**5. Management of bleeding associated with the use of DAPT**

A higher reduction in thrombotic risk comes at the cost of an increase in significant bleedings, which occur in 1–8% of patients in the first year after starting DAPT [53–55]. Even less severe bleeding has been linked to an increased risk of death through indirect mechanisms such as unplanned hospitalization, the necessity for urgent operations, and the termination of DAPT [56]. Bleeding is reportedly linked to an increased risk of death and is also linked to the recurrence of ischemic events such myocardial infarction (MI) and stroke [57, 58].

## **5.1 Intracranial bleeding (ICB)**

The most significant DAPT-related adverse event is intracranial bleeding (ICB). With recurrence rates of more than 15% and 3%, respectively, ICB is classed as lobar (affecting the cerebral cortex and underlying white matter) or deep (affecting the basal ganglia, thalamus, and brainstem). Antiplatelet therapy on admission was linked with a greater 24-hour in-hospital [59] and 3-month death rate compared to naive patients in a recent study on patients with ICB [60].

Patients with ICB should be observed and managed in an intensive care unit or a dedicated stroke unit with a high level of skill in the acute environment. All the anticoagulant and antiplatelet medications should be stopped immediately.

#### **5.2 Gastrointestinal bleeding**

GI hemorrhage is the most prevalent significant DAPT-related bleeding event following PCI [61, 62].

Owing to its direct suppression of cyclooxygenase-1, aspirin promotes GI bleeding by lowering the endothelium protective action of prostaglandins. P2Y12 inhibitors are thought to affect ulcer healing through limiting platelet aggregation, angiogenesis, and endothelial proliferation rather than being directly ulcerogenic. When compared to clopidogrel, ticagrelor and prasugrel have been linked to a greater incidence of GI bleeding [61].

Owing to its insidious nature, GI bleeding in patients with recent ACS and/or PCI poses a significant treatment challenge. The need to achieve hemostasis frequently necessitates the early termination of antithrombotic therapy. Furthermore, acute bleeding causes platelet activation, and the formation of a prothrombotic environment could explain why patients with GI bleeding who get DAPT after ACS have a higher risk of ischemic stroke [63].

Proton pump inhibitors (PPIs) should be prescribed alongside antiplatelet medication since gastrointestinal (GI) bleeding is the most prevalent major bleeding event [64]. PPIs are only recommended by the ACC/AHA for individuals who are at risk of bleeding (previous GI bleeding, advanced age, and concurrent use of warfarin, steroids, or nonsteroidal anti-inflammatory medicines); however, the ESC supports PPIs for all DAPT patients [7]. The disparity in recommendations stems from different interpretations of a big clinical research that found a pharmacokinetic interaction between clopidogrel and omeprazole, but no effect on cardiovascular events. Given the known cytochrome pharmacokinetic interaction, it is best to avoid co-prescribing clopidogrel with omeprazole/esomeprazole if at all possible [65]. However, there is no known interaction between PPIs and prasugrel.

#### **5.3 Role of tranexamic acid (TXA) in management of DAPT induced bleeding**

Antiplatelet drugs commonly block glycoprotein receptors in ACS because they are required for platelet aggregation. Tranexamic acid (TXA) has been demonstrated to be an effective drug for reduce antiplatelet-related bleeding in a number of clinical scenarios, including trauma, and has a good safety profile [66]. TXA has specifically been shown to increase in vitro platelet activity among coronary artery bypass graft (CABG) patients taking antiplatelet medication as well as demonstrating a reduction in operational blood loss [67]. By enhancing platelet function, TXA can be regarded a potential strategy for reducing bleeding problems associated with antiplatelet monotherapy or DAPT.

#### **5.4 Role of platelet infusions in the management of DAPT-induced bleeding**

Platelet concentrates (PCs) are sometimes infused to patients with ICH who are on antiplatelet medications to enhance primary hemostasis before neurosurgery. Platelet concentrates (PCs) are frequently given to patients on APT who develop ICH to overcome platelet inhibition induced by antiplatelet medications [68]. Preoperative transfusion of at least two PCs can enhance primary hemostasis in individuals who require decompression neurosurgery owing to ICH while on APT. Rebleeding could still be a concern especially in individuals with chronic ICH and those using P2Y12 inhibitors. Other options can be explored in the control of bleeding in patients on antiplatelet

agents especially DAPT. The options include prothrombin complex concentrates [69] and fresh frozen plasma [70] although they are mostly used for bleeding associated with vitamin K antagonists and direct oral anticoagulants.
