Is the duration of dual antiplatelet therapy (DAPT) excessive in post-angioplasty in chronic coronary syndrome? Data from the France-PCI registry (2014-2019).

Background: while the duration of dual antiplatelet therapy (DAPT) following coronary angioplasty for chronic coronary syndrome (CCS) recommended by the European Society of Cardiology has decreased over the last decade, little is known about the adherence to those guidelines in clinical practice in France. Aim: To analyze the real duration of DAPT post coronary angioplasty in CCS, as well as the factors affecting this duration. Methods: Between 2014 and 2019, 8.836 percutaneous coronary interventions for CCS from the France-PCI registry were evaluated, with 1 year follow up, after exclusion of patients receiving oral anticoagulants, procedures performed within one year of an acute coronary syndrome, and repeat angioplasty. Results: Post-percutaneous coronary intervention (PCI) DAPT duration was > 12 months for 53.1% of patients treated for CCS; 30.5% had a DAPT between 7 and 12 months, and 16.4% a DAPT ≤ 6 months. Patients with L-DAPT (>12 months) were at higher ischemic risk [25.0% of DAPT score ≥2 vs. 18.8% DAPT score ≥2 in S&I-DAPT group (≤12 months)]. The most commonly used P2Y12 inhibitor was clopidogrel (82.2%). The prescription of ticagrelor increased over the period. Conclusions: post-PCI DAPT duration in CCS was higher than international recommendations in the France PCI registry between 2014 and 2019. More than half of the angioplasty performed for CCS are followed by a DAPT > 12 months. Ischemic risk assessment influences the duration of DAPT. This risk is probably overestimated nowadays, leading to a prolongation of DAPT beyond the recommended durations, thus increasing the bleeding risk.

ATP-binding cassette transporter 1 (ABCA1) deficiency decreases platelet reactivity and reduces thromboxane A2 production independently of hematopoietic ABCA1.

UNLABELLED: ESSENTIALS: The role of ATP-binding cassette transporter 1 (ABCA1) in platelet functions is poorly characterized. We studied the impact of ABCA1 deficiency on platelet responses in a mouse model and two Tangier patients. ABCA1-deficient platelets exhibit reduced positive feedback loop mechanisms. This reduced reactivity is dependent on external environment and independent of hematopoietic ABCA1. BACKGROUND: The ATP-binding cassette transporter ABCA1 is required for the conversion of apolipoprotein A-1 to high-density lipoprotein (HDL), and its defect causes Tangier disease, a rare disorder characterized by an absence of HDL and accumulation of cholesterol in peripheral tissues. The role of ABCA1 in platelet functions remains poorly characterized. OBJECTIVE: To determine the role of ABCA1 in platelet functions and to clarify controversies concerning its implication in processes as fundamental as platelet phosphatidylserine exposure and control of platelet membrane lipid composition. METHODS AND RESULTS: We studied the impact of ABCA1 deficiency on platelet responses in a mouse model and in two Tangier patients. We show that platelets in ABCA1-deficient mice are slightly larger in size and exhibit aggregation and secretion defects in response to low concentrations of thrombin and collagen. These platelets have normal cholesterol and major phospholipid composition, granule morphology, or calcium-induced phosphatidylserine exposure. Interestingly, ABCA1-deficient platelets display a reduction in positive feedback loop mechanisms, particularly in thromboxane A2 (TXA2) production. Hematopoietic chimera mice demonstrated that defective eicosanoids production, particularly TXA2, was primarily dependent on external environment and not on the hematopoietic ABCA1. Decreased aggregation and production of TXA2 and eicosanoids were also observed in platelets from Tangier patients. CONCLUSIONS: Absence of ABCA1 and low HDL level induce reduction of platelet reactivity by decreasing positive feedback loops, particularly TXA2 production through a hematopoietic ABCA1-independent mechanism.

Platelet membrane phospholipid asymmetry: from the characterization of a scramblase activity to the identification of an essential protein mutated in Scott syndrome.

Like all eukaryotic cells, platelets maintain plasma membrane phospholipid asymmetry in normal blood circulation via lipid transporters, which control transbilayer movement. Upon platelet activation, the asymmetric orientation of membrane phospholipids is rapidly disrupted, resulting in a calcium-dependent exposure of the anionic phospholipid, phosphatidylserine (PS), at the outer platelet surface. This newly-exposed PS surface is a major component of normal hemostasis because it supports platelet procoagulant function. Binding of blood clotting enzyme complexes to this negatively-charged membrane surface allows a dramatic increase in the rate of conversion of zymogens to active serine proteases, which in turn produce a burst of thrombin leading to the formation of a fibrin clot and further platelet activation. Cells have the capacity to catalyze transbilayer phospholipid exchange via ATP-requiring translocase enzymes (flippases and floppases), which control unidirectional phospholipid transport against a concentration gradient. They also use an energy-independent, calcium-dependent scramblase activity to govern the bidirectional exchange of phospholipids between the two leaflets of the bilayer; this activity is essential for PS exposure during platelet activation. Scramblase activity, biochemically characterized in the 1980s, is deficient in patients with Scott syndrome, a rare inherited bleeding disorder with defective platelet procoagulant activity. Despite considerable efforts, the platelet scramblase protein remained elusive for years but a significant advance has recently been made with the identification of TMEM16F, a membrane protein essential for calcium-dependent PS exposure whose loss of function mutations are found in Scott syndrome. This review recalls historical aspects of platelet membrane asymmetry characterization, summarizes the mechanisms and roles of PS exposure following platelet activation and discusses the recent identification of TMEM16F and its significance in the scrambling process.

Targeted drug therapy: the platelet side.

Targeted therapy is certainly considered the future of cancer treatment. Several new molecules targeting critical intracellular signaling actors, particularly kinases, are arriving in clinics and many other are under development. However, proteins targeted by these drugs are common to many cell types and are particularly implicated in the highly dynamic processes of platelet activation. Therefore, the effects of targeted drugs, including kinase inhibitors, on platelet activation have to be considered in clinical practice. Moreover, their analysis also represents an opportunity to increase our knowledge in platelet biology and physiology and to develop novel antiplatelet strategies. In this review we briefly describe the major platelet signaling pathways that may be affected by these new drugs and discuss some clinical implications of their use.

The Syk-kinase inhibitor R406 impairs platelet activation and monocyte tissue factor expression triggered by heparin-PF4 complex directed antibodies.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a rare but severe complication of heparin therapy in which immunoglobulin G (IgG) antibodies against the platelet factor 4-heparin complex activate platelets through the FcγRIIA receptor. Clustering of FcγRIIA initiates signaling cascades involving tyrosine kinases including the spleen tyrosine kinase (Syk). Moreover, besides the critical role of platelets, the expression of tissue factor (TF) by human monocytes triggered by HIT antibodies has been shown to contribute to the hypercoagulability and the thrombotic complications in HIT patients. OBJECTIVES: We investigated the effect of R406, a small molecule inhibitor of Syk developed as a potential treatment of autoimmune diseases, allergic disorders and B-cell related hematological malignancies, on FcγRIIA-mediated platelet activation. To further assess the potential activity of Syk inhibitors in HIT treatment, the effect of R406 was also evaluated on HIT antibodies-induced expression of TF and procoagulant activity of monocytic cells. RESULTS: We show that R406 is a potent inhibitor of platelet signaling and functions initiated by FcγRIIA cross-linking by specific antibodies or by sera from HIT patients. Syk inhibition efficiently prevents FcγRIIA-induced LAT phosphorylation and activation of phosphoinositide 3-kinase, Akt, phospholipase Cγ2 and p38 MAP-kinase. As a consequence, FcγRIIA-induced platelet aggregation, granule secretion and microparticles production are strongly inhibited by R406. Moreover, the Syk inhibitor efficiently impairs the expression of TF and the procoagulant activity of human monocytes triggered by HIT antibodies. CONCLUSION: Syk inhibitors may be of therapeutic interest in the treatment of HIT by reducing HIT antibodies-mediated platelet activation and monocyte procoagulant activity.

[Left ventricular assist devices in cardiogenic shock]. / Assistances circulatoires dans les chocs cardiogéniques.

Cardiogenic shock is the leading cause of in-hospital death for myocardial infarction. Despite therapeutic improvements, such as medical treatment with inotropes, myocardial revascularization, circulatory assistance can be an option. Intra-aortic balloon pumping is highly recommended in the presence of haemodynamic impairment. If the patient continues to deteriorate and cardiac function cannot maintain adequate circulation to prevent end-organ failure, several mechanical circulatory assist devices can be considered: extracorporeal membrane oxygenator (ECMO), Impella(®)… These devices should be used at tertiary centres either as bridge to recovery or as bridge to transplantation or as bridge to long-term left ventricle assist device.

Long-term clinical outcome after percutaneous coronary interventions in the elderly: results for 512 consecutive patients.

AIMS: Elderly patients are increasingly being referred for percutaneous coronary intervention (PCI), but there is a paucity of current data on the long-term outcome of elective PCI in elderly patients. We sought to define the risks facing elderly patients undergoing contemporary PCIs. METHODS AND RESULTS: Retrospectively, in a single-centre registry, we studied the mortality and the outcome of 512 consecutive patients > 75 years old who underwent PCI, between January 1st 2000 and December 31st 2001. Clinical endpoints included in-hospital mortality; major adverse cardiovascular and cerebro-vascular events (MACCE) defined by the components of death, myocardial infarction, stroke, and repeat coronary revascularisation (target vessel revascularisation or not) by surgery or PCI, within the hospitalisation period and at long-term follow up. We compared 315 patients 75-79 years old (group I) with 197 patients > 80 years old (group II). In-hospital mortality and MACCE rates were not different between the two groups. Independent predictors of in-hospital major events found by multivariate analysis were: ST-segment elevation myocardial infarction or STEMI (Odds Ratio [OR]=2.58, 95% CI=1.15-5.78), left ventricular ejection fraction or LVEF <40% (OR=4.98, 95% CI=2.19-11.36) and prior coronary artery bypass grafting or CABG (OR=3.13, 95% CI=1.06-9.26). Mean long-term follow-up was 51.3 months. Death was significantly more frequent in the older group (42% vs 26%, p<0.0001). Independent predictors of long-term mortality found by multivariate analysis were: LVEF < 40% (Hazard Ratio=4.12, 95% CI=2.69-6.32), creatinine rate (HR=1.00, 95% CI=1.00-1.006) use cut-off see table and prior carotid surgery or stroke (HR=2.2, 95% CI=1.19-4.14). CONCLUSIONS: Although age is not an independent predictive factor of morbidity or mortality, co-morbidities in the elderly strongly influence long-term clinical outcomes after PCI.

Evaluation of in-stent restenosis in proximal coronary arteries with multidetector computed tomography (MDCT).

The purpose of this study was to assess the ability of 16-slice computed tomography (CT) to detect in-stent restenosis of proximal coronary arteries. From November 2002 to April 2004, 134 consecutive patients with proximal stents (3.25 +/- 0.47 mm) were prospectively studied. Multidetector CT (MDCT) was performed 24 h (baseline) and 6 months after angioplasty and analysed by two radiologists blinded to the results of the coronary angiography. Sensitivity, specificity, positive and negative predictive values for in-stent restenosis were compared with conventional quantitative coronary angiography (QCA). Stenosis with a diameter >or=50% was considered diagnostic of in-stent restenosis. The CT analysis was performed in 131 and 114 patients at baseline and 6 months, respectively. The in-stent lumen was evaluable in 111 (121 stents) and 99 patients (108 stents) at baseline and 6 months, respectively. The prevalence of in-stent restenosis was 22.5%. Restenoses were correctly identified in 91.7 and 87.5% by the two radiologists. The sensitivity, specificity, positive and negative predictive values for the assessment of significant in-stent restenosis were 92, 67, 43, 97% and 87, 66, 41, 95% for the radiologists, respectively. MDCT is a potential non-invasive technique for the screening of in-stent restenosis of proximal coronary arteries that needs further improvements.