Background: The recent literature has shown that triple antiplatelet therapy with cilostazol in addition to the standard dual antiplatelet therapy with aspirin and clopidogrel may reduce platelet reactivity and improve clinical outcomes following percutaneous coronary intervention. The purpose of this meta-analysis is to compare the efficacy of triple antiplatelet therapy and dual antiplatelet therapy in regard to on-treatment platelet reactivity. Methods: Nine studies (n = 2179) comparing on-treatment platelet reactivity between dual antiplatelet therapy (n = 1193) and triple antiplatelet therapy (n = 986) in patients undergoing percutaneous coronary intervention were included. Primary end points were P2Y12 reaction unit (PRU) and platelet reactivity index (PRI). Secondary end points were platelet aggregation with adenosine diphosphate (ADP) 5 and 20 μmol/L and P2Y12% inhibition. Mean difference (MD) and 95% confidence intervals (CI) were computed and 2-sided α error <.05 was considered as a level of significance. Results: Compared to dual antiplatelet therapy, triple antiplatelet therapy had significantly lower maximum platelet aggregation with ADP 5 μmol/L (MD: -14.4, CI: -21.6 to -7.2, P < .001) and 20 mmol/L (MD: -14.9, CI: -22.9 to -6.8, P < .001), significantly lower PRUs (MD: -45, CI: -59.4 to -30.6, P < .001) and PRI (MD: -26, CI: -36.8 to -15.2, P < .001), and significantly higher P2Y12% inhibition (MD: 18.5, CI: 2.3 to 34.6, P = .025). Conclusion: Addition of cilostazol to conventional dual antiplatelet therapy significantly lowers platelet reactivity and may explain a decrease in thromboembolic events following coronary intervention; however, additional studies evaluating clinical outcomes will be helpful to determine the benefit of triple antiplatelet therapy.

Background: The recent literature has shown that triple antiplatelet therapy with cilostazol in addition to the standard dual antiplatelet therapy with aspirin and clopidogrel may reduce platelet reactivity and improve clinical outcomes following percutaneous coronary intervention. The purpose of this meta-analysis is to compare the efficacy of triple antiplatelet therapy and dual antiplatelet therapy in regard to on-treatment platelet reactivity. Methods: Nine studies (n = 2179) comparing on-treatment platelet reactivity between dual antiplatelet therapy (n = 1193) and triple antiplatelet therapy (n = 986) in patients undergoing percutaneous coronary intervention were included. Primary end points were P2Y12 reaction unit (PRU) and platelet reactivity index (PRI). Secondary end points were platelet aggregation with adenosine diphosphate (ADP) 5 and 20 μmol/L and P2Y12% inhibition. Mean difference (MD) and 95% confidence intervals (CI) were computed and 2-sided α error <.05 was considered as a level of significance. Results: Compared to dual antiplatelet therapy, triple antiplatelet therapy had significantly lower maximum platelet aggregation with ADP 5 μmol/L (MD: -14.4, CI: -21.6 to -7.2, P < .001) and 20 mmol/L (MD: -14.9, CI: -22.9 to -6.8, P < .001), significantly lower PRUs (MD: -45, CI: -59.4 to -30.6, P < .001) and PRI (MD: -26, CI: -36.8 to -15.2, P < .001), and significantly higher P2Y12% inhibition (MD: 18.5, CI: 2.3 to 34.6, P = .025). Conclusion: Addition of cilostazol to conventional dual antiplatelet therapy significantly lowers platelet reactivity and may explain a decrease in thromboembolic events following coronary intervention; however, additional studies evaluating clinical outcomes will be helpful to determine the benefit of triple antiplatelet therapy.

Background In the event of an acute coronary syndrome (ACS), the risk of death and complications such as stroke and re-infarction is high during the first month. Diabetes, impaired kidney function, elevated markers of systemic inflammation and high level of platelet reactivity have all been associated with worsened prognosis in ACS patients. Impaired kidney function is a condition with high cardiovascular morbidity and there is an established association between level of kidney function and outcome in the event of an ACS. Aims We sought to investigate the level of platelet reactivity during the first days of an ACS and specifically the level of platelet reactivity in patients with different conditions associated with worsened prognosis in the event of an ACS. We also wanted to investigate the prognostic impact of baseline levels of cystatin C as well as the importance of decreasing kidney function during the first days of an ACS. Methods We included 1028 unselected patients with ACS or suspected ACS during the years 2002 and 2003, of which 534 were diagnosed with an acute myocardial infarction (AMI). Blood samples for measuring platelet aggregation, cystatin C levels and other clinically important biomarkers were collected day 1, 2, 3 and 5 following admission. Platelet reactivity was measured using 2 different methods. Platelet aggregation was measured using Pa-200, a particle count method, based on scattering of laser light. PFA 100 is a method of measuring primary hemostasis in whole blood. Results Platelet aggregation and comorbidities. We found an increase in platelet aggregation when an ACS was complicated by an infection and there was an increased frequency of aspirin non-responsiveness in patients suffering from pneumonia during the first days of an ACS. Furthermore, we found an independent association between levels of C-reactive protein and platelet aggregation. During the first 3 days following an acute myocardial infarction, platelet aggregation increased despite treatment with anti-platelet agents. Platelet aggregation was found to be more pronounced in patients with diabetes. Patients with impaired kidney function, showed increased platelet aggregation compared to patients with normal renal function, however, this difference was explained by older age, higher prevalence of DM and levels of inflammatory biomarkers. We found no independent association between chronic kidney disease (CKD) and levels of platelet aggregation. Kidney function and outcome Serum levels of cystatin C on admission had an independent association with outcome following an acute myocardial infarction. With a mean follow-up time of 2.9 years, the adjusted HR for death was 1.62 (95% CI 1.28-2.03; p&lt;0.001) for each unit of increase in cystatin C on admission. The level of dynamic changes in cystatin C during admission for an acute myocardial infarction was independently associated with prognosis in patients with normal or mild impairment of renal function. The adjusted HR for death was 10.1 (95% CI 3.4-29.9; p&lt;0.001). Conclusion In patients suffering from an AMI platelet aggregation increases during the first days, despite anti-platelet treatment. Diabetes, age and biomarkers of inflammation are independently associated with platelet aggregation. Admission levels of cystatin C as well as changes in cystatin C levels during hospitalisation are independently associated with outcome.

L’angioplastie coronaire est la première forme de revascularisation coronaire. Elle présente cependant 2 limites qui restreignent encore son utilisation : la thrombose et la resténose de stent. La thrombose de stent est un événement précoce associé à une mortalité élevée. Les plaquettes y jouent un rôle déterminant. Le développement de tests fonctionnels plaquettaires permettant d’analyser le niveau de réactivité plaquettaire sous traitement a permis de mettre en évidence les limites de celui-ci sur le plan biologique. Nous avons démontré l’impact clinique de l’utilisation de ces tests dans la prédiction et la réduction du risque de thrombose de stent chez des patients traités par angioplastie coronaire. La resténose est quant à elle une complication tardive de l’angioplastie coronaire avec implantation d’un stent non-actif. Sa physiopathologie repose sur des mécanismes de lésion et de régénération endothéliale. Des marqueurs endothéliaux circulants ont récemment été développés. Nous avons montré qu’ils pouvaient permettre d’évaluer la lésion et la régénération endothéliale induite par une angioplastie coronaire. Les cellules endothéliales circulantes s’élèvent transitoirement après l’angioplastie et ce de façon variable en fonction de la réactivité plaquettaire sous traitement démontrant les interactions étroites entre ces différents acteurs. Dans le même temps, on observe une mobilisation de progéniteurs d’origine médullaire suite à l’angioplastie. Nos travaux suggèrent un rôle clé de la régénération endothéliale dans la cicatrisation vasculaire après angioplastie. En effet, il apparait que la proportion de progéniteurs de profil de différenciation endothélial en réponse à l’angioplastie coronaire détermine la survenue d’une resténose intra-stent. Ces données ouvrent la voie à une meilleure compréhension des mécanismes physiopathologie menant à la resténose mais aussi à des perspectives thérapeutiques intéressantes. / Percutaneous coronary intervention is the most commonly used revascularization technique. However it has 2 main complications limiting its widespread: stent thrombosis and in stent restenosis. Stent thrombosis is an early event associated with a high mortality rate. Platelets are key in its physiopathology. The availability of platelet function tests allowing to determine platelet reactivity levels under therapy showed a variable ant platelet effect following aspirin and clopidogrel intake. We further demonstrated that tailoring anti platelet therapy according to platelet function tests results decrease the rate of stent thrombosis following PCI without increasing bleedings. In stent-restenosis is a late complication of PCI with bare metal stents. The pathophysiology of in-stent restenosis is dependent on the lesion and regeneration of the endothelium. Circulating endothelial biomarkers have recently been developed. We have demonstrated that this marker allow to evaluate the lesion and regeneration of the endothelium following PCI. We evidenced a transient increase in circulating endothelial cells following PCI which is dependent on the level of platelet reactivity inhibition demonstrating the interaction between platelets and the endothelium. At the same time, PCI induces mobilization of progenitor cells which is detectable early after the intervention. Our work suggests that these progenitor cells have a key role in endothelial regeneration after PCI. We evidenced for the first time that the proportion of endothelial progenitor cells among progenitor cells mobilized after PCI determine the occurrence of in stent restenosis. Altogether these data give critical inside into vascular regeneration after PCI in human and on the mechanisms associated with in stent restenosis thus providing new potential therapeutic target.

Με δεδομένο το γεγονός ότι η αιμοπεταλιακή αναστολή είναι θεμελιώδους σημασίας σε ασθενείς με οξύ έμφραγμα του μυοκαρδίου με ανάσπαση του ST τμήματος που υποβάλλονται σε πρωτογενή αγγειοπλαστική (PPCI), η αναγνώριση παραγόντων που σχετίζονται με την εμφάνιση στην οξεία φάση υψηλής αντιδραστικότητας των αιμοπεταλίων (HTPR) παρά τη θεραπεία με κλοπιδογρέλη μπορεί να είναι σημαντική. Σε ασθενείς με STEMI και επακόλουθη PPCI εκτιμήθηκε η αιμοπεταλιακή αντιδραστικότητα 2 ώρες μετά τη φόρτιση με 600mg κλοπιδογρέλης με τη χρήση της παρακλίνιας μεθόδου VerifyNow P2Y12. Το όριο ≥235 P2Y12 μονάδων αντιδραστικότητας (PRU) θεωρήθηκε ενδεικτικό HTPR. Από τους 92 ασθενείς με STEMI, 63 (68,5%) βρέθηκαν να έχουν υψηλή αιμοπεταλιακή αντιδραστικότητα στις 2 ώρεςμετά τη φόρτιση. Οι ασθενείς με την υψηλή αντιδραστικότητα είχαν λάβει ‘πρώιμη φόρτιση’ με κλοπιδογρέλη πιο συχνά, είχαν χαμηλότερη τιμή αιμοσφαιρίνης και έτειναν να έχουν επηρεασμένη νεφρική λειτουργία σε σε σχέση με αυτούς που είχαν ικανοποιητική απάντηση στην κλοπιδογρέλη. Στην πολυπαραγοντική ανάλυση, η ‘πρώιμη φόρτιση’ και η κάθαρση κρεατινίνης <60ml/min είχαν ανεξάρτητη συσχέτιση με υψηλότερο κίνδυνο εμφάνισης HTPR (σχετικός κίνδυνος [RR]=1,55 95% διάστημα εμπιστοσύνης [CI]:1,11-2,17 P=0,01 και RR=1,31 95% CI: 1,008-1,71 P=0,04 αντίστοιχα). Επομένως σε ασθενείς με STEMI που υποβάλλονται σε PPCI, η ‘πρώιμη φόρτιση’ με κλοπιδογρέλη και η επηρεασμένη νεφρική λειτουργία αποτελούν ανεξάρτητους προβλεπτικούς παράγοντες εμφάνισης υψηλής υπολειπόμενης αντιδραστικότητας των αιμοπεταλίων (εκτιμούμενης με τη μεθοδο VerifyNow) 2 ώρες μετά την αρχική φόρτιση με 600mg κλοπιδογρέλης / Given that platelet inhibition is crucial when ST-elevation myocardial infarction (STEMI) patients undergo primary PCI (PPCI), the identification of factors associated with early high on-treatment platelet reactivity may be important. Consecutive STEMI patients admitted for PPCI were considered for platelet reactivity assessment 2 h after loading with 600 mg clopidogrel using the VerifyNow point-of-care P2Y12 assay. A cut-off of ≥235 P2Y12 reaction units indicated high on-treatment platelet reactivity. Out of 92 STEMI patients, 63 (68.5%) were found to have high on-treatment platelet reactivity. Patients with high on-treatment platelet reactivity had received upstream clopidogrel loading more frequently, had lower admission hemoglobin and tended to have an impaired renal function compared to those with an adequate response to clopidogrel. On multivariate analysis, upstream clopidogrel loading and creatinine clearance <60 ml/min were independently associated with higher risk for high on-treatment platelet reactivity (relative risk [RR]=1.55, 95% confidence interval [CI]: 1.11–2.17, P=0.01; RR=1.31, 95% CI: 1.008–1.71, P=0.04, respectively). In patients with STEMI undergoing PPCI, use of upstream clopidogrel and impaired renal function independently predict high on-treatment platelet reactivity assessed as early as 2 h following 600 mg of clopidogrel loading dose on point-of-care P2Y12 function assay.

L’activité plaquettaire joue un rôle clé dans la physiopathologie de l’infarctus du myocarde avec sus-décalage du segment ST (IDM ST+). La réactivité plaquettaire est augmentée lors d’un IDM ST+, traité par angioplastie primaire ou par fibrinolyse avec succès. La relation entre la réactivité plaquettaire résiduelle après un pré-traitement, la charge athérothrombotique et la qualité de la reperfusion myocardique reste peu décrite dans le cadre des IDM ST+. La tomographie par cohérence optique et celle plus récente par domaine de fréquence offrent une imagerie de haute résolution permettant l’identification et la quantification précise de la charge athérothrombotique intracoronaire (CAT). La CAT résiduelle intra-stent peut aider à mieux comprendre la relation entre la réactivité plaquettaire et la reperfusion. Dans un premier temps, nous avons évalué la précision des tests VerifyNow et PFA en comparaison à l’agrégométrie optique pour la détection de l’hyperréactivité plaquettaire dans le contexte particulier des IDM ST+ traités par fibrinolyse avec succès. Nous avons aussi décrit les caractéristiques de la CAT avant et après angioplastie selon la présence d’une rupture de plaque ou d’une érosion coronaire chez des patients traités par fibrinolyse avec succès. Ensuite, nous avons étudié la relation entre la réactivité plaquettaire résiduelle (en réponse au ticagrelor et à l’aspirine) mesurée par VerifyNow et la reperfusion myocardique chez des patients traités par angioplastie primaire. En parallèle, nous avons décrit la relation entre la reperfusion myocardique et la CAT résiduelle intra-stent dans la même cohorte. / Platelet activity plays a key role in the pathophysiology of ST-segment elevation myocardial infarction (STEMI). Platelet reactivity is enhanced after STEMI treated with primary percutaneous coronary intervention (PCI) or successful thrombolysis. The relationship between residual platelet reactivity after pre-treatment, the atherothrombotic burden and the quality of reperfusion remains poorly described in STEMI. Optical coherence tomography (OCT) and optical frequency domain imaging (OFDI) provide high resolution imaging allowing identification and accurate quantification of intracoronary atherothrombotic burden (ATB). Residual in-stent ATB may help to better understand the relation between platelet reactivity and reperfusion. First, we assessed the accuracy of the point-of-care tests VerifyNow and PFA in comparison to light transmittance aggregometry to detect high on-treatment platelet reactivity (HPR) in the particular setting of STEMI successfully treated with fibrinolysis. We also described the characteristics of ATB before and after PCI according to the underlying presence of rupture or erosion in patients successfully treated with fibrinolysis. Then, we assessed the relationship between residual platelet reactivity (in response to ticagrelor and aspirin) using VerifyNow and myocardial reperfusion in primary PCI patients. In parallel, we studied the relationship between myocardial reperfusion and residual in-stent ATB in the same cohort.