Bleeding in acute coronary syndrome: from definitions, incidence, and prognosis to prevention and management.

INTRODUCTION: In patients with acute coronary syndrome (ACS), the ischemic benefit of antithrombotic treatment is counterbalanced by the risk of bleeding. The recognition that bleeding events have prognostic implications (i.e. mortality) similar to recurrent ischemic events led to the development of treatment regimens aimed at balancing both ischemic and bleeding risks. AREAS COVERED: This review aims at describing definitions, incidence, and prognosis related to bleeding events in ACS patients as well as bleeding-avoidance strategies for their prevention and management of bleeding complications. EXPERT OPINION: Management of ACS patients has witnessed remarkable progress after the shift in focusing on the trade-off between ischemia and bleeding. Efforts in standardizing bleeding definitions will allow for better defining the prognostic impact of different types of bleeding events and enable to identify the high-bleeding risk patient. Such efforts will allow to balance the trade-off between the thrombotic and bleeding risk of the individual patient translating into better downward diagnostic and therapeutic decision-making. Novel strategies aiming at maximizing the safety and efficacy of antithrombotic regimens as well as the development of novel antithrombotic drugs and reversal agents and technological advances will allow for optimization of bleeding-avoidance strategies and management of bleeding complications.

Ticagrelor alone vs. ticagrelor plus aspirin following percutaneous coronary intervention in patients with non-ST-segment elevation acute coronary syndromes: TWILIGHT-ACS.

AIMS: The aim of this study was to determine the effect of ticagrelor monotherapy on clinically relevant bleeding and major ischaemic events in relation to clinical presentation with and without non-ST elevation acute coronary syndromes (NSTE-ACS) among patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES). METHODS AND RESULTS: We conducted a pre-specified subgroup analysis of The Ticagrelor With Aspirin or Alone in High Risk Patients After Coronary Intervention (TWILIGHT) trial, which enrolled 9006 patients with high-risk features undergoing PCI with DES. After 3 months of dual antiplatelet therapy (DAPT) with ticagrelor plus aspirin, 7119 adherent and event-free patients were randomized in a double-blind manner to ticagrelor plus placebo versus ticagrelor plus aspirin for 12 months. The primary outcome was Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding while the composite of all-cause death, myocardial infarction (MI), or stroke was the key secondary outcome. Among patients with NSTE-ACS (n = 4614), ticagrelor monotherapy reduced BARC 2, 3, or 5 bleeding by 53% [3.6% vs. 7.6%; hazard ratio (HR) 0.47; 95% confidence interval (CI) 0.36-0.61; P < 0.001) and in stable patients (n = 2503) by 24% (4.8% vs. 6.2%; HR 0.76; 95% CI 0.54-1.06; P = 0.11; nominal Pint = 0.03). Rates of all-cause death, MI, or stroke among those with (4.3% vs. 4.4%; HR 0.97; 95% CI 0.74-1.28; P = 0.84) and without (3.1% vs. 3.2%; HR 0.96; 95% CI 0.61-1.49; P = 0.85) NSTE-ACS were similar between treatment arms irrespective of clinical presentation (Pint = 0.96). CONCLUSION: Among patients with or without NSTE-ACS who have completed an initial 3-month course of DAPT following PCI with DES, ticagrelor monotherapy reduced clinically meaningful bleeding events without increasing ischaemic risk as compared with ticagrelor plus aspirin. The benefits of ticagrelor monotherapy with respect to bleeding events were more pronounced in patients with NSTE-ACS. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02270242.

Role of platelets and antiplatelet therapy in cardiovascular disease.

Platelets have a key role in normal hemostasis and in the pathogenesis of atherothrombotic events, such as acute coronary syndrome. Following plaque rupture, platelets adhere to the subendothelial matrix, become activated and then aggregate to form a prothrombotic surface that promotes clot formation and subsequently vascular occlusion. Multiple pathways are involved in platelet activation, including those activated by adenosine diphosphate (ADP), thromboxane A2, epinephrine, serotonin, collagen, and thrombin. Currently, two groups of inhibitors of platelet activation are approved for clinical use in patients with acute coronary syndromes: cyclooxygenase-1 inhibitors, namely aspirin, and oral ADP receptor antagonists such as clopidogrel. These agents have shown improved short- and long-term clinical outcomes but are associated with increased bleeding risk, and the rates of recurrent ischemic events remain high. These considerations underscore the need for novel antiplatelet agents that can provide greater reduction in recurrent atherothrombotic events without increasing the risk of bleeding. Several novel antiplatelet agents are currently under clinical development, such as more potent ADP receptor antagonists and protease-activated receptor-1 antagonists. This article provides an overview of the basic principles of platelet biology and the current status of knowledge on available oral antiplatelet therapy, as well as those under clinical development.

Acute stent thrombosis after early withdrawal of platelet glycoprotein IIb/IIIa antagonists: potential rebound prothrombotic effect?

We report on two cases of acute coronary stent thrombosis after early withdrawal of different competitive inhibitors of the platelet glycoprotein IIb/IIIa receptor, eptifibatide and tirofiban. Differences in pharmacokinetics between different types of glycoprotein IIb/IIIa receptor blockers and a potential rebound prothrombotic effect with the use of these antiplatelet drugs are reviewed.