Maintenance Dose Of Clopidogrel Research Articles

Clopidogrel loading dose versus maintenance dose to treat patients with acute ischaemic stroke in China (CLASS-China): results from a prospective double-blind randomised clinical trial

AimThe role of clopidogrel in treating patients with acute ischaemic stroke is unclear. We have conducted the clinical trial in order to evaluate the efficacy and safety of clopidogrel with...

Sepsis favors high-on-clopidogrel platelet reactivity

High-on-treatment platelet reactivity (HPR) is associated with ischemic events in patients on antiplatelet therapy with a history of cardiovascular disease. On the other hand, recent data have associated sepsis with adverse cardiovascular events in patients admitted with bacteremia or respiratory infection. We aimed to assess P2Y12-mediated platelet reactivity (PR) during sepsis and recovery in patients under clopidogrel. This was a prospective observational study. Incoming patients presenting with signs/symptoms of sepsis already on a maintenance dose of clopidogrel of 75 mg qd for cardiovascular events were included in this study. Patients were assessed for their PR on presentation and following septic syndrome, using the VerifyNow point-of-care P2Y12 assay. Patients were excluded in the presence of evidence of noncompliance to antiplatelet regimen or in need of discontinuation during this study. Twenty-two septic patients on clopidogrel were included in this study (Supplemental Figure S1). Clopidogrel was administered for previous stroke, coronary, and peripheral artery disease in 27.3, 40.9, and 31.8% of patients, respectively. The main site of infection was respiratory tract followed by urinary tract, while the same amounts of gram-negative and -positive pathogens were isolated. HPR was noted in 77% and 29% of patients during sepsis and recovery, respectively, presenting a significant decrease in P2Y12 reaction units values during follow-up [240.7 ± 58.3 versus 179.5 ± 58.4, 95% CI (–102.7, –39.76), p = 0.0002]. Five patients died of infection, while no adverse cardiovascular events were noted in our study. Our study shows that sepsis may favor HPR, which is reversed when recovery occurs. This finding may underlie the adverse cardiovascular events in patients admitted with sepsis, possibly requiring alteration of antiplatelet regimen during the inflammation period.

Individualized dual antiplatelet therapy based on platelet function testing in patients undergoing percutaneous coronary intervention: a meta-analysis of randomized controlled trials

BackgroundHigh on-treatment platelet reactivity (HPR) represents a strong risk factor for thrombotic events after PCI. We aim to evaluate the efficacy and safety of individualizing intensified dual antiplatelet therapy (DAPT) in PCI-treated patients with HPR based on platelet function testing (PFT).MethodsElectronic databases were searched for randomized control trials that reported the clinical outcomes of using an intensified antiplatelet protocol with P2Y12 receptor inhibitor comparing with standard maintenance dose of clopidogrel on the basis of platelet function testing. Clinical endpoints were assessed.ResultsFrom 2005 to 2016, thirteen clinical studies comprising 7290 patients were included for analysis. Compared with standard antiplatelet therapy with clopidogrel, the intensified protocol based on platelet function testing was associated with a significant reduction in major adverse cardiovascular events (RR:0.55, 95% CI: 0.36–0.84, p = 0.005), cardiovascular death (RR:0.60, 95% CI: 0.38–0.96, p = 0.03), stent thrombosis (RR:0.58, 95% CI: 0.36–0.93, p = 0.02) and target vessel revascularization (RR:0.33, 95% CI: 0.14–0.76, p = 0.009). No significant difference was found in the rate of bleeding events between intensified and standard protocol.ConclusionsCompared with standard clopidogrel therapy, individualized intensified antiplatelet therapy on the basis of platelet reactivity testing reduces the incidence of cardiovascular events in patient undergoing PCI, without increasing the risk of bleeding.

Gene variants in responsiveness to clopidogrel have no impact on clinical outcomes in Chinese patients undergoing percutaneous coronary intervention — A multicenter study

BackgroundGene variants contribute to variability in individual responsiveness to clopidogrel and influence cardiovascular outcomes in Caucasian patients with acute coronary syndrome (ACS). However, limited data is available in Asian populations. MethodsWe resequenced 14 genes in metabolizing and activity pathway of clopidogrel in 138 patients with ACS and prospectively assessed the modulating effects of 13 variants possibly related to clopidogrel efficacy on one-year cardiovascular event occurrence in 5820 ACS patients after percutaneous coronary intervention (PCI). In addition, platelet aggregation rate was measured in 1084 participants and plasma levels of active metabolite were determined in 15 patients to test whether increasing clopidogrel maintenance doses increases active metabolite exposure. ResultsNo significant associations were found between any of the tested variants and risk of cardiovascular events (P>0.05), although CYP2C19*2 carriers had slightly higher on-treatment platelet aggregation rate and lower active metabolite exposure compared with that of non-carriers (Median [IQR] 51.49 [35.43–66.75] vs. 49.05 [32.36–63.38], P=0.012) (means±SD AUC, 22.84±5.00 vs. 35.05±12.34, P=0.008). Switching from 75mg daily clopidogrel to 150mg daily fully overcomes low exposure to clopidogrel active metabolite in CYP2C19*2 carriers (means±SD AUC, 32.35±8.65 vs. 35.05±12.34, P=0.314). ConclusionDifferent from Caucasian populations, genetic variants have no significant influence on clinical outcomes and have much milder effects on inhibition of platelet and active clopidogrel metabolite levels in Chinese patients with ACS after PCI, an effect which could be overcome with a dose escalation to 150mg daily.

INFLUENCE OF SWITCHING OF CLOPIDOGREL TO TICAGRELOR ON THE DEVELOPMENT OF CARDIOVASCULAR EVENTS IN PATIENTS WITH ST SEGMENT ELEVATION

Aim. To study the effect of replacing clopidogrel with ticagrelor on endpoints of hospital period and one year after ST Segment Elevation Myocardial Infarction (STEMI). Material and methods . The study enrolled 80 patients with STEMI. At the stage of emergency medical service, all patients received loading doses of acetylsalicylic acid (250 mg) and clopidogrel (600 mg). After 12-24 hours, the patients were randomized into two groups. Patients of the first group received maintenance doses of acetylsalicylic acid (100 mg/day) and clopidogrel 75 mg/day. Patients of the second group received maintenance doses of acetylsalicylic acid (100 mg/day) and ticagrelor 90 mg twice a day. ADP-induced platelet aggregation (1.25 and 2.5 mg/ml) and proinflammatory factors blood levels (C-reactive protein [CRP], interleukin 6 [IL-6]) were investigated before clopidogrel replacement, as well as 2 hours and 7 days after its replacement. Endpoints were recorded at the patient's discharge and one year later. Results. After a year in the ticagrelor group there was a trend towards fewer endpoints compared to clopidogrel group (combined endpoint 14.2% vs 25%, p=0.14). In the ticagrelor group, there was no significant increase in the incidence of bleeding compared with the clopidogrel group both in the hospital period and during the year after the STEMI (large bleeding – 0 vs 3.3%, small bleeding – 25.4% vs 26.6%, p=0.48). On the 8th day of STEMI (7 days after clopidogrel replacement), platelet aggregation in the clopidogrel group was significantly higher compared to platelet aggregation in the ticagrelor group (p=0.00). The level of CRP and IL-6 on the 8th day of hospitalization in the clopidogrel group was significantly higher in comparison with the ticagrelor group (p=0.04 and p=0.01, respectively). Conclusion. When clopidogrel is replaced with ticagrelor on the 1st day of STEMI, there is a tendency to a lower incidence of endpoints during the first year of follow-up. Such switching is safe from the point of view of hemorrhagic complications and is associated with lower platelet aggregation and inflammation activity estimated 7 days after clopidogrel replacement (on the 8th day of STEMI).

LEVELS OF PROINFLAMMATORY MARKERS IN STEMI PATIENTS IN DIFFERENT TYPES OF DUAL ANTIPLATELET THERAPY

Aim. To assess levels of interleukin-6 (IL-6) and cardial infarction patients receiving clopidogrel or ticaC-reactive protein (CRP) in ST-segment elevation myogrelor in the in-hospital period. Methods. 80 patients with STEMI were included in the study. All patients received a loading dose of aspirin (250 mg) and clopidogrel (600 mg) in the ambulance. All patients underwent urgent coronary angiography with the further stenting of the infarct-related artery with bare-metal stents. All patients were assigned to two groups using simple random sampling. Group 1 patients received a daily maintenance dose of clopidogrel 75 mg. Group 2 patients received a maintenance dose of ticagrelor 90 mg twice daily. Plasma levels of IL-6 and CRP were measured on day 1 after the hospital admission before replacing clopidogrel to ticagrelor and on day 7 after switching clopidogrel to ticagrelor (day 8 of the in-hospital period). Results. Levels of CRP and IL-6 in the early period after STEMI in the groups of patients receiving clopidogrel and ticagrelor were similar (p=0.82 vs. p=0.27, respectively). On day 8, CRP levels in the clopidogrel group were significantly higher than CRP levels in the ticagrelor group on day 8 (25.3 (4.6; 46.4) ml / l vs. 17.5 (4.6; 20.9) mg / l, respectively (p = 0.04). The level of IL-6 in the clopidogrel group on day 8 was significantly higher than the level of IL-6 on day 8 in the ticagrelor group (7.03 (2.7; 11.3) pg / mL, vs. 2.8 (1.8; 4.2) pg / mL, respectively (p = 0.01). Conclusion. Levels of proinflammatory markers were significantly lower in the ticagrelor group on day 8 after STEMI compared to the clopidogrel group.

CYP2C19 PHARMACOGENETIC TESTING FOR PERSONALIZATION OF ANTIPLATELET THERAPY IN PATIENTS WITH ACUTE CORONARY SYNDROME IN ROUTINE CLINICAL PRACTICE

Aim. To study the use of CYP2C19 pharmacogenetic testing (PhGT) for personalization of antiplatelet therapy in patients with acute coronary syndrome (ACS) in routine practice. Material and methods . The study included 103 patients with ACS without indications for long-term anticoagulant therapy, which underwent CYP2C19 PhGT aimed at antiplatelet therapy personalization. Results. According to CYP2C19 genotyping the GG, GA, AA allelic variants were detected. CYP2C19*2 PhGT revealed that genotypes GG , GA and AA were carried by 76 (73.8%), 23 (22.3%) and 4 (3.9%) patients, respectively. Initially 86 (83.5%) patients received clopidogrel, 17 (16.5%) – ticagrelor. After therapy correction based on genotype GA and AA , the proportion of ticagrelor receiving patients increased from 25.9% to 55.5% (relative risk=0.172; 95% confidence interval 0.075-0.396; p<0.001). In 40.7% of patients who were poor clopidogrel metabolizers increased clopidogrel doses during maintaining therapy can be associated with the increased risk of bleeding. Conclusion. PhGT results (detection of carriage of the CYP2C19*2 allele variant) was a significant predictor of antiplatelet therapy correction in ACS patients. Therapy personalization included the replacement of clopidogrel with ticagrelor or an increase in the clopidogrel maintenance dose to 150 mg per day, which did not affect significant clinical outcomes.

Switching between ticagrelor and clopidogrel in patients who underwent percutaneous coronary intervention: insight into contemporary practice in Chinese patients.

Ticagrelor has been proved to be more effective than clopidogrel; however, little is known about the switching between ticagrelor and clopidogrel in real-world clinical practice. We assessed the prevalence, related factors, dose bridging, compliance, and short-term outcomes of in-hospital switching between ticagrelor and clopidogrel in consecutively recruited patients treated by ticagrelor after percutaneous coronary intervention (PCI). A total of 417 eligible patients administrated with ticagrelor in-hospital after PCI were recruited. Switching between ticagrelor and clopidogrel occurred in 362 (86.8%) patients, with 318 (76.3%) from clopidogrel to ticagrelor occurring mainly after PCI and 44 (10.6%) from ticagrelor to clopidogrel primarily at discharge. History of cerebrovascular disease, final diagnosis of acute coronary syndrome, left main disease, ostial lesion, co-administration with warfarin, CYP2C19 loss-of-function alleles' carriage status, and ticagrelor-related dyspnoea emerged as related factors for the switching between clopidogrel and ticagrelor. Dose bridging between clopidogrel loading dose and ticagrelor maintenance dose (MD) was more frequent in patients switching from clopidogrel to ticagrelor, while the bridging between ticagrelor MD and clopidogrel MD was more likely to occur in patients switched from ticagrelor to clopidogrel. At 6 month follow-up, poor compliance was observed in patients from clopidogrel to ticagrelor (64.8%) or treated only by ticagrelor (50.9%), but perfect compliance in patients from ticagrelor to clopidogrel (100%). After excluding the cases with incompliance, patients switching from ticagrelor to clopidogrel had a relatively lower bleeding risk in comparison with patients with constant ticagrelor treatment and those switching from clopidogrel to ticagrelor (29.5% vs. 50.0% vs. 46.6%, adjusted P = 0.02). In-hospital switching between ticagrelor and clopidogrel is frequent in patients undergoing PCI. In comparison with constant ticagrelor treatment, switching from clopidogrel to ticagrelor in ischaemic high-risk patients confers similar antiplatelet efficacy and safety, while switching from ticagrelor to clopidogrel in ischaemic low-risk patients relates to lower hazard for bleeding events.

Platelet reactivity in patients receiving a maintenance dose of P2Y12-ADP receptor antagonists undergoing elective percutaneous coronary intervention

BackgroundP2Y12-ADP receptor blockade during percutaneous coronary intervention (PCI) is critical to prevent thrombotic events. In patients under chronic P2Y12 blockers, the use of additional loading dose (LD) before an elective PCI is debated. We aimed to investigate the rate of high on-treatment platelet reactivity (HTPR) in patients undergoing elective PCI during chronic clopidogrel or ticagrelor therapy. Methods and resultsWe performed a sub-group analysis of a randomized trial comparing ticagrelor and clopidogrel in acute coronary syndrome (ACS) patients undergoing PCI. Multi-vessel disease patients requiring a staged PCI one month after the ACS were included. The VASP (vasodilatatory phosphoprotein) index, which is a specific and reproducible platelet assay to measure P2Y12-ADP receptor activity, was used to assess the biological efficacy of the maintenance dose (MD) of ticagrelor and clopidogrel before PCI. Forty-one patients in each group of randomization required a staged PCI. They were similar regarding the baseline demographic, clinical and angiographic characteristics. The mean VASP index in the ticagrelor group was 20.7±8.8% compared to 51.8±17% in the clopidogrel group (p<0.001) before PCI. No patients had a VASP index ≥50% in the ticagrelor group compared to 56% in the clopidogrel group (p<0.001). Following PCI the rate of peri-procedural MI was higher in the clopidogrel group (p=0.02). ConclusionsUnlike clopidogrel MD, ticagrelor MD achieves an optimal PR inhibition in all patients during a staged PCI.

Diabetes mellitus, CYP2C19 genotype, and response to escalating doses of clopidogrel. Insights from the ELEVATE-TIMI 56 Trial.

Both diabetes mellitus (DM) and carriage of the CYP2C19*2 allele are associated with a reduced response to clopidogrel. The relative contributions of these factors and whether higher clopidogrel doses can overcome both factors remain unknown. The objective of this study was to test the ability of clopidogrel doses up to 300 mg daily to decrease platelet reactivity in patients with DM and/or CYP2C19*2. ELEVATE-TIMI 56 randomised 333 patients with coronary artery disease to different maintenance doses of clopidogrel in four treatment periods, each lasting approximately 14 days. On-treatment platelet reactivity was compared between patients stratified by DM, CYP2C19*2 status and clopidogrel dose. Both DM and CYP2C19*2 were independently associated with elevated on-treatment platelet reactivity with clopidogrel 75 mg daily (p<0.0001 for each). With 75 mg, mean on-treatment PRU was progressively higher (p trend <0.001) when evaluating patients: with neither DM nor CYP2C19*2 (150.7; 95 % CI 140.5-162.6), with only DM (187.2; 95 % CI, 171.3-206.9), with only CYP2C19*2 (227.9; 95 % CI, 205.1-250.8), and with both DM and CYP2C19*2 (239.9; 95 % CI, 209.7-270.1). Notably, with 75 mg, patients with only CYP2C19*2 had higher on-treatment platelet reactivity than those with only DM (p=0.0068). To achieve on-treatment platelet reactivity similar to that seen with clopidogrel 75 mg in patients with neither DM nor CYP2C19*2, the following doses were required: 150 mg with only DM, 225 mg with only CYP2C19*2, and 300 mg with both DM and CYP2C19*2. Patients with both DM and CYP2C19*2 required a four-fold increase in clopidogrel maintenance dose as compared to patients without these factors to achieve a similar antiplatelet response.

Relationship between clopidogrel-related polymorphisms and variable platelet reactivity at 1 year: A cohort study from Han Chinese.

Background:This study was designed to investigate the effect of clopidogrel-related gene polymorphisms on platelet reactivity and clinical outcome in Chinese Han patients.Materials and Methods:Three hundred and thirty-six percutaneous coronary intervention - treated patients were recruited and followed for 1 year. Blood samples were collected from all patients for DNA genotyping. The platelet reactivity unit was measured by the VerifyNow technique. The CYP2C19*2, CYP2C19*3, CYP2C19*17, ATP-binding cassette subfamily B member 1, ITGB3, CYP2C9*3, CYP2B6*9, and P2Y12 alleles were assessed.Results:The clinical endpoints were related to previous heart disease history (11.90% vs. 28.57%, P = 0.017), stroke (12.24% vs. 16.67%, P = 0.039), and diabetes (27.55% vs. 52.38%, P = 0.047). High on-treatment platelet reactivity (HTPR) was frequent in advanced age (P = 0.019), male gender (P = 0.016), hypertension (P = 0.033), and chronic renal failure (P = 0.040). There were more endpoints in the CYP2C19*2 and P2Y12 mutant carriers (76.19% vs. 43.20%, P < 0.001; 50.00% vs. 35.71%, P = 0.001, respectively), whereas fewer in the CYP2C19*17 mutant carriers (11.90% vs. 56.46%, P = 0.001). CYP2C19*2 and P2Y12 polymorphism manifested HTPR (194.25 ± 45.91 vs. 151.38 ± 58.14, P < 0.001; 180.33 ± 67.25 vs. 161.89 ± 56.49, P = 0.008, respectively), whereas CYP2C19*17 mutant improved platelet reactivity (97.17 ± 45.38 vs. 169.08 ± 57.15, P = 0.003). However, there were no further cardiovascular deaths in endpoint patients.Conclusion:In Han Chinese people of mainland China, clopidogrel-related gene polymorphisms are related to variable platelet reactivity after clopidogrel maintenance dosing, which influences major adverse cardiovascular events, without an effect on cardiac death.

0321: In the aera of new P2Y12 inihibitors, high platelet reactivity on aspirin in patients with ST elevation myocardial infarction remains a predictor of ischemic events

Despite dual antiplatelet treatment with the new P2Y12 platelet receptor antagonists (P2Y12i), major ischemic events are common following ST elevation myocardial infarction (STEMI). To assess separately resistance to aspirin (HPR-aspirin), resistance to P2Y12i (HPR-P2Y12i) and their association during the acute phase of STEMI in relation to the occurrence of ischemic events. We included all consecutive patients admitted for STEMI in our center between January 2013 and December 2013. All patients received a loading dose followed by a maintenance dose of aspirin (75mg/day) and either clopidogrel, prasugrel or ticagrelor. Platelet reactivity was assessed 4±1 days and 75±15 days after admission using light transmission aggregometry (LTA) with arachidonic acid (AA) and serum Thromboxane-B2 concentration to assess HPR-aspirin and LTA-ADP and VASP index to assess HPR-P2Y12i. Major cardiac and cerebrovascular events (MACCE) were recorded during one year. 106 patients (61years old, 76% male, 20% with diabetes) were included. STEMI was anterior in 52% and LV ejection fraction at discharge was 51±9%. At day 4 after STEMI, HPR-aspirin measured by LTA-AA alone was found in 23% patients and was correlated with serum thromboxane inhibition, HPR-P2Y12i (VASP≥50% and LTA-ADP≥65%) was observed only in 7% and combined resistance was present in 4% of the patients. Diabetes and age were predictors of HPR-aspirin. The large use of ticagrelor (34%) and prasugrel (50%) explained the low rate of P2Y12i resistance. HPR-aspirin was persistent 75 days later in 36% patients who were resistance at day 4. At 1 year, 7.9% patients had experienced MACCE. HPR-aspirin alone and HPR for both aspirin and P2Y12i were significantly associated with MACCE. Aspirin resistance is frequent just after STEMI and is associated with MACCE especially when associated with P2Y12i resistance.

Relationship between Inflammation and Aspirin and Clopidogrel Antiplatelet Responses in Acute Ischemic Stroke

We measured serum levels of proinflammatory/prothrombotic markers P-selectin, CD40L, matrix metalloproteinase 9 (MMP-9), intracellular adhesion molecule 1 (ICAM-1), and interleukin (IL)-6 in ischemic stroke patients, correlating their levels with the results of aspirin (ASA) and clopidogrel antiplatelet responses, using 3 "point of care" platelet function instruments, thromboelastograph (TEG), Accumetrics (ACU), and impedance aggregometer (IMP). Patients on chronic ASA regimen at the time of stroke were switched to 300 mg clopidogrel loading dose and 75 mg clopidogrel maintenance dose. Serum levels of the aforementioned inflammatory mediators were measured in 51 patients at baseline (on ASA regimen), and at 26 ± 5 hours and 64 ± 18 hours postclopidogrel administration by enzyme-linked immunosorbent assay. P-selectin, CD40L, and MMP-9 serum levels were reduced; ICAM-1 and IL-6 serum levels showed no difference postclopidogrel administration relative to baseline. Patients' stratification based on ASA dose showed more significant reductions in P-selectin, CD40L, and MMP-9 serum levels postclopidogrel administration in patients who were on baseline 81 mg ASA, as compared to patients on 325 mg ASA. Measurement with TEG was sensitive for correlating ASA antiplatelet responses to serum levels of inflammatory markers, whereas measurements with ACU and IMP were sensitive for correlating clopidogrel antiplatelet responses to serum levels of inflammatory markers. Clopidogrel exerts both platelet-dependent and platelet-independent anti-inflammatory effects. The association between platelet function and inflammation depends on the platelet function analyzer, the type of antiplatelet agent, the nature of the inflammatory marker, and the time of measurement relative to the time of drug administration.

High maintenance dose of clopidogrel in patients with high on-treatment platelet reactivity after a percutaneous coronary intervention: a meta-analysis.

High on-treatment platelet reactivity (HTPR) has been linked to cardiovascular (CV) events after a percutaneous coronary intervention. There have been some controversies on whether a high maintenance dose (MD) of clopidogrel is effective for HTPR patients. Thus, we carried out a meta-analysis to assess the efficacy and safety of a high MD of clopidogrel in patients with HTPR. Searches of PubMed (from 1966 to May 2014), EMBASE (from 1974 to May 2014), and the Cochrane Library (2 May 2014) were performed. All randomized-controlled trials assessing the efficacy and safety of a high MD of clopidogrel in patients with HTPR were included. A total of eight randomized-controlled trials including 3865 patients were included for analysis. In patients with HTPR, high-dose clopidogrel significantly reduced the risk of major adverse CV events or major adverse cardiac and cerebrovascular events [risk ratio (RR) 0.59; 95% confidence interval (CI) 0.39-0.88], stent thrombosis (RR 0.43; 95% CI 0.20-0.92), and target vessel revascularization (RR 0.31; 95% CI 0.10-0.93), without increasing major bleeding (RR 0.75; 95% CI 0.43-1.31) compared with standard-dose clopidogrel. A high MD of clopidogrel may be a feasible and readily available treatment to lower the risk of recurrent CV events in patients with HTPR after undergoing percutaneous coronary intervention, especially in HTPR patients with coronary artery disease and chronic kidney disease.

Influence of Genetic Polymorphisms on Clopidogrel Response and Clinical Outcomes in Patients with Acute Ischemic Stroke CYP2C19 Genotype on Clopidogrel Response.

This study sought to evaluate the influence of the genetic polymorphisms on platelet reactivity and clinical outcomes in acute ischemic stroke patients taking clopidogrel. Little research has been published on relationships between genetic polymorphisms, platelet reactivity, and clinical outcomes in stroke patients treated with clopidogrel. Patients hospitalized in Changhai Hospital with acute ischemic stroke were randomly enrolled into treatment with a 75-mg daily maintenance dose of clopidogrel. Genotyping was detected by the MassARRAY iPLEX genotyping system (Sequenom Inc, San Diego, CA), and platelet reactivity was evaluated by the VerifyNow P2Y12 test (Accumetrics Inc., San Diego, CA). Sixteen single nucleotide polymorphisms (SNPs) within 9 genes were selected and high on-clopidogrel platelet reactivity (HPR) was defined as P2Y12 reaction units (PRU) value ≥230. The primary endpoint was ischemic events, including major adverse cardiac events (MACE), recurrence of stroke, transient ischemic attack (TIA), and the composite of vascular death, and the secondary endpoint was bleeding. Of the 345 patients recruited, 275 (79.7%) patients were followed up for 1 year and 122 (35.4%) patients were categorized as HPR. Among the SNPs selected, only the CYP2C19*2 allele and the CYP2C19*3 allele were statistically significantly associated with PRU (P < 0.001 and P = 0.003, respectively). Similarly, the prevalence of HPR was associated with CYP2C19*2 and CYP2C19*3 (P < 0.001 and P = 0.001, respectively). During the 1 year of follow-up, a total of 64 (23.3%) cases of clinical events occurred, including 60 ischemic events and 4 bleeding events. There were no correlation between CYP2C19 variant alleles and clinical outcomes (P > 0.05), but a statistically significant relevance was found between the HPR and the ischemic events in 1 year of follow-up (P = 0.001). CYP2C19*2 and CYP2C19*3 had a significant impact on clopidogrel response, but was not associated with ischemic events during 1 year of follow-up in patients with acute ischemic stroke. HPR was an independent risk factor for ischemic events, and the VerifyNow P2Y12 test may be available to guide individualized antiplatelet therapies in stroke patients in China.

Prediction of high risk of non-adherence to antiplatelet treatment.

Dual antiplatelet therapy with acetylsalicylic acid (ASA) and clopidogrel is the standard of care for secondary prevention. Premature discontinuation of clopidogrel is associated with an increased risk of myocardial infarction (MI) or death, and greater health care expenditure. To develop an objective method for identification of patients with high risk of non-adherence to clopidogrel after MI. A total of 189 patients were enrolled into a prospective, observational, single-centre study with a nine-month follow-up. Patients received a 600-mg loading dose and 75-mg maintenance dose of clopidogrel in combination with ASA doses of 300 mg and 75 mg, respectively. Adenosine diposphate-induced platelet aggregation (ADP-PA) was assessed during baseline hospitalisation and at three, six, and nine months after discharge. Adherence to medication with clopidogrel was defined as the proportion of drug availability based on data from the National Health Fund regarding prescribed drug purchases. Adherence was arbitrarily judged adequate when the proportion exceeded 80%. According to our hypothesis, ADP-PA in non-adherent patients should be higher at follow-up visits (at least once) as compared with measurement at hospitalisation. Based on the ROC curve analysis, the optimal cut-off point equal to 4 U was defined (p < 0.0001, 95% CI 0.562-0.654; sensitivity: 60.6%, specificity: 57.1%, positive predictive value: 63.3%, negative predictive value: 54.2%). The prevalence of true adherence to medication in groups of high and low probability of adherence defined according to developed criteria amounted 60 (50.8%) and 23 (32.4%) cases, respectively (p = 0.01). The newly developed method of objective identification of patients with high risk of non-adherence to clopidogrel after MI is easily applicable and cheap, and, despite relatively low sensitivity and specificity, it efficiently differentiates patients with regard to clinical end-points during follow-up.

ACP Journal Club. Review: In patients having PCI, high-dose clopidogrel reduces major cardiac events vs standard-dose clopidogrel.

Source Citation Ma W, Liang Y, Zhu J, Wang Y, Wang X. Meta-analysis appraising high maintenance dose clopidogrel in patients who underwent percutaneous coronary intervention with and without high on-clopidogrel platelet reactivity. Am J Cardiol. 2014;115:592-601. 25613665

Is a high maintenance dose of clopidogrel suitable for overcoming clopidogrel resistance in patients?

A double maintenance dose of clopidogrel at 150 mg daily has been suggested as an effective alternative treatment for patients who have clopidogrel resistance. To determine if a double maintenance dose of clopidogrel can overcome the low drug response rate observed in patients who have clopidogrel resistance while on a 75 mg daily standard maintenance dose of clopidogrel. A retrospective analysis was conducted in South Korean patients who underwent a platelet function test and received a double maintenance dose of clopidogrel at a secondary medical institution between January 2011 and June 2012. The primary endpoint was to assess clopidogrel response using an adenosine diphosphate test after a double maintenance dose of clopidogrel. The secondary endpoint was the presence of factors that could affect response to clopidogrel. Of 389 patients identified, 77 patients were eligible for this study. Values from the adenosine diphosphate test decreased significantly in 63 patients (82%) after a double maintenance dose of clopidogrel (p < 0.001). A total of 37 patients (48%) overcame clopidogrel resistance. Concurrent disease appeared to be a contributory factor in clopidogrel resistance. A double maintenance dose of clopidogrel at 150 mg daily was associated with a reduction in adenosine diphosphate-induced platelet aggregation in South Korean patients who previously exhibited clopidogrel resistance.

CYP2C19*2 genotype influence in acute coronary syndrome patients undergoing serial clopidogrel dose tailoring based on platelet function testing: Analysis from randomized controlled trial NCT02096419

Aspirin and a P2Y12 inhibitor administration are crucial in acute coronary syndrome (ACS) and percutaneous coronary intervention. ADP- induced high on-treatment platelet reactivity (HTPR) increases the rate of adverse ischemic events and whether it is a modifiable risk factor for future events is not clear. CYP2C19 enzyme plays a significant role in clopidogrel bioactivation and its polymorphism can cause clopidogrel pharmacodynamic effect reduction. Earlier, we performed a clopidogrel dose tailoring trial based on serial platelet function testing (PFT) using Multiplate® electrode aggregometry during 12 months to maintain optimal platelet reactivity (PR) in ACS patients presenting with HTPR. Patients were randomly assigned to an interventional group taking up to two additional 600 mg loading doses and a range of 75-300 mg maintenance dose, and a control group on standard clopidogrel maintenance dose. Patients in the interventional group maintained better PR during follow-up and had better outcome. In this exploratory analysis we sought to evaluate the effect of CYP2C19*2 genotype on PR levels in both groups of patients during the initial trial. There were no differences in PR between CYP2C19*2 carriers and non-carriers in the interventional group (p=0.187) while CYP2C19*2 carriers had significantly higher PR compared to non-carriers in the control group (p<0.05). Adjusting clopidogrel dose after PFT to reach and maintain optimal PR might overcome unfavorable genotype in ACS patients initially presenting with HTPR. This implies that strategies of antiplatelet therapy tailoring studies should be focused on maintaining optimal PR phenotype, rather than adjusting P2Y12 inhibition based on genotype to improve outcomes.

Intrinsic platelet reactivity before start with clopidogrel as predictor for on-clopidogrel platelet function and long-term clinical outcome

High on-clopidogrel platelet reactivity is associated with worse clinical outcome. Previous data suggest that intrinsic platelet reactivity before initiation of clopidogrel contributes significantly to on-clopidogrel platelet reactivity. It is unknown whether intrinsic reactivity can sufficiently predict on-clopidogrel reactivity and therefore identify patients with insufficient response to clopidogrel before initiation of treatment and at risk for worse clinical outcome. This analysis included 765 consecutive patients undergoing elective coronary stent implantation. Platelet reactivity was assessed by light transmission aggregometry (5 µM ADP) before administration of clopidogrel 600mg and after intake of first maintenance dose of clopidogrel on day 1 following coronary stenting. Patients were followed for up to seven years. The combined primary endpoint was death of any cause or non-fatal myocardial infarction. Intrinsic and on-clopidogrel platelet reactivity were significant correlated (r=0.31; p < 0.001). Among all tested clinical and genetic factors including the cytochrome P450 2C19*2 polymorphism, intrinsic platelet reactivity was the strongest predictor for on-clopidogrel platelet reactivity. However, intrinsic platelet reactivity could only explain 8 % of variability of on-clopidogrel platelet function. Only on-treatment platelet reactivity was predictive for long-term clinical outcome (HR 1.47, 95 % CI 1.05-2.05; p = 0.02) whereas intrinsic platelet reactivity was not (HR 1.03, 95 % CI 0.74-1.43; p = 0.86). In conclusion, intrinsic platelet reactivity before initiation of clopidogrel is the strongest predictor of early on-clopidogrel platelet reactivity but can only explain a minor proportion of its variability and is not significantly associated with clinical outcome. Thus, baseline testing cannot substitute on-clopidogrel platelet function testing.