The role of platelet reactivity assessment in dual antiplatelet prophylaxis after transcatheter aortic valve implantation.

BACKGROUND: Dual antiplatelet therapy (DAPT) is recommended prophylaxis after transcatheter aortic valve implantation (TAVI). The usefulness of platelet reactivity (PLTR) tests in predicting the safety of periprocedural DAPT in the TAVI population is unknown. AIM: To analyze the value of aspirin/clopidogrel PLTR testing in predicting the risk of in-hospital TAVI-related bleeding. METHODS: PLTR, expressed as P2Y12/aspirin reaction units (PRU/ARU), was performed using optical aggregometry with the VerifyNow® device, in the 24h before and on the sixth day after TAVI. Follow-up was by telephone. Bleeding was defined according to VARC-2, and comprised in-hospital, major and life-threatening events. RESULTS: Overall, 100 patients undergoing TAVI were included; 30 (30%) had bleeding. Clopidogrel PLTR before TAVI (area under the curve [AUC] 0.686, 95% confidence interval [CI] 0.542-0.808; P=0.02) and after TAVI (AUC 0.970, 95% CI 0.904-0.995; P<0.001) correlated with bleeding, with PRU cut-off values of ≤204 and ≤124 as bleeding predictors, respectively. A significant periprocedural decrease in clopidogrel PLTR was noted, with a PRU drop of >78 as bleeding predictor (AUC 0.851, 95% CI 0.725-0.935; P<0.001). Only postprocedural aspirin PLTR was associated with bleeding (AUC 0.697, 95% CI 0.585-0.794; P=0.008). Follow-up (359±73 days after TAVI) included 85 patients (85%) (after exclusion for in-hospital death [n=4] and lack of contact [n=11]). Major bleeding was noted in four patients (4.7%), all on combined prophylaxis. CONCLUSIONS: TAVI-related bleeding occurs mainly during the procedure or in the early postprocedural period. Testing of periprocedural clopidogrel PLTR, but not aspirin PLTR, seems useful because of its predictive value for TAVI-related bleeding. PLTR testing suggests that premedication with clopidogrel, enhanced response to clopidogrel early after TAVI and significant periprocedural drop in clopidogrel PLTR might increase the risk of TAVI-related bleeding.

Comparative pharmacodynamic effects of two clopidogrel formulations under steady-state conditions in healthy Thai volunteers
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OBJECTIVE: Clopidogrel is a commonly used antiplatelet aggregation agent. Compared with the reference clopidogrel product, most commercially available generic clopidogrel products contain different crystalline forms of clopidogrel. This study was aimed to compare the pharmacodynamics of a commonly used generic clopidogrel product in Thailand with the reference clopidogrel product under steady state conditions. METHODS: A multiple-dose, randomized 2-way crossover study was conducted in 32 healthy male Thai volunteers. The subjects were assigned to receive 75 mg once daily of the test or the reference product for 7 days with a 2-week wash out period. Blood samples were collected on days 1, 5, 6, and 7 prior to drug administration and at 1, 2, 3, 4, 8, 12, and 24 hours after the last dose administered. The antiplatelet aggregation effects of clopidogrel were determined by using two different ex-vivo platelet aggregation tests including the whole blood impedance assay (WBA) and the VerifyNow® P2Y12 assay. Both pharmacodynamic parameters, the maximal antiplatelet effect (Emax) and the areas under the antiplatelet effect-time curve (AUEC0-24h), were calculated. RESULTS: Neither the mean values of Emax (90.70 ± 15.15 vs. 89.50 ± 10.71% inhibition) nor of AUEC0-24h (1,892.84 ± 657.22 vs. 1,853.58 ± 673.95% inhibition × h) under steady-state conditions obtained using the WBA method of these two clopidogrel products were significantly different. The results obtained using the VerifyNow® P2Y12 assay were consistent with those of the WBA assay. CONCLUSION: This study clearly demonstrated that ex-vivo antiplatelet aggregation effect under steady-state conditions of the test product was not significantly different from the reference product.
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Optimal P2Y12 Inhibitor in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention: A Network Meta-Analysis.

OBJECTIVES: The study sought to compare the clinical efficacy and safety of P2Y12 inhibitors in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous intervention (PPCI). BACKGROUND: Limited data exist regarding the comparative efficacy and safety of P2Y12 inhibitors in STEMI patients undergoing PPCI. METHODS: Clinical trials enrolling STEMI patients were identified and relevant data was extracted. Major adverse cardiovascular events (MACE) were defined as the composite of all cause mortality, MI, and target vessel revascularization. Network meta-analysis was performed using Bayesian methods. RESULTS: A total of 37 studies with 88,402 STEMI patients and 5,077 MACE were analyzed. Outcomes at 1 month (22 studies and 60,783 patients) suggest that prasugrel was associated with: lower MACE than clopidogrel (standard dose odds ratio [OR]: 0.59, 95% confidence interval [CI]: 0.50 to 0.69; high-dose OR: 0.60, 95% CI: 0.51 to 0.71; upstream OR: 0.79, 95% CI: 0.66 to 0.94), and ticagrelor (standard dose OR: 0.69, 95% CI: 0.56 to 0.84; upstream OR: 0.72, 95% CI: 0.50 to 1.05); lower mortality and MI than clopidogrel and standard ticagrelor; lower stroke risk than standard clopidogrel and standard or upstream ticagrelor; and lower stent thrombosis than standard or upstream clopidogrel. At 1-year (10 studies, n = 40,333) prasugrel was associated with lower mortality and MACE than other P2Y12 inhibitors. MACE was particularly lower with prasugrel in studies where patients received bivalirudin, drug-eluting stents, and but not glycoprotein IIb/IIIa inhibitor. CONCLUSIONS: In STEMI patients undergoing PPCI, prasugrel and ticagrelor are more efficacious than clopidogrel; in addition, prasugrel was superior to ticagrelor particularly in conjunction with bivalirudin and drug-eluting stents.

Is There an Ideal Level of Platelet P2Y12-Receptor Inhibition in Patients Undergoing Percutaneous Coronary Intervention?: "Window" Analysis From the ADAPT-DES Study (Assessment of Dual AntiPlatelet Therapy With Drug-Eluting Stents).

OBJECTIVES: This study sought to determine whether there is an ideal level of platelet reactivity (PR) to optimize safety and efficacy within the large multicenter ADAPT-DES (Assessment of Dual AntiPlatelet Therapy With Drug-Eluting Stents) study of 8,582 patients receiving successful drug-eluting stent implantation. BACKGROUND: Patients with high PR on clopidogrel have a greater incidence of adverse ischemic events after stent implantation, whereas low PR may increase bleeding. Due to limited sample size, previous studies have not been able to adjust for differences in baseline characteristics that may confound the relationship of PR and outcomes. METHODS: In the ADAPT-DES study, routine platelet function testing (VerifyNow) was performed following clopidogrel loading. To characterize the independent association between PR and clinical events, patients were stratified into quintiles of P2Y12 reaction units (PRU). RESULTS: The PRU medians of the 5 quintiles were 57, 130, 187, 244, and 317 (most to least inhibited). There was a monotonic association between successively higher PRU quintiles and stent thrombosis, whereas for clinically relevant bleeding, the greatest risk occurred in the lowest PRU quintile, with similar risks across the 4 higher quintiles. These relationships remained significant in fully adjusted multivariable analyses (adjusted hazard ratio [HR] for stent thrombosis in Q5 versus Q1: 2.32; 95% confidence interval [CI]: 1.17 to 4.59; p = 0.02; adjusted HR for clinically relevant bleeding in Q5 versus Q1: 0.61; 95% CI: 0.47 to 0.77; p < 0.001). However, there were no significant independent associations between the level of PRU and mortality. CONCLUSIONS: In this large observational study, increasing PRU was associated with a monotonic increase in stent thrombosis, whereas bleeding risk was confined to the lowest PRU quintile, suggesting an optimal therapeutic window of platelet inhibition at moderately inhibited PRU. However, there was no demonstrable threshold effect for PRU and mortality in adjusted analyses, perhaps due to the offsetting impact of bleeding and ischemia across the spectrum of platelet inhibition. (Assessment of Dual AntiPlatelet Therapy With Drug-Eluting Stents [ADAPT-DES]; NCT00638794).

High on-treatment platelet reactivity in patients with ischemic cerebrovascular disease: assessment of prevalence and stability over time using four platelet function tests.

High on-treatment platelet reactivity (HTPR), referred to as a higher than expected platelet reactivity in patients under antiplatelet therapy, could influence outcome in cerebrovascular disease (CVD), but its prevalence and its stability over time is uncertain. Platelet reactivity was assessed in 18 patients with ischemic stroke/transient ischemic attack (TIA) 7 days (D7) and 90 days (D90) after prescription of clopidogrel, using four methods: light transmission aggregometry with 5 µmol/l ADP (LTA-ADP), vasodilator-stimulated phosphoprotein (VASP), Verify Now P2Y12 and platelet function analyzer (PFA) P2Y. HTPR was defined as LTA-ADP more than 46%; PFA-100-P2Y closure time less than 106 s; VerifyNow P2Y12, PRU greater than 235, VASP, PRI greater than 50%. Patients displayed, both at D7 and D90, a marked inhibition of platelet reactivity towards ADP in all tests as compared with reference levels. Correlations between the results obtained with all the tests at D7 and D90 and between measurements on each day in each test were low-to-moderate. The prevalence of HTPR for all the tests was 40% at D7 and 42% at D90. There was a moderate degree of agreement (k statistic < 0.5) between tests with regard to categorizing patients as HTPR/No-HTPR (D7 and D90). The on-clopidogrel platelet reactivity phenotype, HTPR/No-HTPR, remained stable in 55-72% of patients, depending on the test. A high prevalence of HTPR is found among CVD patients treated with clopidogrel and this platelet reactivity phenotype remains over time. There is poor agreement between the different platelet function tests for categorizing the platelet reactivity phenotype in these patients. The new PFA-100 P2Y equals other platelet function assays for evaluating HTPR in CVD.

A model-based analysis of the clinical and economic impact of personalising P2Y12-receptor inhibition with platelet function testing in acute coronary syndrome patients.

Although some observational studies reported that the measured level of P2Y12-inhibition is predictive for thrombotic events, the clinical and economic benefit of incorporating PFT to personalize P2Y12-receptor directed antiplatelet treatment is unknown. Here, we assessed the clinical impact and cost-effectiveness of selecting P2Y12-inhibitors based on platelet function testing (PFT) in acute coronary syndrome (ACS) patients undergoing PCI. A decision model was developed to analyse the health economic effects of different strategies. PFT-guided treatment was compared with the three options of general clopidogrel, prasugrel or ticagrelor treatment. In the PFT arm, low responders to clopidogrel received prasugrel, while normal responders carried on with clopidogrel. The associated endpoints in the model were cardiovascular death, stent thrombosis and major bleeding. With a simulated cohort of 10,000 patients treated for one year, there were 93 less events in the PFT arm compared to general clopidogrel. In prasugrel and ticagrelor arms, 110 and 86 events were prevented compared to clopidogrel treatment, respectively. The total expected costs (including event costs, drug costs and PFT costs) for generic clopidogrel therapy were US$ 1,059/patient. In the PFT arm, total costs were US$ 1,494, while in the prasugrel and ticagrelor branches they were US$ 3,102 and US$ 3,771, respectively. The incremental-cost-effectiveness-ratio (ICER) was US$ 46,770 for PFT-guided therapy, US$ 185,783 for prasugrel and US$ 315,360 for ticagrelor. In this model-based analysis, a PFT-guided therapy may have fewer adverse outcomes than general treatment with clopidogrel and may be more cost-effective than prasugrel or ticagrelor treatment in ACS patients undergoing PCI.

Cost-effectiveness of universal and platelet reactivity assay-driven antiplatelet therapy in acute coronary syndrome.

Assays monitoring P2Y12 platelet reactivity can accurately predict which patients will have a poor response to clopidogrel. We sought to determine the cost-effectiveness of using platelet reactivity assays (PRAs) to select a dual-antiplatelet regimen for patients with acute coronary syndrome. A hybrid decision tree Markov model was developed to determine the cost-effectiveness of universal clopidogrel, ticagrelor, or prasugrel (given to all patients) or PRA-driven ticagrelor or prasugrel (given to patients with high platelet reactivity, defined as >230 on the VerifyNow P2Y12 assay; the others received generic clopidogrel). We assumed a cohort of 65-year-old patients with acute coronary syndrome and an incidence of high platelet reactivity of 32% and 13% at ~24 to 48 hours after revascularization and 1 month, respectively. The 5-year costs, quality-adjusted life-years, and incremental cost-effectiveness ratios were calculated for PRA-driven ticagrelor and prasugrel compared with universal clopidogrel, ticagrelor, or prasugrel. PRA-driven ticagrelor and prasugrel were cost-effective compared with universal clopidogrel (incremental cost-effectiveness ratio $40,100 and $49,143/quality-adjusted life-year, respectively); however, universal ticagrelor and prasugrel were not (incremental cost-effectiveness ratio $61,651 and $96,261/quality-adjusted life-year, respectively). Monte Carlo simulation suggested PRA-driven ticagrelor, PRA-driven prasugrel, universal ticagrelor, and universal prasugrel would have an incremental cost-effectiveness ratio <$50,000/quality-adjusted life-year in 52%, 40%, 23%, and 2% of the iterations compared with universal clopidogrel, respectively. Universal ticagrelor and prasugrel were not cost-effective compared with their respective PRA-driven regimens (incremental cost-effectiveness ratio $68,182; $116,875/quality-adjusted life-year, respectively). Monte Carlo simulation suggested universal ticagrelor and prasugrel would have an incremental cost-effectiveness ratio <$50,000/quality-adjusted life-year in 26% and 4% of iterations compared with their respective PRA-driven regimens. The results were most sensitive to differences in agent costs and drug-specific relative risks of death. In conclusion, even with generic clopidogrel, PRA-driven selection of antiplatelet therapy appeared to be a cost-effective strategy with the potential to decrease the overall acute coronary syndrome-associated healthcare costs.

The platelet P2Y(12) receptor under normal and pathological conditions. Assessment with the radiolabeled selective antagonist [(3)H]PSB-0413.

Various radioligands have been used to characterize and quantify the platelet P2Y(12) receptor, which share several weaknesses: (a) they are metabolically unstable and substrates for ectoenzymes, (b) they are agonists, and (c) they do not discriminate between P2Y(1) and P2Y(12). We used the [(3)H]PSB-0413 selective P2Y(12) receptor antagonist radioligand to reevaluate the number of P2Y(12) receptors in intact platelets and in membrane preparations. Studies in humans showed that: (1) [(3)H]PSB-0413 bound to 425 ± 50 sites/platelet (K (D) = 3.3 ± 0.6 nM), (2) 0.5 ± 0.2 pmol [(3)H]PSB-0413 bound to 1 mg protein of platelet membranes (K (D) = 6.5 ± 3.6 nM), and (3) competition studies confirmed the known features of P2Y(12), with the expected rank order of potency: AR-C69931MX > 2MeSADP ≫ ADPßS > ADP, while the P2Y(1) ligand MRS2179 and the P2X(1) ligand α,ß-Met-ATP did not displace [(3)H]PSB-0413 binding. Patients with severe P2Y(12) deficiency displayed virtually no binding of [(3)H]PSB-0413 to intact platelets, while a patient with a dysfunctional P2Y(12) receptor had normal binding. Studies in mice showed that: (1) [(3)H]PSB-0413 bound to 634 ± 87 sites/platelet (K (D) = 14 ± 4.5 nM) and (2) 0.7 pmol ± 0.3 [(3)H]PSB-0413 bound to 1 mg protein of platelet membranes (K (D) = 9.1 ± 5.3 nM). Clopidogrel and other thiol reagents like pCMBS or DTT abolished the binding both to intact platelets and membrane preparations. Therefore, [(3)H]PSB-0413 is an accurate and selective tool for radioligand binding studies aimed at quantifying P2Y(12) receptors, to identify patients with P2Y(12) deficiencies or quantify the effect of P2Y(12) targeting drugs.

Clinical predictors of high posttreatment platelet reactivity to clopidogrel in Koreans.

INTRODUCTION: High posttreatment platelet reactivity to clopidogrel (HPPR) is associated with major adverse cardiac events. However, the clinical predictors of HPPR in Asians have not been studied previously. AIMS: We sought to determine clinical predictors of HPPR in Koreans. RESULTS: We measured platelet reactivity with the VerifyNow P2Y12 assay in 1431 consecutive patients undergoing coronary angiography. We used the cut-off value of greater than 275 P2Y12 Reaction Unit (PRU) to define patients with HPPR. The clinical characteristics were compared between patients with HPPR (36.3%) and those without HPPR (63.7%). The mean age (65.4 ± 9.1 vs. 62.2 ± 9.7 years) was higher, hypertension (68.5% vs. 62.0%), diabetes mellitus (35.4% vs. 28.5%), chronic kidney disease (36.3% vs. 22.5%), renal replacement treatment (1.2% vs. 0.2%), and congestive heart failure (1.3% vs. 0.3%) were more common among patients with HPPR, while male gender (72.6% vs. 54.8%) and smoking (19.9% vs. 13.1%) were more common among non-HPPR patients. Mean glomerular filtration rate (63.5 ± 18.6 vs. 69.7 ± 16.1 mL/min/1.73 m(3) ) was lower and C-reactive protein (hs-CRP) (6.6 ± 20.5 mg/L vs. 4.2 ± 12.1 mg/L) level was higher among those with HPPR. Independent predictors of HPPR were female gender (OR 1.90, P≤ 0.001), chronic kidney disease (OR 1.51, 0 = 0.004), diabetes mellitus (OR 1.35, P= 0.024), hs-CRP ≥ 2.0 mg/L (OR 1.31, P= 0.005), and age increase in decades (OR 1.21, P= 0.002), while smoking was negative risk factor (OR 0.63, P= 0.015). The number of risk factors was linearly associated with the risk of HPPR, with most patients having one or two predictors. CONCLUSION: In Korean population, independent clinical predictors of HPPR included diabetes mellitus, increased age, female gender, chronic kidney disease, and hs-CRP ≥ 2.0 mg/L, while cigarette smoking was associated with better responsiveness. Mean platelet reactivity and HPPR prevalence steadily increased with the number of clinical predictors.

Enhanced clopidogrel responsiveness in smokers: smokers' paradox is dependent on cytochrome P450 CYP1A2 status.

OBJECTIVE: Observational studies have reported enhanced response to clopidogrel in smokers (the smokers' paradox). We examined whether genetic variations in the cytochrome and drug transporter system are associated with the effect of smoking on clopidogrel response. METHODS AND RESULTS: Clopidogrel on-treatment platelet reactivity (OPR) was measured in 1431 consecutive patients who underwent coronary angiography. Gene samples were available and genotyping was successful in 1123 patients. Nine candidate single-nucleotide polymorphisms in 5 cytochrome genes and 1 drug transporter gene were assessed. The mean OPR of the entire population was 241.9 ± 79.3 (P2Y(12) reaction units). Two hundred forty-nine (17%) smokers had lower OPR compared with 1182 (83%) nonsmokers (227.6 ± 76.0 versus 244.9 ± 79.7, P=0.001). Among the 9 single-nucleotide polymorphisms, only CYP1A2 showed a genotype-dependent change in the effect of smoking on OPR. After adjustment for possible confounding factors, cigarette smoking was associated with a lower OPR by -19 P2Y(12) reaction units (P=0.009) and lower risk for high OPR (odds ratio [OR], 0.48; 95% CI, 0.31 to 0.74) in the AA and CA genotypes but not in the CC genotype. CONCLUSIONS: Enhanced clopidogrel response in smokers, known as the smokers' paradox, is not universal but was observed only in cytochrome P450 CYP1A2 (-163C>A) A-allele carriers, suggesting a genotype-dependent effect of smoking on clopidogrel responsiveness.