Does Intraoperative Fibrinogen Affect Blood Loss or Transfusion Practice After Aortic Arch Surgery: A Prematurely Ended Randomized Trial.

Cardiovascular surgery is often complicated by significant bleeding due to perioperative coagulopathy. The effectiveness of treatment with fibrinogen concentrate to reduce the perioperative blood transfusion rate after thoracic aortic replacement surgery in prior studies has shown conflicting results. Therefore, we conducted a double-blind randomized controlled trial to investigate if a single dose of intraoperative fibrinogen administration reduced blood loss and allogeneic transfusion rate after elective surgery for thoracic arch aneurysm with deep hypothermic circulatory arrest. Twenty patients were randomized to fibrinogen concentrate (N = 10) or placebo (N = 10). The recruitment of study patients was prematurely ended due to a low inclusion rate. Perioperative transfusion, 5-minute bleeding mass after study medication and postoperative blood loss were not different between the groups with fibrinogen concentrate or placebo. Due to small volumes of postoperative blood loss and premature study termination, a beneficial effect of fibrinogen concentrate on the number of blood transfusions could not be established. However, treatment with fibrinogen efficiently restored fibrinogen levels and clot strength to preoperative values with a more effective preserved postoperative thrombin generation capacity. This result might serve as a pilot for further multicenter studies to assess the prospective significance of automated and standardized thrombin generation as a routine assay for monitoring perioperative coagulopathy and its impact on short- and long-term operative results.

Association of Plasma Fibrinogen and Thromboelastography With Blood Loss in Complex Cardiac Surgery.

Postoperative coagulopathic bleeding is common in cardiac surgery and is associated with increased morbidity and mortality. Ideally, real-time information on in-vivo coagulation should be available. However, up to now it is unclear which perioperative coagulation parameters can be used best to accurately identify patients at increased risk of bleeding. The present study analyzed the associations of perioperative fibrinogen concentrations and whole blood viscoelastic tests with postoperative bleeding in 89 patients undergoing combined cardiac surgery procedures. Postoperative bleeding was recorded until 24 hours after surgery. Regression analyses were performed to establish associations between blood loss and coagulation parameters after cardiopulmonary bypass including a prediction model with known confounding factors for bleeding. Coagulation tests show large changes over the perioperative course with the strongest coagulopathic deviations from baseline after cardiopulmonary bypass. After adjustment for multiple confounders, viscoelastic clot strength instead of fibrinogen concentration showed a similar performance for 24 hour blood loss and a better performance for 6 hour blood loss. This makes intraoperative viscoelastic testing a useful tool to strengthen early clinical decision-making with the potential to reduce perioperative blood transfusions.

Blood loss after coronary artery bypass by aspirin responsiveness assessed with preoperative VerifyNow aspirin testing.

BACKGROUND: Aspirin is important for preventing thrombotic events but also increases bleeding complications. Minimizing bleeding while preventing thrombotic events remains challenging in patients undergoing coronary artery bypass grafting (CABG). Establishing the patient's preoperative aspirin response could distinguish patients at risk for perioperative blood loss. OBJECTIVE: Aim was to compare 12-h blood loss after CABG between aspirin-sensitive and aspirin-resistant patients. PATIENTS/METHODS: The primary analysis of this substudy of the POPular CABG trial (NCT02352402) included patients that used aspirin monotherapy preoperatively. A preoperative platelet function test by the VerifyNow aspirin assay was performed before CABG and patients were classified as aspirin-sensitive or aspirin-resistant based on an aspirin reaction units cutoff value of 550. The primary end point was 12-hour blood loss after CABG. The secondary end point was, among others, clinical bleeding events after CABG. RESULTS: A total of 128 patients were included in the primary analysis. Of these, 116 patients were aspirin sensitive and 12 were aspirin resistant. Mean blood loss 12 hours after CABG was 555 ± 278 mL in aspirin-sensitive patients and 406±110 mL in aspirin-resistant patients (P = .04). All bleeding events (n = 15; 11.7%) occurred in aspirin-sensitive patients. CONCLUSIONS: In patients who are on aspirin preoperatively, aspirin sensitivity was associated with 12-hour blood loss after CABG, suggesting that preoperative VerifyNow aspirin testing could identify patients undergoing CABG at high risk for perioperative bleeding.

Effect of CYP3A4*22 and PPAR-α Genetic Variants on Platelet Reactivity in Patients Treated with Clopidogrel and Lipid-Lowering Drugs Undergoing Elective Percutaneous Coronary Intervention.

This study aims to determine whether genetic variants that influence CYP3A4 expression are associated with platelet reactivity in clopidogrel-treated patients undergoing elective percutaneous coronary intervention (PCI), and to evaluate the influence of statin/fibrate co-medication on these associations. A study cohort was used containing 1124 consecutive elective PCI patients in whom CYP3A4*22 and PPAR-α (G209A and A208G) SNPs were genotyped and the VerifyNow P2Y12 platelet reactivity test was performed. Minor allele frequencies were 0.4% for CYP3A4*22/*22, 6.8% for PPAR-α G209A AA, and 7.0% for PPAR-α A208G GG. CYP3A4*22 was not associated with platelet reactivity. The PPAR-α genetic variants were significantly associated with platelet reactivity (G209A AA: -24.6 PRU [-44.7, -4.6], p = 0.016; A208G GG: -24.6 PRU [-44.3, -4.8], p = 0.015). Validation of these PPAR-α results in two external cohorts, containing 716 and 882 patients, respectively, showed the same direction of effect, although not statistically significant. Subsequently, meta-analysis of all three cohorts showed statistical significance of both variants in statin/fibrate users (p = 0.04 for PPAR-a G209A and p = 0.03 for A208G), with no difference in statin/fibrate non-users. In conclusion, PPAR-α G209A and A208G were associated with lower platelet reactivity in patients undergoing elective PCI who were treated with clopidogrel and statin/fibrate co-medication. Further research is necessary to confirm these findings.

Tailored P2Y12 inhibitor treatment in patients undergoing non-urgent PCI-the POPular Risk Score study.

PURPOSE: The POPular Risk Score was developed for the selective intensification of P2Y12 inhibitor treatment with prasugrel instead of clopidogrel in patients undergoing non-urgent percutaneous coronary intervention (PCI) with stent implantation. This score is based on platelet reactivity (VerifyNow P2Y12 assay), CYP2C19 genotyping, and clinical risk factors. Our aim was to determine if the use of this score in clinical practice is associated with a reduction in thrombotic events without increasing bleeding events. METHODS: In a single-center prospective cohort study, patients with a high risk score were treated with prasugrel and patients with a low risk score with clopidogrel. The risk score-guided cohort was compared with a historic cohort of clopidogrel-treated patients. The endpoint consisted of all-cause death, myocardial infarction, stroke, or stent thrombosis during 1 year of follow-up. TIMI major and minor bleeding events were also analyzed. RESULTS: The guided cohort contained 1127 patients, 26.9% of whom were switched to prasugrel according to the POPular Risk Score. The historic cohort contained 893 patients. The incidence of the combined thrombotic endpoint was significantly lower in the guided cohort as compared with the historic cohort (8.4% versus 3.7%, p < 0.001). This strategy was safe with respect to bleeding (4.0% versus 1.3%, p < 0.001, for TIMI major or minor bleeding). Results were comparable after multivariate and propensity score matched and weighted analysis. CONCLUSION: Selective intensification of P2Y12 inhibitor treatment after non-urgent PCI based on the POPular Risk Score is associated with a reduction in thrombotic events without an increase in bleeding events.

Perioperative point of care platelet function testing and postoperative blood loss in high-risk cardiac surgery patients.

Postoperative coagulopathic bleeding is common in cardiac surgery and associated with increased morbidity and mortality. Platelet function is affected by multiple factors, including patient and procedural characteristics. Point-of-care (POC) multiple electrode aggregometry (MEA) can rapidly detect and quantify platelet dysfunction and could contribute to optimal patient blood management. In patients undergoing CABG and heart valve surgery platelet function was assessed using POC MEA at four different perioperative timepoints in response to stimulation with four specific receptor agonists (ADP, AA, COL, TRAP). Postoperative bleeding was recorded during 24 h after surgery. Regression analyses were performed to establish associations between perioperative platelet function and postoperative blood loss. Ninety-nine patients were included in the study. Fifty-nine patients (60%) were on antiplatelet therapy (APT) at time of surgery. ADP- and AA-induced platelet aggregation declined during CPB and after decannulation from CPB, with a maximum decrease of 55% for ADP (35 vs. 77 AU at baseline; P < 0.001) and 78% for ASPI (14 vs. 64 AU at baseline; P < 0.001). A linear relationship was present between ADP-induced platelet aggregometry at baseline and postoperative blood loss (r = -0.249; P = 0.015). In aspirin users, the maximum decline in platelet function between baseline and CPB decannulation was related to postoperative blood loss (r = 0.308; P = 0.037). In multivariate analysis, a reduced ADP platelet function prior to surgery remained associated with postoperative blood loss (r = -0.239; P = 0.012). Reduced ADP-induced platelet aggregation at baseline is associated with increased postoperative blood loss in high-risk cardiac surgery patients.

How Long Does It Take for Clopidogrel and Ticagrelor to Inhibit Platelets in Patients Undergoing Primary Percutaneous Coronary Intervention? A Detailed Pharmacodynamic Analysis: Time Course of Platelet Reactivity in STEMI (TOPS).

Antiplatelet therapy plays a pivotal role in patients with an ST-segment elevation myocardial infarction (STEMI) to prevent further atherothrombotic events, such as stent thrombosis. Although the risk of stent thrombosis is highest in the first hours after primary percutaneous coronary intervention (pPCI), little is known about when an adequate level of platelet inhibition is achieved following a clopidogrel or ticagrelor loading dose in STEMI patients. Patients presenting with STEMI in whom pPCI was performed and who were loaded with 600 mg clopidogrel or 180 mg ticagrelor were eligible for enrolment in this nonrandomized, open label, single-center study. Platelet reactivity was measured before PCI, 6 and 24 hours after loading dose and after 2, 7, and 14 days, using the VerifyNow P2Y12 assay as well as 20 µmol/L adenosine diphosphate stimulated light transmittance aggregometry (LTA). We analyzed the time until a VerifyNow result of < 236 P2Y12 reaction units or LTA maximum platelet aggregation of < 64.5% was reached. A total of 28 patients were participated in this study. Platelet reactivity dropped below the high platelet reactivity cutoff level after 11.4 (VerifyNow) and 5.7 (LTA) hours in patients who were loaded with clopidogrel, and after 2.4 (VerifyNow) and 3.9 (LTA) hours in patients who were loaded with ticagrelor. Despite the administration of a clopidogrel or ticagrelor loading dose, it still takes multiple hours (2-11) to reach adequate platelet inhibition in STEMI patients. This might indicate the need for additional antiplatelet therapy in the first hours after loading in patients undergoing pPCI with stenting.

Effect of Tailored Antiplatelet Therapy to Reduce Recurrent Stent Thrombosis and Cardiac Death After a First Episode of Stent Thrombosis.

The recurrence rate of coronary stent thrombosis (ST) is high. Patients with ST often demonstrate high on-treatment platelet reactivity (HPR). It is suggested that patients at high risk of atherothrombotic events, that is patients with ST, could benefit from tailored antiplatelet therapy (APT). This study evaluated whether tailored APT, based on platelet function testing, reduced the rate of cardiac death and/or recurrent ST at 1 year after ST, compared with a historical cohort of patients with ST without tailored APT. Patients with definite ST visited our ST outpatient clinic for platelet function testing and tailored APT. These patients were evenly matched to a historical cohort of patients with ST treated with aspirin and clopidogrel, which was the standard of care at that time. The primary end point was a composite of cardiac death and/or recurrent definite ST after 1 year. In total, 113 patients who visited the outpatient clinic were included. HPR was observed in 46%, 6.7%, and 0% of the patients on clopidogrel, prasugrel, and ticagrelor, respectively. After tailored APT, 93% of the patients with HPR demonstrated normal platelet reactivity. The primary end point was observed in 4 patients who had visited the outpatient clinic and in 23 patients of the historical cohort. The odds ratio of tailored APT on the primary end point was 0.26 (95% confidence interval 0.11 to 0.64, p = 0.003), independent from the possible confounders prior myocardial infarction and stent type. In conclusion, the outpatient ST clinic was associated with lower HPR rates in patients with ST after tailored APT. Patients who visited the ST outpatient clinic had a lower risk for cardiac death and/or recurrent ST compared with a historical cohort of patients with ST without tailored APT. Regarding the high HPR rate in patients with ST on clopidogrel, these patients might benefit in particular from the strategy of tailored APT.

Fibrin clot formation and fibrinolysis in patients with a history of coronary stent thrombosis.

INTRODUCTION: Coronary stent thrombosis is a devastating complication of percutaneous coronary intervention (PCI). Multiple factors underlie the pathophysiological mechanisms of stent thrombosis. Previous studies demonstrated that patients with stent thrombosis, compared to control PCI patients, formed denser fibrin clots in vitro which were more resistant to fibrinolysis, suggesting that altered fibrin clot properties may contribute to the pathophysiology of stent thrombosis. We assessed the plasma fibrin clot formation and fibrinolysis of patients with and without stent thrombosis. METHODS: Cases (patients with stent thrombosis) and matched controls (patients without stent thrombosis) were included for a matched case-control study. Matching was performed on indication and time of the index PCI (initial stent implantation) from the cases. Fibrin clot formation and fibrinolysis were assessed in vitro by turbidimetric assays, with human thrombin to initiate fibrin polymerization and tissue type plasminogen activator to initiate fibrinolysis. Lag time, maximal absorbance and clot lysis time were determined by these assays. RESULTS: In total, 27 cases and 27 controls were included. No significant differences were observed between cases and controls in lag time (173 vs. 162s, p=0.18), maximal absorbance (0.78 vs. 0.83, p=0.36), and clot lysis time (69 vs. 71min, p=0.78). Fibrin clot formation and fibrinolysis were not associated with stent thrombosis. CONCLUSIONS: Plasma fibrin clot formation and fibrinolysis were not significantly different between patients with stent thrombosis and matched control patients, suggesting that fibrin clot formation and fibrinolysis play no significant role in the pathophysiology of stent thrombosis.

The effect of acenocoumarol on the antiplatelet effect of clopidogrel.

Patients exhibiting high on-clopidogrel platelet reactivity (HPR) are at an increased risk of atherothrombotic events following percutaneous coronary interventions (PCI). The use of concomitant medication which is metabolised by the hepatic cytochrome P450 system, such as phenprocoumon, is associated with HPR. We assessed the level of platelet reactivity on clopidogrel in patients who received concomitant treatment with acenocoumarol (another coumarin derivative). Patients scheduled for PCI were included in a prospective, single centre, observational registry. Patients who were adequately pre-treated with clopidogrel were eligible for this analysis, which included 1,582 patients, of whom 104 patients (6.6%) received concomitant acenocoumarol treatment. Platelet reactivity, as measured with the VerifyNow P2Y12 assay and expressed in P2Y12 Reaction Units (PRU), was significantly higher in patients on concomitant acenocoumarol treatment (mean PRU 229 ± 88 vs 187 ± 95; p < 0.001). In patients with concomitant acenocoumarol use, the proportion of patients with HPR was higher, defined as PRU > 208 (57.7% vs 41.1%; p=0.001) and PRU ≥ 236 (49.0% vs 31.4%; p< 0.001). In multivariable analysis, concomitant acenocoumarol use was independently associated with a higher PRU and the occurrence of HPR defined as PRU ≥ 236 (OR 2.00, [1.07-3.79]), but not with HPR defined as PRU > 208 (OR 1.37, [0.74-2.54]). PRU also was significantly increased after 1:1 propensity matching (+28.2; p < 0.001). As this was an observational study, confounding by indication cannot be excluded, although multivariable analyses and propensity matching were performed. The impact of the findings from this hypothesis-generating study on clinical outcome requires further investigation.

Population pharmacodynamic model for low molecular weight heparin nadroparin in morbidly obese and non-obese patients using anti-Xa levels as endpoint.

PURPOSE: In absence of specific dosing guidelines, the optimal dose of low molecular weight heparins for thrombosis prophylaxis in morbidly obese patients (BMI>40 kg/m(2)) remains unknown. In order to guide dosing in this patient group, a pharmacodynamics model is developed for nadroparin in morbidly obese and non-obese patients using anti-Xa levels as an endpoint, thereby characterizing the influence of excessive body weight on different pharmacodynamic model parameters. METHODS: Twenty-eight morbidly obese and seven non-obese patients receiving 5700 IU and 2850 IU subcutaneous (s.c.) nadroparin for surgery, respectively, were included with a mean total body weight (TBW) of 135 kg (range 72-252 kg). Up to 11 anti-Xa levels were collected from the start until 24 h after nadroparin administration. Population pharmacodynamic modelling with covariate analysis was performed using NONMEM. RESULTS: In a two-compartment pharmacodynamic model with baseline endogenous anti-Xa levels, the effect of nadroparin was found to be delayed and could be best described using a transit compartment. TBW was the most predictive covariate for clearance (CL=23.0 mL/min × (TBW/70)), while lean body weight (LBW) proved the most predictive covariate for central volume of distribution (V1=7.0 L × (LBW/60)). CONCLUSIONS: A pharmacodynamic model was developed characterizing anti-Xa levels after s.c. administration of nadroparin in patients weighing between 72 and 252 kg with TBW and LBW as the major determinants for clearance and volume of distribution, respectively.

The use of platelet function testing in PCI and CABG patients.

Antiplatelet drugs are widely used in the treatment of patients with coronary artery disease. Dual anti-platelet therapy with acetylsalicylic acid (ASA) and a P2Y12 inhibitor (clopidogrel, prasugrel or ticagrelor) is the recommended strategy for patients undergoing a percutaneous coronary intervention (PCI), while patients that undergo coronary artery bypass grafting (CABG) are treated with ASA monotherapy. However, the response to these drugs as assessed with platelet function tests varies between patients. Despite these drugs, many patients still exhibit high on-treatment platelet reactivity (HPR), while platelet reactivity seems to be excessively inhibited in other patients. This review will discuss the use of platelet function testing in the prediction of atherothrombotic and bleeding events in patients undergoing PCI or CABG. Furthermore, options for tailoring based on platelet function testing in these patients are described.

Anti-Xa Levels 4 h After Subcutaneous Administration of 5,700 IU Nadroparin Strongly Correlate with Lean Body Weight in Morbidly Obese Patients.

BACKGROUND: Morbidly obese patients (BMI > 40 kg/m(2)) are at increased risk for venous thromboembolism, especially after surgery. Despite limited evidence, morbidly obese patients are often administered a double dose of nadroparin for thromboprophylaxis compared to non-obese patients. The aim of this study was to evaluate the influence of different body size descriptors on anti-Xa levels after a double dose of nadroparin (5,700 IU) in morbidly obese patients. METHODS: In 27 morbidly obese patients with a mean total body weight of 148 kg (range 107-260 kg), anti-Xa levels were determined peri-operatively until 24 h after administration of a subcutaneous dose of 5,700 IU of nadroparin. RESULTS: Anti-Xa level 4 h after administration (A(4h), mean 0.22 ± 0.07 IU/ml) negatively correlated strongly with lean body weight (r = -0.66 (p < 0.001)) and moderately with total body weight (r = -0.56 (p = 0.003)) and did not correlate with body mass index (r = -0.26 (p = 0.187)). The area under the anti-Xa level-time curve from 0 to 24 h (AUA(0-24h), mean 2.80 ± 0.97 h IU/ml) correlated with lean body weight (r = -0.63 (p = 0.007)), but did not correlate with total body weight (r = -0.44 (p = 0.075)) or body mass index (r = -0.10 (p = 0.709)). CONCLUCIONS: Following a subcutaneous dose of nadroparin 5,700 IU, A(4h) and AUA(0-24h) were found to negatively correlate strongly with lean body weight. From these results, individualized dosing of nadroparin based on lean body weight should be considered in morbidly obese patients.

The influence of CYP2C19*2 and *17 on on-treatment platelet reactivity and bleeding events in patients undergoing elective coronary stenting.

OBJECTIVES: To investigate the impact of genotypes on the basis of the loss-of-function variant CYP2C19*2 and the gain-of-function variant CYP2C19*17 on on-treatment platelet reactivity and on the occurrence of Thrombolysis in Myocardial Infarction (TIMI) major bleedings in 820 clopidogrel-treated patients who underwent elective coronary stenting. METHODS: On-treatment platelet reactivity was quantified using ADP-induced light transmittance aggregometry (LTA) and the VerifyNow P2Y12 assay. Postdischarge TIMI major bleedings within 1 year after enrollment were recorded. RESULTS: In total, 25 major bleedings (3.0% of the study population) were observed. Patients with the CYP2C19*1/*17 and *17/*17 diplotypes exhibited a lower magnitude of platelet reactivity as compared with patients with the CYP2C19*1/*1 diplotype (for the light transmittance aggregometry-adjusted mean difference: -5.8%, 95% confidence interval: -9.6 to -2.1, P=0.002). Patients with the *1/*17 and *17/*17 genotype had a 2.7-fold increased risk in the occurrence of major bleedings [adjusted hazard ratio: 2.7, 95% confidence interval: 1.1-7.0, P=0.039]. The diplotypes *2/*17, *1/*2, and *2/*2 exhibited higher on-treatment platelet reactivity as compared with the wild type (P<0.0001). However, this was not translated into an altered risk on major bleedings as compared with the wild type [hazard ratio: 1.3 (0.45-4.0), P=0.60]. Results have not been adjusted for multiple testing. CONCLUSION: Patients with the CYP2C19*1/*17 and *17/*17 diplotype have a lower magnitude of on-treatment platelet reactivity and are at a 2.7-fold increased risk of postdischarge TIMI major bleeding events after coronary stenting than patients with the *1/*1 genotype. The diplotypes *2/*17, *1/*2, and *2/*2 are associated with increased on-treatment platelet reactivity; however, this is not translated into a lower risk of bleeding events.

The relationship between platelet reactivity and infarct-related artery patency in patients presenting with a ST-elevation myocardial infarction.

Both heightened platelet reactivity and an occluded infarct related artery (IRA) on initial angiography and at the time of primary percutaneous coronary intervention (PCI) are associated with a worsened clinical outcome in patients with ST-elevation myocardial infarction (STEMI). However, the relationship between platelet reactivity and IRA patency has not yet been established. Consecutive STEMI-patients were enrolled in this study. Patients who had TIMI-flow (thrombolysis in myocardial infarction) 0 or 1 on initial angiography constituted the occluded IRA group and patients having TIMI-flow 2 or 3 comprised the IRA patent group. Platelet function measurements were performed using the PFA-100 COL/ADP cartridge and light transmittance aggregometry without agonist (spontaneous) and after stimulation with adenosine diphosphate (ADP) and arachidonic acid (AA). Ninety-nine patients were enrolled, of whom 49 presented with an occluded IRA. Multivariate analysis identified the following independent factors to be associated with an occluded IRA; short COL/ADP closure time (ORper quartile increase=0.60; 95% CI, 0.39-.93; p=0.02), the 20 µM ADP-induced light transmittance aggregometry (ORper quartile increase =1.77; 95% CI, 1.15-2.73; p=0.01) and leukocyte counts (odds ratio [OR]=1.21; 95% CI, 1.05-1.39; p = 0.008). In conclusion, heightened platelet reactivity and elevated leukocyte counts are associated with an occluded IRA upon presentation in STEMI-patients. These results emphasise the importance of potent antithrombotic therapy early after the onset of symptoms, to obtain early recanalisation of the IRA.

Variability in on-treatment platelet reactivity explained by CYP2C19*2 genotype is modest in clopidogrel pretreated patients undergoing coronary stenting.

BACKGROUND: An inadequate response to clopidogrel is mainly attributable to the variable formation of its active metabolite. The CYP2C19*2 loss-of-function polymorphism leads to reduced generation of the active metabolite and is, similarly to high on-treatment platelet reactivity (HPR), associated with recurrent atherothrombotic events following coronary stent implantation. AIM: To determine the relative contribution of CYP2C19*2 genotype to HPR. METHODS AND RESULTS: CYP2C19*2 genotyping and platelet function testing using 5 and 20 µmol/l ADP-induced light transmittance aggregometry (LTA), the PlateletWorks assay and the VerifyNow P2Y12 assay, were performed in 1069 clopidogrel pretreated patients undergoing elective coronary stenting (POPular study, http://clinicalTrials.gov/ NCT00352014). The relative contributions of CYP2C19*2 genotype and clinical variables to the interindividual variability of on-treatment platelet reactivity and the occurrence of HPR were established using multivariate regression models. CYP2C19*2 carrier status was associated with a more frequent occurrence of HPR. CYP2C19*2 genotype alone could explain 5.0%, 6.2%, 4.4% and 3.7% of the variability in 5 and 20 µmol/l ADP-induced LTA, the PlateletWorks assay and the VerifyNow P2Y12 assay, respectively, which increased to 13.0%, 15.2%, 5.6% and 20.6% when clinical variables were considered as well. Besides the CYP2C19*2 genotype, multiple clinical variables could be identified as independent predictors of HPR, including age, gender, body mass index, diabetes mellitus, clopidogrel loading dose regimen, use of amlodipine and platelet count. CONCLUSION: The CYP2C19*2 loss-of-function polymorphism is associated with a more frequent occurrence of HPR. However, the part of the interindividual variability in on-treatment platelet reactivity explained by CYP2C19*2 genotype is modest.

High on-treatment platelet reactivity to both aspirin and clopidogrel is associated with the highest risk of adverse events following percutaneous coronary intervention.

AIM: High on-clopidogrel platelet reactivity (HCPR) and high on-aspirin platelet reactivity (HAPR) are associated with atherothrombotic events following coronary stenting. There are, however, few data concerning high on-treatment platelet reactivity to both aspirin and clopidogrel simultaneously. The aim of the present study was to determine the incidence of dual high on-treatment platelet reactivity (DAPR) and its impact on clinical outcome. METHODS: On-treatment platelet reactivity was measured in parallel by ADP- and arachidonic acid-induced light transmittance aggregometry (LTA) (n=921) and the point-of-care VerifyNow system (P2Y12 and aspirin) (n=422) in patients on dual antiplatelet therapy undergoing elective stent implantation. HCPR and HAPR were established by receiver-operator characteristic curve analysis. The primary endpoint was a composite of all-cause death, non-fatal acute myocardial infarction, stent thrombosis and ischaemic stroke at 1-year follow-up. RESULTS: The incidence of DAPR varied between 14.7% and 26.9% depending on the platelet function test used. DAPR, assessed by LTA and the VerifyNow system, was highly associated with an adverse clinical outcome. At 1-year follow-up the primary endpoint occurred more frequently in patients with isolated HCPR (11.7%), isolated HAPR (9.6%) or DAPR (10.7%) compared with patients without high on-treatment platelet reactivity (4.2%, all p<0.01) when platelet function was evaluated with LTA. Using the VerifyNow system, patients exhibiting DAPR had the highest risk for the primary endpoint (17.7% vs 4.1% in patients without high on-treatment platelet reactivity, p=0.001). CONCLUSIONS: In patients undergoing elective percutaneous coronary intervention, DAPR to aspirin and clopidogrel is present in one in five patients and is associated with a high risk for atherothrombotic events. DAPR measured by the point-of-care VerifyNow system has a higher predictability for atherothrombotic events than LTA. CLINICAL TRIAL REGISTRATION INFORMATION: www.clinicaltrials.gov: NCT00352014.