistance remains incompletely investigated, and future studies are needed to clarify the role of resistance testing in patients with vascular disease.

Atorvastatin Effect on Clopidogrel Efficacy in Patients with Peripheral Artery Disease.

BACKGROUND: Both clopidogrel and atorvastatin metabolism are rooted in hepatic cytochrome p450 activation. There are published reports of atorvastatin interfering with clopidogrel metabolism by inhibiting the activation of clopidogrel. This in turn would decrease the therapeutic effect of clopidogrel potentially resulting in an increase in thrombotic events in patients who are taking both medications. The emergence of viscoelastic assays, such as Thromboelastography with platelet mapping (TEG-PM), has been utilized to identify prothrombotic states and may provide insight into a patient's microvascular coagulation profile. The aim of this prospective, observational study was to delineate the differences in platelet function between patients on clopidogrel alone versus those on clopidogrel and atorvastatin in patients that are undergoing peripheral revascularization. METHODS: All patients undergoing revascularization between December 2020 and August 2022 were prospectively evaluated. Patients on clopidogrel and atorvastatin were compared to those on clopidogrel alone. Serial perioperative TEG-PM analysis was performed up to 6 months postoperatively and the platelet function in terms of percent inhibition was evaluated in both groups. Statistical analysis was performed using unpaired t-test to identify differences in platelet function. RESULTS: Over the study period, a total of 182 patients were enrolled. Of this cohort 72 patients met study criteria. 87 samples from the 72 patients were analyzed. 31 (43.05%) patients were on clopidogrel alone and 41 (56.94%) were on clopidogrel and atorvastatin. Patients on clopidogrel alone showed significantly greater platelet inhibition compared to those on clopidogrel and atorvastatin [49.01% vs. 34.54%, P = 0.03]. There was no statistical difference in platelet inhibition between groups in terms of aspirin use alone versus aspirin and atorvastatin. CONCLUSIONS: Patients on clopidogrel and atorvastatin showed significantly less platelet inhibition compared to those on clopidogrel alone, supporting the concept that atorvastatin may interfere with the therapeutic effect of clopidogrel. Patients taking atorvastatin may require an alternative antiplatelet therapy regimen that does not include clopidogrel to achieve adequate thromboprophylaxis.

Clopidogrel resistance is common in patients undergoing vascular and coronary interventions.

OBJECTIVES: "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. METHODS: 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. RESULTS: 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). CONCLUSION: "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.

Associations of CYP2C19 and F2R genetic polymorphisms with platelet reactivity in Chinese ischemic stroke patients receiving clopidogrel therapy.

OBJECTIVES: Genetic variation has been considered a major contributor to the high variability in the response to dual antiplatelet therapy in patients with acute ischemic stroke or transient ischemic attack. Recently, incidences of ischemic stroke are increasing rapidly in China. We aimed to evaluate the influence of potential determinants on the response of antiplatelet therapy and adverse events in Chinese ischemic stroke patients receiving clopidogrel-aspirin treatment. METHODS: Based on the clopidogrel drug response pathway and the coagulation and anticoagulation function, we systematically selected 34 genetic polymorphisms in 12 candidate genes. Three hundred and eight patients were divided into 2 groups according to their degree of inhibition of platelet aggregation. Multivariate analysis was then performed to assess the influence of demographic, clinical and genetic factors on platelet reactivity in Chinese ischemic stroke patients. RESULTS: We found that polymorphisms in CYP2C19 and F2R genes were still significantly associated with platelet reactivity in Chinese ischemic stroke patients (P = 0.037 and 0.015). The newly identified rs168753 in F2R gene may influence the efficacy to clopidogrel-aspirin therapy for ischemic stroke patients. We also found that ischemic stroke patients with low level of inhibition of platelet aggregation had higher risk of recurrent ischemic events (P = 0.001). CONCLUSIONS: Together, these results emphasized the necessity of genotype-directed antiplatelet therapy and facilitated to minimize adverse ischemic events.

Clinical Outcomes After Percutaneous Coronary Intervention Over Time on the Basis of CYP2C19 Polymorphisms.

ABSTRACT: The aim of this study was to investigate the association between CYP2C19 gene polymorphisms and the risk of cardiovascular events in the early stage and subsequent period after percutaneous coronary intervention (PCI) among patients who received clopidogrel. Between October 2015 and January 2017, CYP2C19 genotyped patients who were treated with clopidogrel after PCI were enrolled in this study. Included patients were categorized as non-loss-of-function metabolizers, intermediate metabolizers, and poor metabolizers based on CYP2C19 genotype. The primary outcome was a composite of any-cause mortality, nonfatal myocardial infarction, nonfatal ischemic stroke, and stent thrombosis occurring during exposure to clopidogrel. The rates of clinical outcome events were compared between CYP2C19 phenotypes. Landmark analyses were processed at 90 days and 1 year post-PCI. Of 1341 patients, 161 (12.0%) had 2 copies of loss-of-function (LOF) alleles, 621(46.3%) had one LOF allele, and 559 (41.7%) had no LOF allele. At the 3-month follow-up, the primary outcome events were more frequent in carriers of 2 LOF alleles (5.6%) than in noncarriers (1.8%) [adjusted hazard ratio (HR) 2.944, 95% confidence interval, 1.184-7.321, P = 0.020). A similar finding was observed among in patients with acute coronary syndrome indications at the index PCI (adjusted HR 3.046, 95% confidence interval, 1.237-7.501, P = 0.015). These differences did not persist within the subsequent 9 months of follow-up, among either all comers or subjects with acute coronary syndrome. In conclusion, these data demonstrate a higher risk for ischemic events in patients with 2 CYP2C19 LOF alleles who are prescribed clopidogrel, seen at 3 months after PCI, that is not sustained for 12 months.

Navigating Antiplatelet Treatment Options for Stroke: Evidence-Based and Pragmatic Strategies.

PURPOSE OF REVIEW: The benefit of using antiplatelet monotherapy in acute ischemic stroke and secondary stroke prevention is well established. In the last few years, several large randomized trials showed that the use of short-term dual antiplatelet therapy in particular stroke subtypes may reduce the risk of recurrent ischemic events. The aim of this article is to provide a critical analysis of the current evidence and recommendations for the use of antiplatelet agents for stroke prevention. RECENT FINDINGS: Long-term therapy with aspirin, clopidogrel, or aspirin plus extended-release dipyridamole is recommended for secondary stroke prevention in patients with noncardioembolic ischemic stroke. Short-term dual antiplatelet therapy with aspirin and clopidogrel is superior to antiplatelet monotherapy in secondary stroke prevention when used in patients with mild noncardioembolic stroke or high-risk transient ischemic attack. Dual therapy, however, is associated with an increased risk of major bleeding, particularly when the treatment is extended for greater than 30 days. Similarly, aspirin plus ticagrelor is superior to aspirin monotherapy for the prevention of recurrent ischemic stroke, although this combination is associated with a higher risk of hemorrhagic complications when compared to other dual antiplatelet regimens. Among patients who carry CYP2C19 genetic polymorphisms associated with a slow bioactivation of clopidogrel, short-term treatment with aspirin plus ticagrelor is superior to aspirin plus clopidogrel for the reduction of recurrent stroke; however, the use of ticagrelor is associated with a higher risk of any bleeding. In patients with symptomatic intracranial stenosis, aggressive medical management in addition to dual antiplatelet therapy up to 90 days is recommended. Antiplatelet therapy has an essential role in the management of ischemic stroke. The specific antiplatelet regimen should be individualized based on the stroke characteristics, time from symptom onset, and patient-specific predisposition to develop hemorrhagic complications.

Proton Pump Inhibitor and Clopidogrel Use After Percutaneous Coronary Intervention and Risk of Major Cardiovascular Events.

PURPOSE: Due to shared hepatic metabolism, concomitant medication with a proton pump inhibitor (PPI) and clopidogrel might reduce the effectiveness of clopidogrel in the prevention of cardiovascular events after percutaneous coronary intervention (PCI). We aimed to examine the risk of major cardiovascular events after PCI comparing patients who used clopidogrel together with PPI with those who used clopidogrel alone. METHODS: This Swedish nationwide cohort study included patients who received clopidogrel after primary PCI in 2005-2019. Patients were followed for up to 12 months after PCI. Data were retrieved from the Swedish Prescribed Drug Registry, Patient Registry, Cancer Registry, and Cause of Death Registry. Multivariable Cox regression provided hazard ratios (HRs) with 95% confidence intervals (CIs) for cardiovascular events comparing PPI users (exposed) with non-users of PPI (non-exposed). The HRs were adjusted for sex, age, comorbidity, calendar period, obesity, diabetes, anti-diabetic medication, tobacco-related diseases, hypertension, and congestive heart failure. RESULTS: The cohort included 99,836 patients who received clopidogrel after primary PCI. Among these, 35,772 (35.8%) received concomitant PPI. Compared to non-users, PPI users had increased adjusted HRs of all study outcomes, i.e., the main outcome myocardial infarction (HR = 1.23, 95% CI 1.15-1.32) and the secondary outcomes coronary heart disease (HR = 1.28, 95% CI 1.24-1.33), stroke (HR = 1.21, 95% CI 1.05-1.40), and death due to coronary heart disease (HR = 1.52, 95% CI 1.37-1.69). The results were similar in analyses including both primary and secondary PCIs. CONCLUSIONS: In patients who receive clopidogrel after PCI, concomitant use of PPI seems to increase the risk of major cardiovascular events.

Platelet function assessed by ROTEM®platelet in patients receiving antiplatelet therapy during cardiac and vascular surgery.

Patients undergoing coronary artery bypass graft (CABG) surgery or carotid endarterectomy (CEA) continue antiplatelet therapy perioperatively, which may increase bleeding risk. We aimed to investigate whether Rotational thromboelastometry (ROTEM®) platelet, a newly marketed platelet function analysis, would detect antiplatelet therapy in CABG and CEA patients; whether detection of reduced platelet function was associated with increased bleeding; and whether ex vivo desmopressin increased platelet function. We included 20 CABG patients continuing aspirin and 20 CEA patients continuing clopidogrel (n = 1) or clopidogrel and aspirin (n = 19). Platelet function was analyzed with ROTEM®platelet and light transmission aggregometry (LTA). According to the lower reference limit, ROTEM®platelet managed to detect aspirin, but clopidogrel detection was inadequate compared to LTA. Using a previously published cut-off for bleeding risk, 6 (30%) patients receiving aspirin and 4 (21%) patients receiving both clopidogrel and aspirin demonstrated platelet function below this cut-off. One of the four CEA patients below the cut-off died from intracerebral hemorrhage postoperatively. CABG patients below (n = 6) and above (n = 14) the cut-off did not differ in chest tube output (median [range]: 373 ml [250-900] vs. 368 ml [195-820]). Ex vivo addition of desmopressin did not increase platelet function. In conclusion, ROTEM®platelet does reveal aspirin treatment whereas clopidogrel treatment is most often overlooked. Due to low bleeding in the study population, it was not possible to conclude on the association with bleeding risk.

Influence of Clinically Significant Genes on Antiplatelet Effect of Clopidogrel and Clinical Outcomes in Patients with Acute Coronary Syndrome and Atrial Fibrillation.

INTRODUCTION: The interindividual variability of the antiplatelet effect of clopidogrel is determined by multiple clinical and genetic factors. A lot of genotype-oriented studies have concentrated on the impact of CYP2C19 gene polymorphisms on platelet aggregation in patients receiving clopidogrel. However, the influence of this polymorphism may be only 12-20%, so other genetic markers should also be investigated. The aim of this work was to study the impact of carriage of CES1, PON1, ABCG2, CYP4F2, CYP3A4, IGTB3, P2Y12, PEAR1, and B4GALT2 polymorphisms on antiplatelet effect of clopidogrel and clinical outcomes in patients with acute coronary syndrome (ACS) and atrial fibrillation (AF). METHODS: 103 patients who underwent ACS with or without percutaneous coronary intervention and concomitant nonvalvular AF were included in an open multicenter prospective study to assess efficacy and safety of combined antithrombotic therapy. The study assessed the frequency of different primary clinical outcomes (incidence of major bleeding, hospital mortality, cardiovascular mortality, stroke and transient ischemic attacks (TIAs), renal mortality) and secondary outcomes (resistance to therapy - high residual platelet reactivity, excessive platelet suppression). Residual platelet reactivity was examined using the VerifyNow system (Accumetrics, Latham, NY, USA). RESULTS: None of the studied genetic markers had no statistically significant effect on the antiaggregant response to clopidogrel in patients with ACS and AF. However, CYP4F2 C(Val433Met) T, PEAR1 rs41273215 C>T were statistically significantly associated with an increased frequency of bleeding on antithrombotic therapy. B4GALT2 rs1061781 was statistically significantly associated with increased frequency of strokes and TIA. CONCLUSION: In our study, we determined that carriers of CYP4F2 gene polymorphisms C(Val433Met)T, PEAR1 rs41273215 C>T (CT+TT) were associated with lower safety of antithrombotic therapy in patients with ACS and AF. And, the B4GALT2 rs1061781 gene polymorphism was associated with a greater risk of insufficient efficacy of the therapy. The data obtained in our study may improve the understanding of the effect of less studied genetic markers on the efficacy and safety of antithrombotic therapy in patients with ACS and AF.

The DNAm levels of CREB5 (cg11301281) were associated with clopidogrel resistance.

PURPOSE: Clopidogrel resistance (CR) is mostly caused by interindividual variability of the platelet inhibition of clopidogrel, which may induce cardiovascular events. The aim of this research was to evaluate whether DNAm levels of CREB5 (cg01534253) are involved in CR among acute coronary syndrome (ACS) patients treated with clopidogrel. METHODS: 72 patients(36 CR and 36 non-CR) who underwent ACS were included in this study. The VerifyNow P2Y12 assay was selected to evaluate residual platelet reactivity, and bisulfite pyrosequencing methods was used to examine DNA methylation levels on cg01534253. Secondly, CREB5 mRNA expression was analyzed via quantitative real-time PCR. Last, we employed logistic regression to test the interaction between genetic factors of CREB5 methylation and multiple clinical variables in CR patients. RESULTS: Subunit analysis indicated that for patients whose HbA1c levels were ≥6.5% or whose GLU levels were ≥7 mmol/L, lower methylation of cg01534253 indicated a poorer clopidogrel response. In addition, CREB5 mRNA expression was increased in CR patients with GLU levels ≥7 mmol/L. Moreover, regression analysis indicated that the values of albumin and uric acid were correlated with the incidence of CR. CONCLUSIONS: Our findings were likely to provide fresh understanding for the new mechanism of platelet inhibition failure and promote individualized antiplatelet therapy.

P2Y12 reaction units and ischemic and bleeding events after neuro-endovascular treatment.

BACKGROUND AND PURPOSE: To investigate the associations of perioperative P2Y12 reaction units (PRU) measured using VerifyNow with ischemic and bleeding events, and to determine the PRU threshold in the setting of elective neuro-endovascular treatment (EVT) for intracranial/extracranial vascular disease in patients taking aspirin and clopidogrel. METHODS: Of the patients undergoing elective neuro-EVT while taking aspirin and clopidogrel, those taking both antiplatelet agents for 7 days or more and whose PRU and aspirin reaction units (ARU) were measured were included. The primary and safety outcomes were defined as symptomatic ischemic and major bleeding events within 30 days after EVT. RESULTS: A total of 197 patients were available for the analyses. Higher PRU was associated with symptomatic ischemic events on multivariable logistic analysis (odds ratio per 10 increase 1.14 [95% confidence interval 1.03-1.27], p=0.011). Receiver operating characteristic curve analysis showed that PRU ≥212 was the threshold to predict symptomatic ischemic events (area under the curve=0.73; sensitivity, 62.5%; specificity, 82.0%). Lower PRU was also associated with major bleeding events (odds ratio per 10 increase 0.87 [0.78-0.96], p=0.004), and the threshold to predict major bleeding events was PRU ≤46 (area under the curve=0.76; sensitivity, 70.0%; specificity, 87.2%) CONCLUSIONS: The PRU value was associated with symptomatic ischemic and major bleeding events after elective neuro-EVT in patients taking aspirin and clopidogrel. PRU ≥212 and PRU ≤46 appeared to be the threshold values to predict symptomatic ischemic and major bleeding events, respectively.

Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA.

BACKGROUND: Combination antiplatelet therapy with clopidogrel and aspirin may reduce the rate of recurrent stroke during the first 3 months after a minor ischemic stroke or transient ischemic attack (TIA). A trial of combination antiplatelet therapy in a Chinese population has shown a reduction in the risk of recurrent stroke. We tested this combination in an international population. METHODS: In a randomized trial, we assigned patients with minor ischemic stroke or high-risk TIA to receive either clopidogrel at a loading dose of 600 mg on day 1, followed by 75 mg per day, plus aspirin (at a dose of 50 to 325 mg per day) or the same range of doses of aspirin alone. The dose of aspirin in each group was selected by the site investigator. The primary efficacy outcome in a time-to-event analysis was the risk of a composite of major ischemic events, which was defined as ischemic stroke, myocardial infarction, or death from an ischemic vascular event, at 90 days. RESULTS: A total of 4881 patients were enrolled at 269 international sites. The trial was halted after 84% of the anticipated number of patients had been enrolled because the data and safety monitoring board had determined that the combination of clopidogrel and aspirin was associated with both a lower risk of major ischemic events and a higher risk of major hemorrhage than aspirin alone at 90 days. Major ischemic events occurred in 121 of 2432 patients (5.0%) receiving clopidogrel plus aspirin and in 160 of 2449 patients (6.5%) receiving aspirin plus placebo (hazard ratio, 0.75; 95% confidence interval [CI], 0.59 to 0.95; P=0.02), with most events occurring during the first week after the initial event. Major hemorrhage occurred in 23 patients (0.9%) receiving clopidogrel plus aspirin and in 10 patients (0.4%) receiving aspirin plus placebo (hazard ratio, 2.32; 95% CI, 1.10 to 4.87; P=0.02). CONCLUSIONS: In patients with minor ischemic stroke or high-risk TIA, those who received a combination of clopidogrel and aspirin had a lower risk of major ischemic events but a higher risk of major hemorrhage at 90 days than those who received aspirin alone. (Funded by the National Institute of Neurological Disorders and Stroke; POINT ClinicalTrials.gov number, NCT00991029 .).

Comparison of one-month versus twelve-month dual antiplatelet therapy after implantation of drug-eluting stents guided by either intravascular ultrasound or angiography in patients with acute coronary syndrome: rationale and design of prospective, multicenter, randomized, controlled IVUS-ACS and ULTIMATE-DAPT trial.

BACKGROUND: Current guidelines recommend administering dual antiplatelet therapy (DAPT) for 12 months to patients with acute coronary syndromes (ACS) and without contraindications after drug-eluting stent (DES) implantation. A recent study reported that 3 months of DAPT followed by ticagrelor monotherapy is effective and safe in ACS patients undergoing DES implantation compared with the standard duration of DAPT. However, it is unclear whether antiplatelet monotherapy with ticagrelor alone versus ticagrelor plus aspirin reduces the incidence of clinically relevant bleeding without increasing the risk of major adverse cardiovascular and cerebrovascular events (MACCEs) in ACS patients undergoing percutaneous coronary intervention (PCI) with DES implantation guided by either intravascular ultrasound (IVUS) or angiography who have completed a 1-month course of DAPT with aspirin plus ticagrelor. METHODS: The IVUS-ACS and ULTIMATE-DAPT is a prospective, multicenter, randomized, controlled trial designed to determine (1) whether IVUS-guided versus angiography-guided DES implantation in patients with ACS reduces the risk of target vessel failure (TVF) at 12 months and (2) whether ticagrelor alone versus ticagrelor plus aspirin reduces the risk of clinically relevant bleeding without increasing the risk of MACCE 1-12 months after the index PCI in ACS patients undergoing DES implantation guided by either IVUS or angiography. This study will enroll 3486 ACS patients eligible for DES implantation, as confirmed by angiographic studies. The patients who meet the inclusion criteria and none of the exclusion criteria will be randomly assigned in a 1:1 fashion to the IVUS- or angiography-guided group (first randomization). All enrolled patients will complete a 1-month course of DAPT with aspirin plus ticagrelor after the index PCI. Patients with no MACCEs or major bleeding (≥Bleeding Academic Research Consortium (BARC) 3b) within 30 days will be randomized in a 1:1 fashion to either the ticagrelor plus matching placebo (SAPT)group or ticagrelor plus aspirin (DAPT)group for an additional 11 months (second randomization). The primary endpoint of the IVUS-ACS trial is TVF at 12 months, including cardiac death, target vessel myocardial infarction (TVMI), or clinically driven target vessel revascularization (CD-TVR). The primary superiority endpoint of the ULTIMATE-DAPT trial is clinically relevant bleeding, defined as BARC Types 2, 3, or 5 bleeding, and the primary non-inferiority endpoint of the ULTIMATE-DAPT trial is MACCE, defined as cardiac death, myocardial infarction, ischemic stroke, CD-TVR, or definite stent thrombosis occurring 1-12 months in the second randomized population. CONCLUSION: The IVUS-ACS and ULTIMATE-DAPT trial is designed to test the efficacy and safety of 2 different antiplatelet strategies in ACS patients undergoing PCI with DES implantation guided by either IVUS or angiography. This study will provide novel insights into the optimal DAPT duration in ACS patients undergoing PCI and provide evidence on the clinical benefits of IVUS-guided PCI in ACS patients.

Efficacy and safety of proton pump inhibitors combined with clopidogrel in patients undergoing percutaneous coronary intervention: a meta-analysis.

Our objective was to systematically evaluate the efficacy and safety of proton pump inhibitors combined with clopidogrel in patients undergoing percutaneous coronary intervention and to provide an evidence basis for clinical treatment decision-making. The database EMBASE, PubMed/Medline, Web of Science, the Cochrane Library and CNKI records from establishment of each database until August 2020 were included. Articles were evaluated for quality. Meta-analysis of selected articles was conducted by RevMan5.3 software. Three RCTs and 4 cohort studies were included, with a total of 9932 patients. Four studies reported gastrointestinal (GI) bleeding events, 3 of which were RCT studies. Overall, there was a significantly lower risk of GI bleeding events in the PPI group compared to the no PPI group [OR = 3.06, 95% CI: 1.89 to 4.95] (P < 0.00001). In 3 RCT studies, there was also a significantly lower risk of GI bleeding events in the PPI group compared to the no PPI group [OR = 3.06, 95% CI: 1.80 to 5.21] (P < 0.0001). Seven studies including 3 RCTs and 4 cohort studies reported MACE. Overall, there was no significant difference in MACE events between PPI group and no PPI group [OR = 1.05, 95% CI: 0.91 to 1.21] (P = 0.50). Both in RCT and cohort studies subgroups, there also was no significant difference in MACE events between the PPI group and the no PPI group [OR = 1.16, 95% CI: 0.87 to 1.53] (P = 0.32), [OR = 1.02, 95% CI: 0.87 to 1.19] (P = 0.84), respectively. For PCI patients taking clopidogrel and PPI therapy, PPI reduced the risk of GI bleeding while having no impact on MACE.

The comparison between the effects of aspirin and clopidogrel monotherapy on postoperative bleeding in diabetic patients after off-pump coronary artery bypass surgery.

There is limited data about the bleeding complication of antiplatelet therapy after coronary artery bypass graft (CABG) operations focused on diabetic patients. Herein, we aimed to evaluate the effects of aspirin and clopidogrel monotherapies on postoperative bleeding in these patients. A total of 165 diabetic patients who underwent isolated off-pump beating heart coronary artery bypass (OPCAB) operation were evaluated, 84 patients were included in this retrospective study. Patients were divided into groups according to the type of antiplatelet regime. Chest tube drainage amounts and the amount of blood product transfusions were evaluated. Acetylsalicylic acid (ASA) - group included 42 aspirin monotherapy and Clopidogrel - group included 42 clopidogrel monotherapy patients after propensity matching. The mean drainage amount in ASA - group was 670.24 ± 185.46 mL, in Clopidogrel - group was 921.43 ± 167.53 mL (p < 0.001). More packed red blood cell (PRBC) and fresh frozen plasma (FFP) units were needed in the Clopidogrel - group than in the ASA - group (2.05 ± 1.13 vs. 0.83 ± 0.93 units of PRBC, and 1.90 ± 0.58 vs. 1.05 ± 0.58 units of FFP, respectively, p < 0.001). In conclusion, clopidogrel had a stronger effect on bleeding in diabetic patients than aspirin after OPCAB surgery.

Ticagrelor versus Clopidogrel in Symptomatic Peripheral Artery Disease.

BACKGROUND: Peripheral artery disease is considered to be a manifestation of systemic atherosclerosis with associated adverse cardiovascular and limb events. Data from previous trials have suggested that patients receiving clopidogrel monotherapy had a lower risk of cardiovascular events than those receiving aspirin. We wanted to compare clopidogrel with ticagrelor, a potent antiplatelet agent, in patients with peripheral artery disease. METHODS: In this double-blind, event-driven trial, we randomly assigned 13,885 patients with symptomatic peripheral artery disease to receive monotherapy with ticagrelor (90 mg twice daily) or clopidogrel (75 mg once daily). Patients were eligible if they had an ankle-brachial index (ABI) of 0.80 or less or had undergone previous revascularization of the lower limbs. The primary efficacy end point was a composite of adjudicated cardiovascular death, myocardial infarction, or ischemic stroke. The primary safety end point was major bleeding. The median follow-up was 30 months. RESULTS: The median age of the patients was 66 years, and 72% were men; 43% were enrolled on the basis of the ABI and 57% on the basis of previous revascularization. The mean baseline ABI in all patients was 0.71, 76.6% of the patients had claudication, and 4.6% had critical limb ischemia. The primary efficacy end point occurred in 751 of 6930 patients (10.8%) receiving ticagrelor and in 740 of 6955 (10.6%) receiving clopidogrel (hazard ratio, 1.02; 95% confidence interval [CI], 0.92 to 1.13; P=0.65). In each group, acute limb ischemia occurred in 1.7% of the patients (hazard ratio, 1.03; 95% CI, 0.79 to 1.33; P=0.85) and major bleeding in 1.6% (hazard ratio, 1.10; 95% CI, 0.84 to 1.43; P=0.49). CONCLUSIONS: In patients with symptomatic peripheral artery disease, ticagrelor was not shown to be superior to clopidogrel for the reduction of cardiovascular events. Major bleeding occurred at similar rates among the patients in the two trial groups. (Funded by AstraZeneca; EUCLID ClinicalTrials.gov number, NCT01732822 .).

Frequency and clinical outcomes of CYP2C19 genotype-guided escalation and de-escalation of antiplatelet therapy in a real-world clinical setting.

PURPOSE: To evaluate the frequency and clinical impact of switches in antiplatelet therapy following implementation of CYP2C19 genotyping after percutaneous coronary intervention (PCI). METHODS: The frequency of escalation (clopidogrel switched to prasugrel/ticagrelor) and de-escalation (prasugrel/ticagrelor switched to clopidogrel) was evaluated in 1063 PCI patients who underwent CYP2C19 genotyping. Risk of major adverse cardiovascular or cerebrovascular (MACCE) and bleeding events over one year was evaluated. RESULTS: Antiplatelet therapy switches were common (19%), with escalation (101/115: 88%) and de-escalation (77/84: 92%) occurring predominantly in patients with and without a CYP2C19 nonfunctional allele, respectively. Nonfunctional allele carriers initiated and continued on clopidogrel had a significantly higher risk of experiencing either a MACCE or bleeding event compared with those escalated to prasugrel/ticagrelor (52 vs. 19 events/100 patient-years; adjusted hazard ratio [HR] 2.89 [1.44-6.13], p = 0.003). Patients without a nonfunctional allele de-escalated to clopidogrel had no difference in risk compared with those initiated and continued on prasugrel/ticagrelor (21 vs. 19 events/100 patient-years; adjusted HR 1.13 [0.51-2.34], p = 0.751). CONCLUSION: CYP2C19-guided escalation and de-escalation is common in a real-world setting. Continuation of clopidogrel in nonfunctional allele carriers is associated with adverse outcomes. De-escalation to clopidogrel in patients without a nonfunctional allele appears safe and warrants prospective study.