Matthias K. Freynhofer

Bleeding and stent thrombosis on P2Y12-inhibitors: collaborative analysis on the role of platelet reactivity for risk stratification after percutaneous coronary intervention

AIMS Although platelet reactivity during P2Y12-inhibitors is associated with stent thrombosis (ST) and bleeding, standardized and clinically validated thresholds for accurate risk stratification after percutaneous coronary intervention (PCI) are lacking. We sought to determine the prognostic value of low platelet reactivity (LPR), optimal platelet reactivity (OPR), or high platelet reactivity (HPR) by applying uniform cut-off values for standardized devices. METHODS AND RESULTS Authors of studies published before January 2015, reporting associations between platelet reactivity, ST, and major bleeding were contacted for a collaborative analysis using consensus-defined, uniform cut-offs for standardized platelet function assays. Based on best available evidence for each device (exploratory studies), LPR-OPR-HPR categories were defined as <95, 95-208, and >208 PRU for VerifyNow, <19, 19-46, and >46 U for the Multiplate analyser and <16, 16-50, and >50% for VASP assay. Seventeen studies including 20 839 patients were used for the analysis; 97% were treated with clopidogrel and 3% with prasugrel. Patients with HPR had significantly higher risk for ST [risk ratio (RR) and 95% CI: 2.73 (2.03-3.69), P < 0.00001], yet a slight reduction in bleeding [RR: 0.84 (0.71-0.99), P = 0.04] compared with those with OPR. In contrast, patients with LPR had a higher risk for bleeding [RR: 1.74 (1.47-2.06), P < 0.00001], without any further benefit in ST [RR: 1.06 (0.68-1.65), P = 0.78] in contrast to OPR. Mortality was significantly higher in patients with HPR compared with other categories (P < 0.05). Validation cohorts (n = 14) confirmed all results of exploratory studies (n = 3). CONCLUSIONS Platelet reactivity assessment during thienopyridine-type P2Y12-inhibitors identifies PCI-treated patients at higher risk for mortality and ST (HPR) or at an elevated risk for bleeding (LPR).

The role of platelets in athero-thrombotic events.

The crucial role of platelets in primary hemostasis and repair of injured endothelium is well established, as is their role in atherothrombosis. No other single cell type is responsible for as much morbidity and mortality, since death from ischemic heart disease or stroke is by far the leading cause of death worldwide. There is no doubt that our understanding of atherothrombosis has guided current antithrombotic strategies that have dramatically reduced ischemic complications and cardiovascular mortality within the last decades. Yet the rate of ischemic complications after optimal revascularization therapy remains disappointingly high. There is still a strong need for new and smart antiplatelet drugs. The ideal antithrombotic drug would spare physiological platelet function, hemostasis and vascular repair in order to avoid bleeding complications, but would exclusively target the pathological atherothrombotic process. As platelet activity might be determined early in the bone marrow, this review starts with insights into the birth of platelets, describes the essential and primary role of platelets in hemostasis with new evidence in signaling cascades, and closes with the deleterious role of platelets in atherosclerosis and atherothrombosis, with a focus on acute coronary syndromes.

Genetic variability in response to clopidogrel therapy and its clinical implications.

This article concentrates on individual genetic differences responsible for variations of action of clopidogrel, which have been found to be partially responsible for increased cardiovascular events in patients with coronary artery disease under dual antiplatelet therapy. According to these results, genotyping for the relevant gene polymorphisms, especially for the CYP2C19 loss-of-function alleles, has been discussed to be an effective method of individualising and optimising clopidogrel treatment. However, due to the facts that 1) there are no prospective studies demonstrating a clinical benefit of personalising antiplatelet therapy based on genotyping; 2) CYP2C19 polymorphisms account for only approximately 12% of variability in clopidogrel platelet response; 3) the positive predictive value of CYP2C19 loss-of-function polymorphisms for cardiovascular events in patients with acute coronary syndrome undergoing percutaneous coronary intervention is only approximately 12% - 20%; 4) it is likely that other clinical factors and risk constellations might be of greater clinical importance; and 5) it is unknown whether a specific genetic polymorphism is capable of influencing outcome for the individual patient; genetic profiling cannot be recommended for routine use at present but will remain of considerable scientific interest.

Antiplatelet drugs in patients with enhanced platelet turnover: biomarkers versus platelet function testing.

Platelets are key players in atherothrombosis. Antiplatelet therapy comprising aspirin alone or with P2Y12-inhibitors are effective for prevention of atherothrombotic complications. However, there is interindividual variability in the response to antiplatelet drugs, leaving some patients at increased risk of recurrent atherothrombotic events. Several risk factors associated with high on-treatment platelet reactivity (HTPR), including elevated platelet turnover, have been identified. Platelet turnover is adequately estimated from the fraction of reticulated platelets. Reticulated platelets are young platelets, characterised by residual messenger RNA. They are larger, haemostatically more active and there is evidence that platelet turnover is a causal and prognostic factor in atherothrombotic disease. Whether platelet turnover per se represents a key factor in pathogenesis, progression and prognosis of atherothrombotic diseases (with focus on acute coronary syndromes) or whether it merely facilitates insufficient platelet inhibition will be discussed in this state-of-the art review.

Vasodilator-stimulated phosphoprotein-phosphorylation assay in patients on clopidogrel: Does standardisation matter?

The vasodilator-stimulated phosphoprotein-phosphorylation (VASP-P) flow-cytometric assay is mainly used in clinical trials to measure thienopyridine effects. However, there are remarkable differences in the reported optimal cut-offs, ranging from 48-61% platelet reactivity index (PRI). We therefore investigated whether a lack of standardisation might explain the differences in the cut-offs. We measured VASP-P in 62 individuals. PRI was calculated using the mean, geometric mean and median fluorescence intensities (FI). Stability of the blood-samples (time-to-assay, 0-2 days) and stability of the processed samples (0-120 minutes) within the recommended time-span were tested. Time-to-assay significantly influenced the PRI (p<0.001): the PRI from mean FI after two days was lower compared to values on day 1 (52 ± 22.9 vs. 57.7 ± 24.1, p<0.001). The PRI from the geometric mean FI after two days was lower compared to day 0 as well as day 1 (51.3 ± 23 vs. 58.2 ± 24.2 and vs. 59.1 ± 23.7, both p<0.001). The PRI from median FI was stable over time (day 0: 59.1 ± 25%, day 1: 59.7 ± 24.1% and day 2: 56.4 ± 23.9%, all p=ns). Furthermore, the lag time of the processed samples significantly altered the PRI (all p<0.001) with a maximum difference for PRI based on geometric mean FI after 90 minutes compared to baseline (Δ=3.92%PRI, p<0.001). The differences in the reported cut-offs might be explained by a lack of standardisation. More precise standardisation is inevitable, as the PRI significantly depends on the method of calculation, the time-to-assay as well as on the lag time after processing. Tolerably stable results were obtained for the PRI from the median FI.

Influence of updated guidelines on short- and long-term mortality in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS)

AIM In 2002 the ACC/AHA guidelines for the management of patients with unstable angina (UA) and non-ST-segment elevation myocardial infarction (NSTEMI) were updated. We aimed to answer whether the implementation of updated guidelines was capable of influencing short- and long-term mortality in these patients. METHODS We analyzed data on 812 consecutive patients who were admitted with either UA or NSTEMI between 2001 and 2004. Patients admitted in the two years before the implementation of updated guidelines (UA(01/02) group and NSTEMI(01/02) group) were compared to patients admitted in the two years thereafter (UA(03/04) group and NSTEMI(03/04) group). Yearly follow-up concerning all-cause mortality was obtained up to four years. RESULTS The rate of revascularizations, the percentage of procedures performed within 48 h of admission, and the administration of clopidogrel increased significantly. However, still many - especially high-risk - patients did not receive revascularization. Patients of both UA groups had an identical in-hospital mortality rate. Differences in mortality between groups gained statistical significance over time (four-year mortality; 15.1% for the UA(03/04) group vs. 26.5% for the UA(01/02) group, p=0.014; HR 0.49 95% CI 0.28-0.87). In patients with NSTEMI in-hospital mortality decreased from 18.4% in the NSTEMI(01/02) group to 9.6% in the NSTEMI(03/04) group (p=0.011; HR 0.47 95% CI 0.26-0.84), and 1-year mortality from 34.7% to 25.1% (p=0.038; HR 0.63 95% CI 0.41-0.98), respectively. Mortality rates beyond one year were still lower in the NSTEMI(03/04) group as compared to the NSTEMI(01/02) group but it did not reach statistical significance. Multivariate Cox-regression analysis revealed furthermore that also patients with higher age and/or renal dysfunction benefit from an early invasive strategy. CONCLUSION The implementation of updated guidelines for NSTE-ACS had significant impact on short- and long-term mortality. However, an early invasive strategy is still withheld to a significant number of high-risk patients, who would benefit from an invasive treatment.

Sex-related differences in baseline characteristics, management and outcome in patients with acute coronary syndrome without ST-segment elevation.

Aim: To detect sex-related differences in baseline characteristics, management and outcome in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Methods: Data from 812 consecutive patients admitted to our cardiology department for NSTE-ACS between 2001 and 2004 were obtained. Early invasive therapy was defined as revascularization during first hospital stay. A seven-year follow-up for the clinical endpoint of all-cause mortality could be obtained in 342 women and 440 men, respectively. Results: Compared with men, women were significantly older and more likely to suffer from renal insufficiency. The proportion treated with clopidogrel at admission was 43.6% for women and 52.7% for men, respectively (p=0.011). Significantly fewer women underwent an early invasive therapy compared with men (27.5% vs. 35.2%; p=0.021). Age and renal insufficiency were the strongest predictors for a conservative approach in both female and male patients. After adjustment for baseline characteristics there was no significant difference in treatment between women and men (odds ratio 0.89; 95% confidence interval 0.59–1.35; p=0.588). While in-hospital mortality was similar between the sexes, long-term mortality was significantly higher in women compared with men (8.2% vs. 7.0%; p=0.549 for in-hospital mortality and 54.8% vs. 39.3%; p<0.001 for seven-year mortality). However, after adjustment for baseline characteristics and treatment there was no significant difference in long-term mortality between women and men (hazard ratio 1.14; 95% confidence interval 0.89–1.47; p=0.307). Conclusion: In these patients with NSTE-ACS women were less likely to undergo an early invasive therapy compared with men due to their higher age and the higher rate of renal insufficiency. After adjustment for age, comorbidities and treatment female sex was not associated with worse long-term outcome.

Variability of on-treatment platelet reactivity in patients on clopidogrel

Abstract Response to clopidogrel therapy is subject to inter-individual variability. However, data with regard to on-treatment platelet reactivity over time in patients undergoing coronary stenting are scarce. For this prospective observational study, 102 consecutive patients on dual antiplatelet therapy undergoing coronary stenting due to stable coronary artery disease (CAD; n = 29), non ST-elevation acute coronary syndrome (NSTE-ACS; n = 45) and ST-elevation myocardial infarction (STEMI; n = 28) were enrolled. Vasodilator-stimulated phosphoprotein-phosphorylation assay was performed at baseline, as well as 1, 3 and 6 months thereafter. Platelet reactivity index (PRI) measured after 1, 3 and 6 months was lower compared to baseline values (p < 0.001). Variables responsible for reduced response to clopidogrel at baseline (reticulated platelet fraction, simvastatin therapy) and during steady-state phase (body mass index, blood glucose concentrations, cholesterol/HDL-ratio and quality of life score) were different. High on-treatment platelet reactivity (HTPR)-phenotype (cut-off = 50% PRI) within the first month changed in 31% of stable CAD, 33% of NSTE-ACS and 39% of STEMI patients, respectively. HTPR-phenotype in the steady-state phase (month 1 to 6) changed in 45% of stable CAD, 33% of NSTE-ACS and 25% of STEMI patients. Response to clopidogrel and accordingly platelet function might vary over time, especially when a cut-off based approach, is used. There was a significant reduction of on-treatment platelet reactivity within the first month after percutaneous coronary intervention with stenting which was maintained for up to 6 months. Variables associated with reduced response to clopidogrel at baseline and during steady-state phase were different, as the latter mainly reflected an unfavorable metabolic profile, comprising elevated BMI, blood glucose levels as well as cholesterol/HDL-ratio.

Is increased platelet turnover responsible for low responsiveness to different thienopyridienes? A case report of recurrent stent thromboses

Is increased platelet turnover responsible for low responsiveness to different thienopyridienes? A case report of recurrent stent thromboses -

Long-term mortality of patients with atrial fibrillation undergoing percutaneous coronary intervention with stent implantation for acute and stable coronary artery disease.

BACKGROUND Patients with atrial fibrillation (AF) are of increased risk for ischemic and bleeding complications, particularly when requiring aggressive antithrombotic therapy after coronary stenting. However, data from unselected patients on long-term mortality are scarce. METHODS We analyzed 2890 patients of a single-center registry undergoing coronary stenting between 2003 and 2012, of whom 1434 patients had stable coronary artery disease (CAD), while 1456 patients presented with acute coronary syndromes (ACS). As the primary endpoint, we compared long-term all-cause mortality between patients with AF and patients in sinus rhythm. RESULTS History or presence of AF was found in 146 (10.2%) patients with stable CAD and 93 (6.4%) patients with ACS. The median CHA2DS2-VASc scores were similar between stable CAD and ACS patients (4[2; 5] vs. 3[2; 5], p=0.92). Patients with AF had a significantly higher atherothrombotic risk profile and more co-morbidities. Patients undergoing PCI before 2011 received triple therapy (aspirin, clopidogrel and a vitamin K antagonist) in 25% of cases, compared to 64% of cases thereafter. Patients undergoing elective or urgent revascularization and suffering from AF had a similar 2-fold increased adjusted relative risk of death after a mean follow-up of 4.8 years (HR 1.95, 95% CI 1.27; 2.99, p<0.01 for stable CAD and HR 1.95, 95% CI 1.23; 3.11, p<0.01 for ACS). CONCLUSION In a general practice setting, patients with AF had significantly increased adjusted long-term mortality than patients without AF. After publication of the consensus document of different working groups of the European Society of Cardiology in 2010, triple therapy increased markedly.