Tobias Geisler

Consensus and Update on the Definition of On-Treatment Platelet Reactivity to Adenosine Diphosphate Associated With Ischemia and Bleeding

Dual antiplatelet therapy with aspirin and a P2Y12 receptor blocker is a key strategy to reduce platelet reactivity and to prevent thrombotic events in patients treated with percutaneous coronary intervention. In an earlier consensus document, we proposed cutoff values for high on-treatment platelet reactivity to adenosine diphosphate (ADP) associated with post-percutaneous coronary intervention ischemic events for various platelet function tests (PFTs). Updated American and European practice guidelines have issued a Class IIb recommendation for PFT to facilitate the choice of P2Y12 receptor inhibitor in selected high-risk patients treated with percutaneous coronary intervention, although routine testing is not recommended (Class III). Accumulated data from large studies underscore the importance of high on-treatment platelet reactivity to ADP as a prognostic risk factor. Recent prospective randomized trials of PFT did not demonstrate clinical benefit, thus questioning whether treatment modification based on the results of current PFT platforms can actually influence outcomes. However, there are major limitations associated with these randomized trials. In addition, recent data suggest that low on-treatment platelet reactivity to ADP is associated with a higher risk of bleeding. Therefore, a therapeutic window concept has been proposed for P2Y12 inhibitor therapy. In this updated consensus document, we review the available evidence addressing the relation of platelet reactivity to thrombotic and bleeding events. In addition, we propose cutoff values for high and low on-treatment platelet reactivity to ADP that might be used in future investigations of personalized antiplatelet therapy.

Platelet-Derived Stromal Cell–Derived Factor-1 Regulates Adhesion and Promotes Differentiation of Human CD34+ Cells to Endothelial Progenitor Cells

Background— Peripheral homing of progenitor cells in areas of diseased organs is critical for tissue regeneration. The chemokine stromal cell–derived factor-1 (SDF-1) regulates homing of CD34+ stem cells. We evaluated the role of platelet-derived SDF-1 in adhesion and differentiation of human CD34+ cells into endothelial progenitor cells. Methods and Results— Adherent platelets express substantial amounts of SDF-1 and recruit CD34+ cells in vitro and in vivo. A monoclonal antibody to SDF-1 or to its counterreceptor, CXCR4, inhibits stem cell adhesion on adherent platelets under high arterial shear in vitro and after carotid ligation in mice, as determined by intravital fluorescence microscopy. Platelets that adhere to human arterial endothelial cells enhance the adhesion of CD34+ cells on endothelium under flow conditions, a process that is inhibited by anti-SDF-1. During intestinal ischemia/reperfusion in mice, anti-SDF-1 and anti-CXCR4, but not isotype control antibodies, abolish the recruitment of CD34+ cells in microcirculation. Moreover, platelet-derived SDF-1 binding to CXCR4 receptor promotes platelet-induced differentiation of CD34+ cells into endothelial progenitor cells, as verified by colony-forming assays in vitro. Conclusions— These findings imply that platelet-derived SDF-1 regulates adhesion of stem cells in vitro and in vivo and promotes differentiation of CD34+ cells to endothelial progenitor cells. Because tissue regeneration depends on recruitment of progenitor cells to peripheral vasculature and their subsequent differentiation, platelet-derived SDF-1 may contribute to vascular and myocardial regeneration.

The Residual Platelet Aggregation after Deployment of Intracoronary Stent (PREDICT) score

Summary.  Background: Recent studies suggest a high interindividual variability of response to clopidogrel associated with adverse cardiovascular outcome. Different clinical factors are considered to influence a persistent residual platelet aggregation (RPA) despite conventional antiplatelet therapy.

CYP2C19 and nongenetic factors predict poor responsiveness to clopidogrel loading dose after coronary stent implantation.

AIMS To investigate an association of responsiveness to clopidogrel loading dose with genotypes of cytochrome P450 (CYP) 2C19, other CYP isozymes and nongenetic factors in patients with coronary artery disease. MATERIALS & METHODS Genotyping for CYP2C19 (*2, *3 and *17), CYP3A4*1B and CYP3A5*3 variants was performed in patients (n = 237) who underwent percutaneous coronary intervention. Adenosine diphosphate-induced platelet aggregation was determined after first administration of 600 mg clopidogrel. RESULTS CYP2C19*2 carriers showed significantly increased residual platelet aggregation (RPA) (OR: 4.6; 95% CI: 2.5-8.7; p < 0.0001) compared with noncarriers. All other polymorphisms had no influence on RPA. For the development of a risk score for better prediction of RPA, CYP2C19*2 genotype and previously identified nongenetic risk factors (age >65 years, Type 2 diabetes mellitus, decreased left ventricular function, renal failure and acute coronary syndrome) were analyzed. Multivariable logistic regression analysis showed a significant correlation of the nongenetic factors (chi (2) = 5.32; p = 0.021) and CYP2C19*2 (chi (2) = 21.31; p < 0.0001) with high RPA, and an even higher association for the combination of both (chi (2) = 25.85; p < 0.0001). CONCLUSIONS Prediction of responsiveness after clopidogrel loading dose may substantially be improved by adding CYP2C19*2 genotype to nongenetic risk factors.

Platelets induce differentiation of human CD34+ progenitor cells into foam cells and endothelial cells

Recruitment of human CD34+ progenitor cells toward vascular lesions and differentiation into vascular cells has been regarded as a critical initial step in atherosclerosis. Previously we found that adherent platelets represent potential mediators of progenitor cell homing besides their role in thrombus formation. On the other hand, foam cell formation represents a key process in atherosclerotic plaque formation. To investigate whether platelets are involved in progenitor cell recruitment and differentiation into endothelial cells and foam cells, we examined the interactions of platelets and CD34+ progenitor cells. Cocultivation experiments showed that human platelets recruit CD34+ progenitor cells via the specific adhesion receptors P‐selectin/PSGL‐1 and β1‐ and β2‐integrins. Furthermore, platelets were found to induce differentiation of CD34+ progenitor cells into mature foam cells and endothelial cells. Platelet‐induced foam cell generation could be prevented partially by HMG coenzyme A reductase inhibitors via reduction of matrix metallo‐proteinase‐9 (MMP‐9) secretion. Finally, agonists of peroxisome proliferator‐activated receptor‐α and ‐γ attenuated platelet‐induced foam cell generation and production of MMP‐9. The present study describes a potentially important mechanism of platelet‐induced foam cell formation and generation of endothelium in atherogenesis and atheroprogression. The understanding and modulation of these mechanisms may offer new treatment strategies for patients at high risk for atherosclerotic diseases.—Daub, K., Langer, H., Seizer, P., Stellos, K., May, A. E., Goyal, P., Bigalke, B., Schönberger, T., Geisler, T., Siegel‐Axel, D., Oostendorp, R. A. J., Lindemann, S., Gawaz, M. Platelets induce differentiation of human CD34+ progenitor cells into foam cells and endothelial cells. FASEB J. 20, E1935–E1944 (2006)

Expression of stromal-cell-derived factor-1 on circulating platelets is increased in patients with acute coronary syndrome and correlates with the number of CD34+ progenitor cells

AIMS Previous experimental studies have suggested that platelet stromal-cell-derived factor-1 (SDF-1) regulates mobilization and recruitment of haematopoietic progenitor cells supporting revascularization in mice. However, there are no clinical data available regarding platelet-bound SDF-1 in patients with acute coronary syndrome (ACS). The objective of this study was to evaluate the platelet-surface expression of SDF-1 in patients with ACS. METHODS AND RESULTS Patients with ACS (n = 418) showed a significantly enhanced SDF-1 expression on admission compared with those with stable angina pectoris (SAP, n = 486) [SAP (mean fluorescence intensity (MFI) +/- SD): 13.48 +/- 5.27; ACS: 18.45 +/- 12.85; P < 0.001) independent of cardiovascular risk factors and medication. Enhanced platelet-bound SDF-1 expression was found in patients with reduced left ventricular ejection fraction (LVEF <55%) in comparison to patients with normal LVEF (P = 0.005). Platelet-bound SDF-1 expression positively correlated with the degree of platelet activation [CD62P: r = 0.325; glycoprotein VI (GPVI): r = 0.277; PAC-1: r = 0.501; P < 0.001 for all] and showed a significant, but slight association with plasma levels of SDF-1 (r = 0.084; P = 0.045). In a subgroup of patients with coronary artery disease, platelet-bound SDF-1, but not other platelet activation markers, significantly correlated with the number of circulating CD34(+) progenitor cells (r = 0.252; P = 0.002) or CD34(+)/CD133(+) endothelial progenitor cells (r = 0.352; P = 0.008). CONCLUSION Platelet-bound SDF-1 may play an important role in peripheral homing of circulating progenitor cells thus in tissue regeneration.

Early but not late stent thrombosis is influenced by residual platelet aggregation in patients undergoing coronary interventions

AIMS Recent studies suggest a relevant association of post-interventional residual platelet aggregation (RPA) under therapy with oral platelet inhibitors and the occurrence of atherothrombotic events. The influence of post-interventional RPA on the incidence of stent thrombosis (ST) has not been sufficiently evaluated in consecutive unselected cohorts of percutaneous coronary intervention (PCI) patients. The aim of this observational study was to investigate the impact of RPA on the incidence of ST within 3 months in patients treated with dual antiplatelet therapy. METHODS AND RESULTS The study population included a consecutive cohort of 1019 patients treated with PCI [n = 741 bare-metal stent (BMS) and n = 278 drug-eluting stent (DES)] due to symptomatic coronary artery disease. Residual platelet activity was assessed by adenosine disphosphate (20 micromol/L)-induced PA after 600 mg clopidogrel loading dose. Maximum RPA was measured as peak of aggregation, final RPA was measured 5 min after addition of agonist. The primary endpoint was the occurrence of ST within 3 months defined according to academic research consortium (ARC) criteria. Final and maximum RPA were independent predictors of ST after 3 months. In secondary analysis, the observed effects were independently associated with early ST (HR 1.05, 95% CI 1.01-1.08 and HR 1.05, 95% CI 1.01-1.09, P < 0.01, respectively). However, incidence of 3-month late stent thrombosis (LAT) was not influenced by post-interventional RPA in multivariable analysis. CONCLUSION Post-interventional RPA is associated with the occurrence of early ST in patients treated with either BMS or DES; however, there is no predictive value of RPA for the incidence of 3-month LAT, suggesting the involvement of other possible mechanisms like discontinuation of antiplatelet therapy.

PCI Strategies in Patients with Acute Myocardial Infarction and Cardiogenic Shock

Background In patients who have acute myocardial infarction with cardiogenic shock, early revascularization of the culprit artery by means of percutaneous coronary intervention (PCI) improves outcomes. However, the majority of patients with cardiogenic shock have multivessel disease, and whether PCI should be performed immediately for stenoses in nonculprit arteries is controversial. Methods In this multicenter trial, we randomly assigned 706 patients who had multivessel disease, acute myocardial infarction, and cardiogenic shock to one of two initial revascularization strategies: either PCI of the culprit lesion only, with the option of staged revascularization of nonculprit lesions, or immediate multivessel PCI. The primary end point was a composite of death or severe renal failure leading to renal‐replacement therapy within 30 days after randomization. Safety end points included bleeding and stroke. Results At 30 days, the composite primary end point of death or renal‐replacement therapy had occurred in 158 of the 344 patients (45.9%) in the culprit‐lesion‐only PCI group and in 189 of the 341 patients (55.4%) in the multivessel PCI group (relative risk, 0.83; 95% confidence interval [CI], 0.71 to 0.96; P=0.01). The relative risk of death in the culprit‐lesion‐only PCI group as compared with the multivessel PCI group was 0.84 (95% CI, 0.72 to 0.98; P=0.03), and the relative risk of renal‐replacement therapy was 0.71 (95% CI, 0.49 to 1.03; P=0.07). The time to hemodynamic stabilization, the risk of catecholamine therapy and the duration of such therapy, the levels of troponin T and creatine kinase, and the rates of bleeding and stroke did not differ significantly between the two groups. Conclusions Among patients who had multivessel coronary artery disease and acute myocardial infarction with cardiogenic shock, the 30‐day risk of a composite of death or severe renal failure leading to renal‐replacement therapy was lower among those who initially underwent PCI of the culprit lesion only than among those who underwent immediate multivessel PCI. (Funded by the European Union 7th Framework Program and others; CULPRIT‐SHOCK ClinicalTrials.gov number, NCT01927549.)

Guided de-escalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL-ACS): A randomised, open-label, multicentre trial

BACKGROUND Current guidelines recommend potent platelet inhibition with prasugrel or ticagrelor for 12 months after an acute coronary syndrome managed with percutaneous coronary intervention (PCI). However, the greatest anti-ischaemic benefit of potent antiplatelet drugs over the less potent clopidogrel occurs early, while most excess bleeding events arise during chronic treatment. Hence, a stage-adapted treatment with potent platelet inhibition in the acute phase and de-escalation to clopidogrel in the maintenance phase could be an alternative approach. We aimed to investigate the safety and efficacy of early de-escalation of antiplatelet treatment from prasugrel to clopidogrel guided by platelet function testing (PFT). METHODS In this investigator-initiated, randomised, open-label, assessor-blinded, multicentre trial (TROPICAL-ACS) done at 33 sites in Europe, patients were enrolled if they had biomarker-positive acute coronary syndrome with successful PCI and a planned duration of dual antiplatelet treatment of 12 months. Enrolled patients were randomly assigned (1:1) using an internet-based randomisation procedure with a computer-generated block randomisation with stratification across study sites to either standard treatment with prasugrel for 12 months (control group) or a step-down regimen (1 week prasugrel followed by 1 week clopidogrel and PFT-guided maintenance therapy with clopidogrel or prasugrel from day 14 after hospital discharge; guided de-escalation group). The assessors were masked to the treatment allocation. The primary endpoint was net clinical benefit (cardiovascular death, myocardial infarction, stroke or bleeding grade 2 or higher according to Bleeding Academic Research Consortium [BARC]) criteria) 1 year after randomisation (non-inferiority hypothesis; margin of 30%). Analysis was intention to treat. This study is registered with ClinicalTrials.gov, number NCT01959451, and EudraCT, 2013-001636-22. FINDINGS Between Dec 2, 2013, and May 20, 2016, 2610 patients were assigned to study groups; 1304 to the guided de-escalation group and 1306 to the control group. The primary endpoint occurred in 95 patients (7%) in the guided de-escalation group and in 118 patients (9%) in the control group (pnon-inferiority=0·0004; hazard ratio [HR] 0·81 [95% CI 0·62-1·06], psuperiority=0·12). Despite early de-escalation, there was no increase in the combined risk of cardiovascular death, myocardial infarction, or stroke in the de-escalation group (32 patients [3%]) versus in the control group (42 patients [3%]; pnon-inferiority=0·0115). There were 64 BARC 2 or higher bleeding events (5%) in the de-escalation group versus 79 events (6%) in the control group (HR 0·82 [95% CI 0·59-1·13]; p=0·23). INTERPRETATION Guided de-escalation of antiplatelet treatment was non-inferior to standard treatment with prasugrel at 1 year after PCI in terms of net clinical benefit. Our trial shows that early de-escalation of antiplatelet treatment can be considered as an alternative approach in patients with acute coronary syndrome managed with PCI. FUNDING Klinikum der Universität München, Roche Diagnostics, Eli Lilly, and Daiichi Sankyo.

Low Responsiveness to Clopidogrel Increases Risk among CKD Patients Undergoing Coronary Intervention

Patients with CKD are at higher risk for major events after percutaneous coronary intervention (PCI) compared with subjects with normal renal function. The aims of this study were to evaluate responsiveness to clopidogrel in patients with CKD and to examine the effect of antiplatelet drug response on post-PCI outcome. We retrospectively evaluated a consecutive cohort of 1567 patients with symptomatic coronary artery disease undergoing PCI, 648 (41%) of whom had stage 3 to 5 CKD. We assessed responsiveness to clopidogrel by ADP-induced platelet aggregation after oral administration of a 600-mg clopidogrel loading dose and 100 mg of aspirin. In a multivariate survival analysis that included 1335 (85%) of the cohort, stage 3 to 5 CKD and low response to clopidogrel were independent predictors of the primary end point (composite of myocardial infarction, ischemic stroke, and death within 1 year). In summary, a low response to clopidogrel might be an additional risk factor for the poorer outcomes in patients with stage 3 to 5 CKD compared with patients with better renal function.