Ticagrelor versus prasugrel in patients with high on-clopidogrel treatment platelet reactivity after PCI: The ISAR-ADAPT-PF study.

Patients with high on-treatment platelet reactivity (HTPR) on clopidogrel are at high risk for adverse cardiovascular events after percutaneous coronary intervention (PCI). The aim of the ISAR-ADAPT-PF study was to assess the antiplatelet efficacy of ticagrelor versus prasugrel in patients with HTPR on clopidogrel. In a prospective and randomized clinical study, 70 patients with HTPR on clopidogrel loading dose (LD) within 24 h post PCI were assigned to receive either ticagrelor [180 mg LD followed by 90 mg maintenance dose (MD) twice daily] or prasugrel (60 mg LD followed by 10 mg MD once daily). The adenosine diphosphate-induced platelet aggregation assessed on the Multiplate analyzer on day 2 after randomization (primary end point) was as follows: the mean difference between the two treatment groups was 6 aggregation units (AU) × min with an upper 95% confidence interval (CI) of 41 AU × min, which was greater than the predefined noninferiority margin of 18 AU × min (P for noninferiority = 0.29). However, no significant differences in absolute platelet reactivity levels between ticagrelor- versus prasugrel-treated patients at that time point were observed (138 ± 100 AU × min vs. 132 ± 64 AU × min, P for superiority = 0.77). In conclusion, neither drug was statistically more effective for inhibition of platelet aggregation in patients with HTPR on clopidogrel post PCI, although the study could not formally demonstrate the assumed noninferiority of ticagrelor versus prasugrel.

High on-treatment platelet reactivity and outcomes after percutaneous endovascular procedures in patients with peripheral artery disease.

BACKGROUND: High on-treatment platelet reactivity (HPR) predicts adverse cardiovascular events in patients with coronary artery disease. The impact of HPR in patients with peripheral artery disease (PAD) after peripheral endovascular procedures is unclear. PATIENTS AND METHODS: A total of 385 patients with PAD and successful percutaneous endovascular procedure were included. Patients received aspirin as a long-term treatment in addition to the P2Y12 receptor antagonist clopidogrel, as recommended after such a procedure for at least 1 month. Platelet function was assessed on a Multiplate analyzer. The primary endpoint was target lesion revascularization (TLR) at one year. Restenosis (≥ 75 %) in duplex sonography, mortality at one year and identification of independent predictors of TLR were secondary endpoints. RESULTS: TLR rates were similar in HPR and no-HPR patients (14.3 % vs. 12.7 %, hazard rate (HR) 0.94, 95 % CI 0.48 - 1.84, P = 0.86). Restenosis (≥ 75 %) in duplex sonography did not differ between the two study groups (15.6 % vs. 16.9 %, HR 1.16, 95% CI 0.62 - 2.12, P = 0.64). Independent predictors of TLR were intervention of restenotic lesions, total vessel occlusions and critical limb ischemia, but not HPR (adjusted HR 1.07, 95% CI 0.55 - 2.10, P = 0.84). No difference in mortality at one year was observed (1.3 % vs. 1.6 %, HR 1.28, 95 % CI 0.15 - 11.0, P = 0.82). CONCLUSIONS: In patients with PAD, HPR did not have a significant impact on outcomes within the first year after percutaneous endovascular intervention.

Prediction of outcome in patients with ARDS: A prospective cohort study comparing ARDS-definitions and other ARDS-associated parameters, ratios and scores at intubation and over time.

BACKGROUND: Early recognition of high-risk-patients with acute respiratory distress syndrome (ARDS) might improve their outcome by less protracted allocation to intensified therapy including extracorporeal membrane oxygenation (ECMO). Among numerous predictors and classifications, the American European Consensus Conferenece (AECC)- and Berlin-definitions as well as the oxygenation index (OI) and the Murray-/Lung Injury Score are the most common. Most studies compared the prediction of mortality by these parameters on the day of intubation and/or diagnosis of ARDS. However, only few studies investigated prediction over time, in particular for more than three days. OBJECTIVE: Therefore, our study aimed at characterization of the best predictor and the best day(s) to predict 28-days-mortality within four days after intubation of patients with ARDS. METHODS: In 100 consecutive patients with ARDS severity according to OI (mean airway pressure*FiO2/paO2), modified Murray-score without radiological points (Murray_mod), AECC- and Berlin-definition, were daily documented for four days after intubation. In the subgroup of 49 patients with transpulmonary thermodilution (TPTD) monitoring (PiCCO), extravascular lung water index (EVLWI) was measured daily. PRIMARY ENDPOINT: Prediction of 28-days-mortality (Area under the receiver-operating-characteristic curve (ROC-AUC)); IBM SPSS 26. RESULTS: In the totality of patients the best prediction of 28-days-mortality was found on day-1 and day-2 (mean ROC-AUCs for all predictors/scores: 0.632 and 0.620). OI was the best predictor among the ARDS-scores (AUC=0.689 on day-1; 4-day-mean AUC = 0.625). AECC and Murray_mod had 4-day-means AUCs below 0.6. Among the 49 patients with TPTD, EVLWI (4-day-mean AUC=0.696) and OI (4-day-mean AUC=0.695) were the best predictors. AUCs were 0.789 for OI on day-1, and 0.786 for EVLWI on day-2. In binary regression analysis of patients with TPTD, EVLWI (B=-0.105; Wald=7.294; p=0.007) and OI (B=0.124; Wald=7.435; p=0.006) were independently associated with 28-days-mortality. Combining of EVLWI and OI provided ROC-AUCs of 0.801 (day-1) and 0.824 (day-2). Among the totality of patients, the use of TPTD-monitoring "per se" and a lower SOFA-score were independently associated with a lower 28-days-mortality. CONCLUSIONS: Prognosis of ARDS-patients can be estblished within two days after intubation. The best predictors were EVLWI and OI and their combination. TPTD-monitoring "per se" was independently associated with reduced mortality.

Combination of factor Xa inhibition and antiplatelet therapy after stenting in patients with iliofemoral post-thrombotic venous obstruction.

OBJECTIVES: Studies addressing optimal postprocedural pharmacological management after endovascular stenting of iliofemoral post-thrombotic venous obstruction are lacking. We report our early clinical experience with a combination of rivaroxaban and clopidogrel in patients after iliofemoral post-thrombotic venous obstruction stenting. METHODS: Demographic, procedural, and follow-up data of nine patients (seven women; mean age of 32 ± 11 years) undergoing 10 procedures for iliofemoral post-thrombotic venous obstruction performed between August 2012 and January 2014 were retrospectively reviewed. After endovascular intervention, all patients were administered 20 mg rivaroxaban once daily (s.i.d.) and 75 mg clopidogrel s.i.d. or every second day depending on the individual drug responsiveness for at least six months. The adenosine diphosphate-induced platelet aggregation (platelet aggregation, in aggregation units × min) was assessed on a Multiplate analyzer. Patency was verified venographically at procedure end and was evaluated with duplex ultrasound in regular follow-ups. RESULTS: Iliofemoral venous flow was successfully re-established by percutaneous endovascular angioplasty and stent implantation in nine left-sided and one bilateral iliofemoral post-thrombotic venous obstruction. Under dual treatment strategy of rivaroxaban and clopidogrel with platelet aggregation control (median (range): 285 aggregation units × min (192; 402)), none of the patients experienced restenosis or stent thrombosis, respectively. After a median follow-up of 14 months (range: 6-26 months), the primary patency rate was 100% and no in-stent restenosis, stent occlusion or relevant minor or major bleeding occurred. CONCLUSION: Combined factor Xa inhibition and tailored antiplatelet therapy after stenting of iliofemoral post-thrombotic venous obstruction were safe and performed favorably in terms of vessel patency.

Randomized comparison of ticagrelor versus prasugrel in patients with acute coronary syndrome and planned invasive strategy--design and rationale of the iNtracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) 5 trial.

In acute coronary syndromes (ACS), a dual antiplatelet regimen with an adenosine diphosphate (ADP) receptor antagonist plus aspirin has become the cornerstone of treatment. The third-generation thienopyridine prasugrel and the cyclopentyl-triazolo-pyrimidine ticagrelor provide a greater, more rapid and consistent platelet inhibition compared to their predecessor clopidogrel. Based on their advantages over clopidogrel in two landmark studies, both drugs received a class I recommendation for their use in ACS patients with and without ST segment elevation. Due to differences in ACS populations and conditions investigated, the relative merits of ticagrelor versus prasugrel in the treatment of ACS patients with planned invasive strategy cannot be reliably estimated from independent trials. To date, no direct head-to-head comparison of ticagrelor and prasugrel in terms of clinical outcome exists. The aim of this multicenter, randomized, open-label trial is to assess whether ticagrelor is superior to prasugrel in ACS patients with planned invasive strategy.

No association of ABCB1 C3435T genotype with clopidogrel response or risk of stent thrombosis in patients undergoing coronary stenting.

BACKGROUND: The prodrug clopidogrel requires intestinal absorption by the efflux pump P-glycoprotein MDR1 (multidrug resistant-1), encoded by the ABCB1 gene. Prior studies suggested that a common and functional genetic variant (C3435T, rs1045642) within ABCB1 influences clopidogrel treatment efficacy; however, existing data are highly inconsistent, because other studies failed to replicate this postulated association. Thus, the aim of this study was to assess the association of ABCB1 C3435T genotypes with the antiplatelet efficacy of clopidogrel and the risk of stent thrombosis (ST) in large cohorts of clopidogrel-treated patients undergoing percutaneous coronary intervention. METHODS AND RESULTS: DNA samples from 1524 clopidogrel-treated patients undergoing percutaneous coronary intervention were genotyped for ABCB1 C3435T, and ADP-induced platelet aggregation was assessed in whole blood on a Multiplate analyzer. The clinical impact of the genetic variant was investigated by comparison of genotype frequencies in a registry of 66 cases with definite drug-eluting stent ST versus an ST-free control cohort (n=1408). Platelet aggregation values were similar across ABCB1 C3435T genotypes (P=0.73). No significant influence of ABCB1 C3435T genotypes on the occurrence of ST was found when ST case subjects were compared with control subjects (P=0.89). CONCLUSIONS: ABCB1 C3435T genotypes did not influence the antiplatelet response to clopidogrel or the risk of ST in clopidogrel-treated patients undergoing percutaneous coronary intervention. Routine genotyping of ABCB1 C3435T polymorphisms should not be recommended for risk stratification in clopidogrel-treated patients undergoing percutaneous coronary intervention who are similar to those evaluated in the present study.

Stability of the high on-treatment platelet reactivity phenotype over time in clopidogrel-treated patients.

Interindividual response variability to clopidogrel treatment is a well established phenomenon. In recent studies and ongoing large-scale trials where patients with high on-treatment platelet reactivity (HPR) to clopidogrel are being randomised to an intensified antiplatelet treatment, confirmation of the HPR phenotype is based on one single platelet function assessment. The stability of the HPR phenotype over time has never been investigated but should be considered crucial for justification of intensified antiplatelet treatment regimens beyond clinical trials. The goal of this study was to test for the stability of the HPR phenotype over time in clopidogrel-treated patients. Patients (n=31) under chronic clopidogrel treatment (75 mg/day) were investigated by serial adenosine diphosphate (ADP)-induced platelet aggregation assessment with multiple electrode aggregometry (MEA) on a Multiplate analyser and light transmission aggregometry (LTA) at three different time points (once per week) during monitored antiplatelet treatment. On the basis of a cut-off level approach (468 AU*min for MEA, 53% for LTA) patients were classified into patients with (n=27) or without (n=4) HPR. For MEA, the phenotype was stable in 93.5% (n=29) of patients whereas 6.5% (n=2) crossed the cut-off level. For LTA, the phenotype was stable in 68% (n=21) of patients whereas 32% (n=10) patients crossed the cut-off level (chi-square P=0.01 for comparison of phenotype stability between both assays). In conclusion, the HPR phenotype is stable over time in the majority of clopidogrel-treated patients. Comparative assessment of phenotype stability across available platelet function assays warrants further investigation.

The novel P2Y 12 antagonist AZD6140 rapidly and reversibly reduces platelet activation in diabetic rats.

INTRODUCTION: Excessive platelet activation fundamentally contributes to cardiovascular events and mortality in patients with diabetes mellitus. Functional resistance has been described for current antiplatelet therapies in broad populations that include patients with diabetes. We investigated acute and chronic effects of AZD6140, a reversible oral rapid-onset P2Y(12) antagonist, on platelet reactivity in diabetic rats. MATERIALS AND METHODS: Diabetes was induced by streptozotocin injection in male Wistar rats. After 4 weeks, AZD6140 was administered (5mg/kg by gavage) and achieved sufficient plasma levels within 30 minutes. Platelet reactivity was determined by ADP-induced P-selectin expression, aggregation and adhesion on fibrinogen coated membranes under arterial flow conditions. RESULTS: At 0.5 hour, AZD6140 strongly reduced ADP-induced P-selectin surface expression, inhibited ADP-induced platelet aggregation, and significantly reduced platelet adhesion to fibrinogen under arterial flow conditions. Chronic treatment with AZD6140 (10mg/kg bid for 2 weeks, based on data obtained in the acute study) starting at day 14 reduced P-selectin surface expression on circulating platelets, indicating lower in vivo platelet activation. Platelet reactivity was improved 12 hours after the last dose, while basal platelet activity remained reduced. AZD6140 was rapidly absorbed in diabetic rats and inhibited platelet reactivity. Chronic treatment lowered in vivo platelet activation of circulating platelets. CONCLUSION: AZD6140 inhibits platelet reactivity in diabetic rats rapidly and reversibly. Markers of tonic platelet activation, which were increased in diabetic rats, were lowered to levels comparable to non-diabetic rats following chronic treatment with AZD6140.

Association between inflammatory biomarkers and platelet aggregation in patients under chronic clopidogrel treatment.

Inflammatory processes in the vessel wall are associated with progression of atherosclerosis and myocardial infarction. Both high levels of C-reactive protein (CRP)and high on-clopidogrel treatment platelet reactivity (HPR) have been linked to an increased risk of ischaemic events after percutaneous coronary intervention (PCI). The aim of this study was to explore the association between biomarker levels of inflammation and platelet reactivity. Stable patients (n=1,223) eligible for this study were under chronic antiplatelet treatment with aspirin and clopidogrel due to prior coronary stent placement. ADP-induced platelet aggregation (in AU*min) was measured on a Multiplate analyser. The primary outcome measure of this retrospective study was the ADP-induced platelet aggregation in patients with versus those without elevated CRP levels. Of the patients 15.5% (n=189) showed elevated CRP levels (≥5 mg/l). Platelet aggregation (median [interquartile range]) was significantly higher in patients with elevated CRP levels compared to patients with normal (<5 mg/l) CRP levels (305 [202-504] AU*min vs. 218 [144-384] AU*min; p<0.001).A multivariable linear regression model that adjusted for known predictors of HPR confirmed a significant independent association between elevated CRP levels and high ADP-induced platelet aggregation values (p=0.0002).Elevated WBC count and fibrinogen levels were also associated with higher platelet aggregation values (p<0.001 for both). In conclusion, elevated levels of CRP, WBC count and fibrinogen were significantly associated with high platelet reactivity in patients under chronic clopidogrel treatment. Whether a direct relation between platelets and inflammation exists, as well as the clinical impact of our results, warrants further investigations.