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Prasugrel Monitoring and Bleeding in Real World Patients

Published:October 04, 2012DOI:https://doi.org/10.1016/j.amjcard.2012.08.043
      The aim of this study was to evaluate platelet reactivity and 30-day bleeding events in patients treated with prasugrel 10 mg after acute coronary syndromes. A total of 444 patients with acute coronary syndromes treated with percutaneous coronary intervention and prasugrel 10 mg/day were monitored by measurement of the vasodilator-stimulated phosphoprotein (VASP) index 2 to 4 weeks after hospital discharge. Platelet reactivity was also assessed using the VerifyNow P2Y12 assay and light transmission aggregometry. Bleeding events (per the Bleeding Academic Research Consortium [BARC] definition) and ischemic events (death, myocardial infarction, and definite stent thrombosis) were collected over 30 days of follow-up. Two thirds of the patients presented with ST-segment elevation myocardial infarctions, 28.8% had diabetes, and 12.4% were aged >75 years. High on-treatment platelet reactivity according to 3 prespecified definitions (VASP index ≥50%, platelet reactivity ≥235 P2Y12 reaction units, and residual platelet reactivity ≥46.2%) was found in 6.8%, 3.4%, and 3.2% of patients, respectively. Obesity (body mass index >30 kg/m2) and multivessel disease were the only independent factors associated with high on-treatment platelet reactivity (p = 0.006 and p = 0.045, respectively). At 30 days, there was no major bleeding complication (BARC grade 3 or 5), and 1.6% of patients had recurrent ischemic events. Nuisance bleeding (BARC grade 1) and minor bleeding (BARC grade 2) occurred in 14.2% (n = 63) and 2.5% (n = 11) of patients, respectively, but were not predicted by VASP index. In conclusion, patients with acute coronary syndromes receiving maintenance doses of prasugrel have low rates of HPR and ischemic events within the first month. Minor or minimal bleeding is frequent, but not major bleeding. VASP was poorly correlated with the risk for minor or minimal bleeding.
      Prasugrel, a third-generation thienopyridine, induces more rapid, more potent, and more predictable platelet inhibition than clopidogrel.
      • Wiviott S.D.
      • Antman E.M.
      • Winters K.J.
      • Weerakkody G.
      • Murphy S.A.
      • Behounek B.D.
      • Carney R.J.
      • Lazzam C.
      • McKay R.G.
      • McCabe C.H.
      • Braunwald E.
      Randomized comparison of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y12 antagonist, with clopidogrel in percutaneous coronary intervention: results of the Joint Utilization of Medications to Block Platelets Optimally (JUMBO)-TIMI 26 trial.
      • Brandt J.T.
      • Payne C.D.
      • Wiviott S.D.
      • Weerakkody G.
      • Farid N.A.
      • Small D.S.
      • Jakubowski J.A.
      • Naganuma H.
      • Winters K.J.
      A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation.
      It was associated with a greater reduction of ischemic events with an excess of bleeding events in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis In Myocardial Infarction 38 (TRITON–TIMI 38) trial.
      • Wiviott S.D.
      • Braunwald E.
      • McCabe C.H.
      • Montalescot G.
      • Ruzyllo W.
      • Gottlieb S.
      • Neumann F.J.
      • Ardissino D.
      • De Servi S.
      • Murphy S.A.
      • Riesmeyer J.
      • Weerakkody G.
      • Gibson C.M.
      • Antman E.M.
      TRITON-TIMI 38 Investigators
      Prasugrel versus clopidogrel in patients with acute coronary syndromes.
      Limited information is available on the level of platelet inhibition obtained in the TRITON–TIMI 38 study patients
      • Michelson A.D.
      • Frelinger 3rd, A.L.
      • Braunwald E.
      • Downey W.E.
      • Angiolillo D.J.
      • Xenopoulos N.P.
      • Jakubowski J.A.
      • Li Y.
      • Murphy S.A.
      • Qin J.
      • McCabe C.H.
      • Antman E.M.
      • Wiviott S.D.
      TRITON-TIMI 38 Investi-gators
      Pharmacodynamic assessment of platelet inhibition by prasugrel vs. clopidogrel in the TRITON-TIMI 38 trial.
      and even less in the real world population. Recent data suggest that high on-treatment platelet reactivity (HPR) is present in 1/4 of patients after prasugrel loading, with a possible relation to ischemic events.
      • Bonello L.
      • Pansieri M.
      • Mancini J.
      • Bonello R.
      • Maillard L.
      • Barnay P.
      • Rossi P.
      • Ait-Mokhtar O.
      • Jouve B.
      • Collet F.
      • Peyre J.P.
      • Wittenberg O.
      • de Labriolle A.
      • Camilleri E.
      • Cheneau E.
      • Cabassome E.
      • Dignat-George F.
      • Camoin-Jau L.
      • Paganelli F.
      High on-treatment platelet reactivity after prasugrel loading dose and cardiovascular events after percutaneous coronary intervention in acute coronary syndromes.
      The rate of HPR in patients with acute coronary syndromes (ACS) receiving 10-mg maintenance doses of prasugrel has not been well explored. Moreover, the relation of platelet reactivity to safety, which remains the main concern for chronic treatment, is not known. Therefore, we decided to routinely evaluate platelet reactivity on prasugrel 10-mg maintenance dose and its relation to clinical tolerance and outcomes.

      Methods

      From February 2010 to August 2011, all consecutive patients with ACS managed invasively with percutaneous coronary intervention at 2 high-volume tertiary centers (Pitié-Salpêtrière University Hospital, Paris, France, and La Timone University Hospital, Marseille, France) and discharged on a maintenance dose of prasugrel 10 mg (the only dose available in France) were invited to participate in the study. To be eligible for this study, patients had to have stents implanted and be treated with the combination of low-dose aspirin (75 to 250 mg/day) and prasugrel 10 mg/day. Patients with histories of stroke were excluded. The decision for treatment with prasugrel 10-mg maintenance dose was left to the discretion of the treating physician according to the expected risk and benefit in each patient.
      Patients were included on the day of discharge. All patients were scheduled for visits 2 to 4 weeks after discharge to check compliance with treatment and measure platelet reactivity. Blood samples were collected by venipuncture into 3.2% citrate Vacuette tubes (Becton, Dickinson, Franklin Lakes, New Jersey) after having discarded the first 2 to 4 ml of blood to avoid spontaneous platelet activation. Samples were processed <2 hours after blood drawing for platelet function testing. Clinical follow-up was performed at 1-month follow-up. The institutional review board of Pitié-Salpêtrière Hospital approved this study.
      The phosphorylation of the vasodilator-stimulated phosphoprotein (VASP) was measured using a Beckman Coulter FC500 cytometer (Beckman Coulter, Villepinte, France) using Platelet VASP kits (Diagnostica Stago [Biocytex], Asnières, France) according to the manufacturer's instructions and as previously described.
      • Schwarz U.R.
      • Geiger J.
      • Walter U.
      • Eigenthaler M.
      Flow cytometry analysis of intracellular VASP phosphorylation for the assessment of activating and inhibitory signal transduction pathways in human platelets–definition and detection of ticlopidine/clopidogrel effects.
      Briefly, blood samples were incubated in vitro with adenosine diphosphate (ADP) and/or prostaglandin E1 (PGE1) before fixation. The VASP platelet reactivity index (PRI) was calculated from the mean fluorescence intensity of each condition as follows: VASP PRI = [(mean fluorescence intensity of PGE1) − (mean fluorescence intensity of PGE1 + ADP)/mean fluorescence intensity of PGE1] × 100.
      Platelet-rich plasma was obtained by centrifugation of citrated whole blood at 100g for 10 minutes at room temperature. Platelet poor plasma was obtained by further centrifugation at 4,500g for 15 minutes. In vitro platelet aggregation in platelet-rich plasma was measured at 37°C in a light transmission aggregometer (model 490-4D; Chrono-Log Corporation, Kordia, The Netherlands) and was induced by the addition of ADP (Sigma-Aldrich, Saint Quentin Fallavier, France) at a final concentration of 20 μmol/L. Residual platelet aggregation measured 6 minutes after the induction of aggregation by agonist was recorded. Prespecified criteria used to define nonevaluable samples were lack of sufficient signal, hemolysis, platelet-rich plasma platelet count <150,000/ml, and an unstable baseline.
      Measurement of platelet response to prasugrel using the VerifyNow P2Y12 assay (Accumetrics Corporation, San Diego, California) was done according to the package insert. Results are expressed in P2Y12 reaction units (PRU) in response to isothrombin receptor–activating peptide and in response to ADP-PGE1. Isothrombin receptor–activating peptide strongly activates platelets despite of P2Y12 receptor blockage by thienopyridine or aspirin and reflects platelet reactivity without treatment.
      • Price M.J.
      Bedside evaluation of thienopyridine antiplatelet therapy.
      The device provides an estimated inhibition (as a percentage) without prethienopyridine sample by reporting the ratio of the results of the ADP-PGE1 and isothrombin receptor–activating peptide channels. Platelet aggregation and VerifyNow were available at 1 center, whereas VASP measurement was performed at both centers using the same method.
      Our main objectives were (1) to evaluate the rate of HPR on prasugrel 10-mg maintenance dose using VASP PRI value ≥50%
      • Bonello L.
      • Tantry U.S.
      • Marcucci R.
      • Blindt R.
      • Angiolillo D.J.
      • Becker R.
      • Bhatt D.L.
      • Cattaneo M.
      • Collet J.P.
      • Cuisset T.
      • Gachet C.
      • Montalescot G.
      • Jennings L.K.
      • Kereiakes D.
      • Sibbing D.
      • Trenk D.
      • Van Werkum J.W.
      • Paganelli F.
      • Price M.J.
      • Waksman R.
      • Gurbel P.A.
      Working Group on High On-Treatment Platelet Reactivity
      Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate.
      and VASP PRI value ≥60%
      • Jeong Y.H.
      • Bliden K.P.
      • Tantry U.S.
      • Gurbel P.A.
      High on-treatment platelet reactivity assessed by various platelet function tests: is the consensus-defined cut-off of VASP-P platelet reactivity index too low?.
      and identify the independent correlates of HPR; (2) to confirm the rate of HPR in a subgroup of this population using 2 additional methods: light transmission aggregometry with residual platelet aggregation value ≥46.2%
      • Breet N.J.
      • van Werkum J.W.
      • Bouman H.J.
      • Kelder J.C.
      • Ten Berg J.M.
      • Hackeng C.M.
      Both peak and late aggregation are capable of identifying patients at risk for atherothrombotic events.
      and VerifyNow P2Y12 assay with PRU ADP-PGE1 value ≥235
      • Bonello L.
      • Tantry U.S.
      • Marcucci R.
      • Blindt R.
      • Angiolillo D.J.
      • Becker R.
      • Bhatt D.L.
      • Cattaneo M.
      • Collet J.P.
      • Cuisset T.
      • Gachet C.
      • Montalescot G.
      • Jennings L.K.
      • Kereiakes D.
      • Sibbing D.
      • Trenk D.
      • Van Werkum J.W.
      • Paganelli F.
      • Price M.J.
      • Waksman R.
      • Gurbel P.A.
      Working Group on High On-Treatment Platelet Reactivity
      Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate.
      • Price M.J.
      • Endemann S.
      • Gollapudi R.R.
      • Valencia R.
      • Stinis C.T.
      • Levisay J.P.
      • Ernst A.
      • Sawhney N.S.
      • Schatz R.A.
      • Teirstein P.S.
      Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation.
      • Marcucci R.
      • Gori A.M.
      • Paniccia R.
      • Giusti B.
      • Valente S.
      • Giglioli C.
      • Buonamici P.
      • Antoniucci D.
      • Abbate R.
      • Gensini G.F.
      Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of-care assay: a 12-month follow-up.
      ; and (3) to evaluate the rate of bleeding events using the Bleeding Academic Research Consortium (BARC) definitions
      • Mehran R.
      • Rao S.V.
      • Bhatt D.L.
      • Gibson C.M.
      • Caixeta A.
      • Eikelboom J.
      • Kaul S.
      • Wiviott S.D.
      • Menon V.
      • Nikolsky E.
      • Serebruany V.
      • Valgimigli M.
      • Vranckx P.
      • Taggart D.
      • Sabik J.F.
      • Cutlip D.E.
      • Krucoff M.W.
      • Ohman E.M.
      • Steg P.G.
      • White H.
      Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium.
      and examine the relation to platelet reactivity. Independent correlates of bleeding events were sought.
      Cardiovascular ischemic events including death, recurrent myocardial infarction, and definite stent thrombosis (per the Academic Research Consortium definition) were also collected at 1-month follow-up.
      • Cutlip D.E.
      • Windecker S.
      • Mehran R.
      • Boam A.
      • Cohen D.J.
      • van Es G.A.
      • Steg P.G.
      • Morel M.A.
      • Mauri L.
      • Vranckx P.
      • McFadden E.
      • Lansky A.
      • Hamon M.
      • Krucoff M.W.
      • Serruys P.W.
      Academic Research Consortium
      Clinical end points in coronary stent trials: a case for standardized definitions.
      Continuous variables are expressed as means ± SD and categorical data as percentages. Chi-square tests or Fisher's exact tests were used for qualitative variables, and Student's unpaired t test was used for continuous variables. Multivariate regression analyses were performed to identify independent correlates of HPR and bleeding events. After univariate analysis, all variables with p values <0.20 were introduced in the multivariate analysis. The variables entered in the HPR multivariate model were β-blocker use, body mass index >30 kg/m2, and 3-vessel disease. The variables entered in the bleeding multivariate model were VASP index <15.05%, age ≥75 years, gender, low weight (<60 kg), diabetes, 3-vessel disease, and creatinine clearance <60 ml/min. A backward procedure was used in the final model. Correlations between tests were assessed using Pearson's test or Spearman's test (when the distribution was not normal). Agreement among the 3 tests was calculated using the κ statistic. All p values are 2 sided, and p values <0.05 were considered significant. Analyses were performed using R version 12.1 (R Foundation for Statistical Computing, Vienna, Austria).

      Results

      Baseline characteristics and procedural details of the study population are listed in Table 1. The mean age of the population was 60.1 ± 12 years, and 2/3 of the patients had ST-segment elevation myocardial infarctions, 28.8% had diabetes, and 12.4% were aged ≥75 years. Percutaneous coronary intervention was performed using a radial approach in 96.4% of patients. Complete 1-month follow-up was achieved in all patients. VASP measurement was available in all patients (n = 444), whereas VerifyNow P2Y12 and platelet measurement by light transmission aggregometry were available in subgroups of the population of 52% (n = 232) and 49% (n = 219), respectively.
      Table 1Patient characteristics (n = 444)
      VariableValue
      Age (yrs)60.1 ± 12
      Age ≥ 75 yrs55(12.4%)
      Women66 (14.8%)
      Weight (kg)79 ± 16
      Body mass index (kg/m2)29.9 ± 5
      Low weight (<60 kg)32 (7.2%)
      Diabetes128 (28.8%)
      Hypercholesterolemia
      Fasting low-density lipoprotein cholesterol ≥131 mg/dl or receiving statin therapy at the time of inclusion.
      205 (46.2%)
      Smoker209 (47%)
      Hypertension
      Systolic blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg.
      194 (43.7%)
      Family history of coronary artery disease
      One or more first-degree relatives developed coronary artery disease at <55 yrs of age (men) or <65 yrs of age (women).
      75 (16.9%)
      ST-segment elevation myocardial infarction257 (57.8%)
      Non–ST-segment elevation myocardial infarction/unstable angina163 (33.7%)
      Stable angina22 (5%)
      1-vessel disease310 (69.9%)
      2-vessel disease89 (20%)
      3-vessel disease45 (10.1%)
      Radial access428 (96.4%)
      Drug-eluting stent271 (61%)
      Platelet count (×103/μl)254.1 ± 70
      Hemoglobin (g/dl)14.1 ± 1
      Creatinine clearance (ml/min)100 ± 73
      Creatinine clearance <60 ml/min62 (14%)
      Creatinine clearance <30 ml/min11 (2.5%)
      Left ventricular ejection fraction (%)53 ± 8
      Aspirin dose (mg)76 ± 10
      β blockers354 (79.7%)
      Angiotensin-converting enzyme inhibitors349 (78.6%)
      Calcium antagonists47 (10.6%)
      Statins424 (95.5%)
      Proton pump inhibitors378 (85.1%)
      Fasting low-density lipoprotein cholesterol ≥131 mg/dl or receiving statin therapy at the time of inclusion.
      Systolic blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg.
      One or more first-degree relatives developed coronary artery disease at <55 yrs of age (men) or <65 yrs of age (women).
      HPR was observed in 6.7% (30 of 444) with the VASP PRI on flow cytometry. Using a cut point of 60% PRI, the rate of HPR was 3.2% (14 of 444). This incidence was confirmed with the other 2 methods: 3.4% (8 of 232) with the VerifyNow P2Y12 assay and 3.2% (7 of 219) with light transmission aggregometry, according to each prespecified definition (see Figure 1). No problems of compliance with prasugrel were detected in this population. The correlations between the different tests were as follows: residual platelet aggregation and PRU, r = 0.66 (95% confidence interval [CI] 0.57 to 0.73, p <0.0001); VASP PRI and PRU, r = 0.61 (95% CI 0.57 to 0.72, p <0.0001); and VASP PRI and residual platelet aggregation, r = 0.42 (95% CI 0.4 to 0.59, p <0.0001). The κ value for the concordance among the 3 platelet function tests to identify patients with HPR was 0.42.
      Figure thumbnail gr1
      Figure 1Platelet reactivity assessed by the VASP PRI, VerifyNow (P2Y12), and light transmission aggregometry in patients receiving prasugrel 10 mg/day. The dotted line represents the cut-off value of HPR for VASP, PRU, and residual platelet aggregation (RPA). Mean and standard deviation are represented for each test.
      Obese patients (body mass index >30 kg/m2) exhibited higher VASP PRI levels compared to nonobese patients (33 ± 16% [n = 91] vs 25 ± 15% [n = 353], p <0.0001). Elderly patients (aged ≥75 years) had lower VASP PRI compared to younger patients (21 ± 15% [n = 54] vs 27 ± 15% [n = 390], p <0.0001). Patients with diabetes (n = 128) had higher VASP PRI compared to those without diabetes (28 ± 16% [n = 128] vs 25 ± 16% [n = 316], p = 0.01).
      After backward multivariate logistic regression analysis, body mass index >30 kg/m2 and 3-vessel disease were the only 2 factors associated with HPR (Table 2).
      Table 2Multivariate logistic regression for association with high on-treatment platelet reactivity (vasodilator-stimulated phosphoprotein ≥50%) in the population treated with prasugrel 10 mg
      VariableUnivariate OR (95% CI)p ValueMultivariate OR (95% CI)p Value
      Age ≥ 75 yrs0.47 (0.1–2.0)0.31
      Male gender1.68 (0.5–5.7)0.41
      Low weight (<60 kg)2.43 (0.3–18.5)0.4
      Body mass index >30 kg/m22.71 (1.3–5.8)0.012.96 (1.4–6.4)0.006
      Hypertension (presence)1.1 (0.5–2.2)0.864
      Diabetes (presence)1.39 (0.6–3.0)0.4
      Dyslipidemia (presence)0.83 (0.4–1.7)0.62
      ST-segment elevation myocardial infarction (presence)0.88 (0.4–1.8)0.72
      3-vessel disease vs 1- or 2-vessel disease2.3 (0.9–5.9)0.092.7 (1.02–7.15)0.045
      Creatinine clearance <60 ml/min0.64 (0.2–2.2)0.48
      Proton pump inhibitor use1.2 (0.4–3.5)0.77
      β-blocker use0.5 (0.2–1.1)0.09
      CI = confidence interval; OR = odds ratio.
      There were neither major bleeding complications (BARC grade 3) nor fatal bleeding (BARC grade 5) (Figure 2). Because none of the patients underwent coronary bypass surgery, there was no BARC grade 4 bleeding (coronary artery bypass graft related). However, there was 14.2% (n = 63) BARC grade 1 bleeding (nuisance bleeding) and 2.5% (n = 11) BARC grade 2 bleeding (bleeding requiring a medical consultation; epistaxis n = 5, gastrointestinal bleeding n = 2, cutaneous bleeding n = 2). In the population of patients aged <75 years and/or weighing >60 kg, the rate of BARC grade 1 bleeding events did not differ significantly at 12.3% (n = 45) and 1.9% (n = 7) for BARC grade 2 bleeding.
      Figure thumbnail gr2
      Figure 2Ischemic and bleeding events after 1-month follow-up.
      Platelet response is presented in Figure 3. The area under the curve for the VASP test to predict bleeding events was low at 0.57 (95% CI 0.51 to 0.64, p = 0.03). The cutoff value of VASP 15.05% offered sensitivity of 35% and specificity of 77% to be associated with bleeding events.
      Figure thumbnail gr3
      Figure 3Platelet reactivity assessed by the VASP PRI in patients with bleeding events (and BARC grades 1 and 2) (n = 74) and in patients without bleeding events 2 to 4 weeks after discharge follow-up (n = 370). Mean and standard deviation are represented for the 2 groups. The dotted line represents the cut-off value of HPR for VASP.
      After multivariate analysis, female gender and nondiabetic status patients were the only 2 independent predictors of minor bleeding (Table 3). Platelet reactivity did not predict bleeding independently of the other variables.
      Table 3Predictors of bleeding events (Bleeding Academic Research Consortium grades 1 and 2) in the population treated with prasugrel 10 mg
      VariableUnivariate OR (95% CI)p ValueMultivariate OR (95% CI)p Value
      Age ≥75 yrs1.9 (1–3.6)0.07
      Male gender0.35 (0.19–0.63)0.00050.33 (0.18–0.60)0.0003
      Low weight (<60 kg)0.35 (0.2–0.8)0.007
      Body mass index >30 kg/m20.81 (0.4–1.6)0.52
      Hypertension (presence)0.8 (0.5–1.3)0.38
      Diabetes (presence)0.47 (0.3–0.9)0.020.439 (0.23–0.84)0.0131
      Dyslipidemia (presence)1.1 (0.7–1.8)0.6
      ST-segment elevation myocardial infarction (presence)0.8 (0.5–1.3)0.31
      3-vessel disease vs 1- or 2-vessel disease1.7 (0.8–3.6)0.15
      Creatinine clearance <60 ml/min1.6 (0.8–3)0.18
      Proton pump inhibitor use0.98 (0.5–2)0.96
      β blocker use1 (0.5–1.9)0.99
      VASP index <15.05%1.8 (1.1–3.1)0.03
      Five cardiovascular ischemic events occurred during follow-up (1.6%), 3 definite stent thromboses (with no evidence that stent thrombosis was related to lack of compliance), 1 recurrent myocardial infarction, and 1 death attributed to a cardiovascular cause. Patients with ischemic events (n = 5) tended to have higher VASP PRI than patients without ischemic events (37 ± 21% vs 26 ± 15%, p = 0.08).

      Discussion

      The present study provides new data on platelet reactivity and bleeding events in real-world patients with ACS receiving maintenance prasugrel treatment. We show that prasugrel is associated with a high and consistent degree of platelet inhibition with a low rate of HPR. These results are consistent among the 3 different platelet function tests. Another important finding in this study is that bleeding events during the first month of treatment with prasugrel 10 mg/day were almost exclusively represented by nuisance bleeding and associated with a higher degree of P2Y12 inhibition, although they were not related independently of each other.
      Very few studies have investigated the biologic response to prasugrel in real-world practice, and to our knowledge, we report here the largest set of data concerning platelet function monitoring with prasugrel 10-mg maintenance dose.
      • Parodi G.
      • Bellandi B.
      • Venditti F.
      • Carrabba N.
      • Valenti R.
      • Migliorini A.
      • Grassellini S.
      • Ramazzotti E.
      • Antoniucci D.
      Residual platelet reactivity, bleedings, and adherence to treatment in patients having coronary stent implantation treated with prasugrel.
      • Armero S.
      • Bonello L.
      • Berbis J.
      • Camoin-Jau L.
      • Lemesle G.
      • Jacquin L.
      • Bonello-Burignat C.
      • Pansieri M.
      • Collet F.
      • Ostorero M.
      • Dignat-George F.
      • Paganelli F.
      Rate of nuisance bleedings and impact on compliance to prasugrel in acute coronary syndromes.
      We observed in our population a high and consistent degree of platelet inhibition in patients treated using prasugrel 10 mg/day. These findings are in line with the pharmacodynamic results obtained previously in healthy volunteers and in patients with stable coronary artery disease.
      • Brandt J.T.
      • Payne C.D.
      • Wiviott S.D.
      • Weerakkody G.
      • Farid N.A.
      • Small D.S.
      • Jakubowski J.A.
      • Naganuma H.
      • Winters K.J.
      A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation.
      • Wiviott S.D.
      • Trenk D.
      • Frelinger A.L.
      • O'Donoghue M.
      • Neumann F.J.
      • Michelson A.D.
      • Angiolillo D.J.
      • Hod H.
      • Montalescot G.
      • Miller D.L.
      • Jakubowski J.A.
      • Cairns R.
      • Murphy S.A.
      • McCabe C.H.
      • Antman E.M.
      • Braunwald E.
      PRINCIPLE-TIMI 44 Investigators
      Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis In Myocardial Infarction 44 trial.
      • Montalescot G.
      • Sideris G.
      • Cohen R.
      • Meuleman C.
      • Bal dit Sollier C.
      • Barthélémy O.
      • Henry P.
      • Lim P.
      • Beygui F.
      • Collet J.P.
      • Marshall D.
      • Luo J.
      • Petitjean H.
      • Drouet L.
      Prasugrel compared with high-dose clopidogrel in acute coronary syndrome. The randomised, double-blind ACAPULCO study.
      In our high–ischemic risk population, HPR was in the range of 4% to 6%, depending on the definition used. This result differs from the pharmacodynamic studies performed in TRITON–TIMI 38 study
      • Michelson A.D.
      • Frelinger 3rd, A.L.
      • Braunwald E.
      • Downey W.E.
      • Angiolillo D.J.
      • Xenopoulos N.P.
      • Jakubowski J.A.
      • Li Y.
      • Murphy S.A.
      • Qin J.
      • McCabe C.H.
      • Antman E.M.
      • Wiviott S.D.
      TRITON-TIMI 38 Investi-gators
      Pharmacodynamic assessment of platelet inhibition by prasugrel vs. clopidogrel in the TRITON-TIMI 38 trial.
      and in another recent study,
      • Bonello L.
      • Pansieri M.
      • Mancini J.
      • Bonello R.
      • Maillard L.
      • Barnay P.
      • Rossi P.
      • Ait-Mokhtar O.
      • Jouve B.
      • Collet F.
      • Peyre J.P.
      • Wittenberg O.
      • de Labriolle A.
      • Camilleri E.
      • Cheneau E.
      • Cabassome E.
      • Dignat-George F.
      • Camoin-Jau L.
      • Paganelli F.
      High on-treatment platelet reactivity after prasugrel loading dose and cardiovascular events after percutaneous coronary intervention in acute coronary syndromes.
      which reported up to 25% of prasugrel-treated patients with inadequate platelet inhibition. Important differences between these studies and the present study may explain these apparent discrepancies: (1) measurements of the effect of a single loading dose rapidly after drug administration, as performed previously, does not reflect steady-state platelet reactivity on a 10-mg maintenance dose as performed here; (2) platelet function testing performed during the acute phase of ongoing ACS with intense platelet activation
      • Bonello L.
      • Pansieri M.
      • Mancini J.
      • Bonello R.
      • Maillard L.
      • Barnay P.
      • Rossi P.
      • Ait-Mokhtar O.
      • Jouve B.
      • Collet F.
      • Peyre J.P.
      • Wittenberg O.
      • de Labriolle A.
      • Camilleri E.
      • Cheneau E.
      • Cabassome E.
      • Dignat-George F.
      • Camoin-Jau L.
      • Paganelli F.
      High on-treatment platelet reactivity after prasugrel loading dose and cardiovascular events after percutaneous coronary intervention in acute coronary syndromes.
      is different from a measurement done several weeks later in stabilized ambulatory patients; and (3) there were also differences in the population characteristics with factors of HPR (e.g., high body weight and diabetes), more frequently found in the TRITON–TIMI 38 substudy
      • Michelson A.D.
      • Frelinger 3rd, A.L.
      • Braunwald E.
      • Downey W.E.
      • Angiolillo D.J.
      • Xenopoulos N.P.
      • Jakubowski J.A.
      • Li Y.
      • Murphy S.A.
      • Qin J.
      • McCabe C.H.
      • Antman E.M.
      • Wiviott S.D.
      TRITON-TIMI 38 Investi-gators
      Pharmacodynamic assessment of platelet inhibition by prasugrel vs. clopidogrel in the TRITON-TIMI 38 trial.
      than in our study.
      Our data were consistent across the 3 tests used in this study, although there was moderate agreement among the different assays. The modest correlations between the different tests are known and have been also extensively described with clopidogrel.
      • Cuisset T.
      • Frere C.
      • Poyet R.
      • Quilici J.
      • Gaborit B.
      • Bali L.
      • Brissy O.
      • Lambert M.
      • Morange P.E.
      • Alessi M.C.
      • Bonnet J.L.
      Clopidogrel response: head-to-head comparison of different platelet assays to identify clopidogrel non responder patients after coronary stenting.
      The high and consistent level of platelet inhibition observed in our study was associated with no excess of major bleeding but with relatively frequent minor or minimal bleeding over 1 month. The rate of minor bleeding observed in our population is in line with 2 recently published studies in patients treated with prasugrel.
      • Parodi G.
      • Bellandi B.
      • Venditti F.
      • Carrabba N.
      • Valenti R.
      • Migliorini A.
      • Grassellini S.
      • Ramazzotti E.
      • Antoniucci D.
      Residual platelet reactivity, bleedings, and adherence to treatment in patients having coronary stent implantation treated with prasugrel.
      • Armero S.
      • Bonello L.
      • Berbis J.
      • Camoin-Jau L.
      • Lemesle G.
      • Jacquin L.
      • Bonello-Burignat C.
      • Pansieri M.
      • Collet F.
      • Ostorero M.
      • Dignat-George F.
      • Paganelli F.
      Rate of nuisance bleedings and impact on compliance to prasugrel in acute coronary syndromes.
      The bleeding events of our population were mainly epistaxis, ecchymosis, superficial bleeding, and gingival bleeding and never led to interruption of treatment. Similar side effects have been previously reported with clopidogrel combined with aspirin.
      • Serebruany V.
      • Rao S.V.
      • Silva M.A.
      • Donovan J.L.
      • Kannan A.O.
      • Makarov L.
      • Goto S.
      • Atar D.
      Correlation of inhibition of platelet aggregation after clopidogrel with post discharge bleeding events: assessment by different bleeding classifications.
      Whether what we observed here in a real-world population is significantly more frequent than what occurs on clopidogrel is unknown. Nevertheless, the possible impact of nuisance bleeding on compliance should not be ignored.
      • Roy P.
      • Bonello L.
      • Torguson R.
      • Okabe T.
      • Pinto Slottow T.L.
      • Steinberg D.H.
      • Kaneshige K.
      • Xue Z.
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      • Kent K.M.
      • Suddath W.O.
      • Pichard A.D.
      • Lindsay J.
      • Waksman R.
      Temporal relation between copidogrel cessation and stent thrombosis after drug-eluting stent implantation.
      We observed that male gender and diabetes status were independently associated with fewer bleeding events. These observations were also made in the TRITON–TIMI 38 study.
      • Hochholzer W.
      • Wiviott S.D.
      • Antman E.M.
      • Contant C.F.
      • Guo J.
      • Giugliano R.P.
      • Dalby A.J.
      • Montalescot G.
      • Braunwald E.
      Predictors of bleeding and time dependence of association of bleeding with mortality: insights from the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38).
      The relation between the level of P2Y12 inhibition and bleeding events has been previously described with clopidogrel
      • Serebruany V.
      • Rao S.V.
      • Silva M.A.
      • Donovan J.L.
      • Kannan A.O.
      • Makarov L.
      • Goto S.
      • Atar D.
      Correlation of inhibition of platelet aggregation after clopidogrel with post discharge bleeding events: assessment by different bleeding classifications.
      • Cuisset T.
      • Cayla G.
      • Frere C.
      • Quilici J.
      • Poyet R.
      • Gaborit B.
      • Bali L.
      • Morange P.E.
      • Alessi M.C.
      • Bonnet J.L.
      Predictive value of post-treatment platelet reactivity for occurrence of post-discharge bleeding after non-ST elevation acute coronary syndrome. Shifting from antiplatelet resistance to bleeding risk assessment?.
      and prasugrel.
      • Parodi G.
      • Bellandi B.
      • Venditti F.
      • Carrabba N.
      • Valenti R.
      • Migliorini A.
      • Grassellini S.
      • Ramazzotti E.
      • Antoniucci D.
      Residual platelet reactivity, bleedings, and adherence to treatment in patients having coronary stent implantation treated with prasugrel.
      Although we observed a significantly lower VASP index in patients with bleeding events compared to patients without bleeding events, VASP was not a factor independently associated with the risk for bleeding as represented by minimal or minor BARC bleeding. Therefore, the link between platelet reactivity and bleeding depends on other factors according to our findings.
      Similar to clopidogrel,
      • Angiolillo D.J.
      • Fernandez-Ortiz A.
      • Bernardo E.
      • Barrera Ramirez C.
      • Sabate M.
      • Fernandez C.
      • Hernandez-Antolin R.
      • Escaned J.
      • Alfonso F.
      • Macaya C.
      Platelet aggregation according to body mass index in patients undergoing coronary stenting: should clopidogrel loading-dose be weight adjusted?.
      • Hochholzer W.
      • Trenk D.
      • Fromm M.F.
      • Valina C.M.
      • Stratz C.
      • Bestehorn H.P.
      • Buttner H.J.
      • Neumann F.J.
      Impact of cytochrome P450 2C19 loss-of-function polymorphism and of major demographic characteristics on residual platelet function after loading and maintenance treatment with clopidogrel in patients undergoing elective coronary stent placement.
      obesity appears to be independently associated with HPR, and we found a threefold higher rate of HPR in this population. We also show that 3-vessel disease is an independent factor associated with HPR. This factor is well recognized in recurrent cardiovascular events in patients with ACS
      • Parodi G.
      • Marcucci R.
      • Valenti R.
      • Gori A.M.
      • Migliorini A.
      • Giusti B.
      • Buonamici P.
      • Gensini G.F.
      • Abbate R.
      • Antoniucci D.
      High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI.
      but has not been associated with HPR before. We speculate that patients with advanced atherosclerosis represent a group of patients likely to have several potential factors of resistance (e.g., diabetes, age, inflammation).
      Finally, our study supports the existence of a therapeutic window for P2Y12 receptor inhibition, which may decrease the risk for bleeding and thrombotic events.
      • Campo G.
      • Parrinello G.
      • Ferraresi P.
      • Lunghi B.
      • Tebaldi M.
      • Miccoli M.
      • Marchesini J.
      • Bernardi F.
      • Ferrari R.
      • Valgimigli M.
      Prospective evaluation of on-clopidogrel platelet reactivity over time in patients treated with percutaneous coronary intervention relationship with gene polymorphisms and clinical outcome.
      • Sibbing D.
      • Steinhubl S.R.
      • Schulz S.
      • Schomig A.
      • Kastrati A.
      Platelet aggregation and its association with stent thrombosis and bleeding in clopidogrel-treated patients: initial evidence of a therapeutic window.
      Our study had several limitations. First, it had the inherent biases of a registry, which in contrast provides an objective snapshot of the prasugrel effect in daily practice. Second, the short follow-up duration is an issue, because bleeding events may accumulate over time. We acknowledge that in-hospital bleeding events were not assessed here but may have led to the exclusion of some patients with recent bleeding episodes. We acknowledge that antiplatelet and anticoagulation regimens during percutaneous coronary intervention may have modified early platelet reactivity, but we believe that these effects disappeared rapidly after discharge.

      Acknowledgments

      We would like to thank Ghalia Anzaha, Delphine Brugier, and Sophie Galier for their technical assistance and Sissel Paulsrud for her editing assistance.

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