With a history of clinically relevant bleeding (Table 12.3) in a patient on antithrombotic therapy, assessment and evaluation of the potential clinical consequences should be made. A search for the source of bleeding and specific (endoscopic or surgical) management should be made. Withdrawal of ongoing antithrombotic agent is often performed, but the risk of (potentially serious) adverse outcomes when interrupting antithrombotic treatment should always be weighed against the risks of continuing it. The risk of stroke and/or stent thrombosis and/or recurrent coronary events may be associated with the interruption of all or part of ongoing antithrombotic therapy.

The risk of (in-hospital) adverse outcomes associated with bleeding depends on several variables, including age, uncontrolled blood pressure, pre-existing comorbidities, and concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) or alcohol excess, as well as type and location of bleeding and degree of over-anticoagulation with warfarin (when ongoing) [1–3].

The risk of stroke is assessed by calculation of the CHA₂DS₂-VASc score [4]. The risk of stroke associated with the absence and/or withdrawal of OAC as estimated by the CHA2DS2-VASc score, however, may not be linear, and therefore just dividing the risk per year by the duration of discontinuation may not provide an adequate estimation of the true risk. The risk of stent thrombosis is related to the type (i.e., bare-metal vs. drug-eluting) of stent, the generation (i.e., early vs. new) of drug-eluting stent, the clinical setting (elective vs. acute) where the stent has been implanted, and the time elapsed from stent implantation. Premature discontinuation of DAPT, however, is the strongest predictor of stent thrombosis [5]. It may be relatively safe to interrupt DAPT and continue with single antiplatelet therapy (preferably clopidogrel) for 1 month and 6 months after bare-metal stent and new-generation drug-eluting stent implantation, respectively. A period of 12 months should be considered after an early-generation drug-eluting stent implantation, irrespective of the elective or acute clinical setting, and either bare-metal, early-, or new-generation drug-eluting stent implantation in an acute coronary syndrome (ACS) [6].

In the event of bleeding, a shorter duration of DAPT, even 1 month, may be considered for (some) new-generation drug-eluting stents (Table 12.1). Care is needed in not interrupting both antiplatelet agents at the same time, given the increased risk of stent thrombosis [7]. The location where the stent was implanted (i.e., proximal in a main and/or largely distributed vessel vs. mid-distal in secondary and/or poorly distributed vessel) should also be taken into account when trying to foresee the potential consequences of stent thrombosis.

The risk of recurrent coronary events is higher after ACS compared to the elective setting. Over the first year after the former, an incidence of < 1 % may be expected, as compared to up to 10 % after the latter. Of note, however, the risk of adverse events (namely, death) after an ACS tends progressively to decrease as long as time passes from index event. After 1 year (with no recurrence) from ACS, a patient is then considered stable, thereby generally requiring low-intensity (i.e., single-agent) antiplatelet therapy, in the non-AF setting. In selected cases at high risk of recurrences, especially because of previous myocardial infarction, prolonged (i.e., up to 3 years) DAPT with aspirin and P2Y₁₂-receptor inhibitor may be considered [8–10].

Once stratification of the risk associated with treatment interruption as compared to continuation has been carried out, proper management of the bleeding complication should be arranged. Management strategies are particularly difficult in patients on triple therapy (TT) of OAC, aspirin, and clopidogrel early after PCI with stent and even more so when the OAC is a newer, non-vitamin K-antagonist oral anticoagulant (NOAC), such as dabigatran, rivaroxaban, apixaban, or edoxaban. The clinical experience with warfarin, and its hemorrhagic complications, has allowed the development of common strategies, which may include the administration of the specific reversal agent vitamin K, as well as of nonspecific, prothrombotic agents, including prothrombin complex concentrates, fresh frozen plasma, and recombinant factor VII [11] (Table 12.4). Whereas only very limited data are available regarding the management and outcome of major bleeding complications in patients on OAC with warfarin who have undergone PCI with stent [12], no evidence is currently available regarding NOACs.

As relates to bleeding, NOACs have a more favorable pharmacological profile than warfarin. In particular, the elimination half-life is much shorter than warfarin (12 h on average vs. 36–42 h), thereby allowing for a rapid decline of the anticoagulant effect upon drug discontinuation (Fig. 12.1). Of note, restoration of (at least partially) effective coagulation is expected to be obtained by approximately 24 h from drug discontinuation, a time lapse similar to that observed after oral administration of vitamin K in patients on OAC with warfarin [11] (Tables 12.4 and 12.5). With the exception of life-threatening bleeding, either because of the severity (i.e., leading to hemodynamic impairment) or the location (e.g., intracranial, intrapericardial, retroperitoneal), discontinuation of the NOAC should be the necessary strategy. Available data show that conservative treatment (i.e., drug discontinuation with or without transfusion of red blood cells and/or plasma) of major bleeding events on NOACs is generally associated with a favorable outcome [13–15]. Also, overall outcome and also mortality appear not different from that with warfarin [13–15].

The availability of specific reversal agents for NOACs, i.e., idarucizumab for dabigatran and eventually andexanet alfa for factor Xa inhibitors (i.e., rivaroxaban, apixaban, and edoxaban) (Table 12.6), which has been shown effective in rapidly and completely reversing the anticoagulant effect of NOACs [16, 17], will further increase the safety of these agents. Both specific and nonspecific (e.g., prothrombin complex concentrates, fresh frozen plasma, recombinant factor VIIa) reversal agents (Table 12.7) are intended to be used only for emergency, life-threatening major bleeding complications [18] (Fig. 12.2). Outside this situation, immediate NOAC discontinuation associated with general measures should generally be sufficient [18].