Management of antithrombotic therapy after bleeding in patients with coronary artery disease and/or atrial fibrillation: expert consensus paper of the European Society of Cardiology Working Group on Thrombosis

Bleeding is a frequent complication of the management of patients with coronary artery disease (CAD), especially those presenting with acute coronary syndromes (ACS) or undergoing percutaneous coronary intervention (PCI), and of patients with atrial fibrillation (AF). Randomized trials have shown a risk of major bleeding of 1–8% at 30 days in ACS patients,1–5 and of 2–5% per year in patients with AF treated with oral anticoagulants (OACs).6 Observational studies suggest that bleeding risk is even higher.7 Major bleeding is associated with a subsequent increase in both short- and long-term mortality.7–13 Even minimal bleeding may have prognostic importance because it frequently leads to disruption of antithrombotic therapy.14,15 Hypothetical mechanisms linking bleeding to thrombotic events and death. Numerous risk factors for bleeding are also risk factors for myocardial infarction, stroke and death (large arrows). VTE, venous thromboembolism. Although several recommendations have been published dealing with the acute management of bleeding in patients treated with antithrombotic drugs,22–24 there is an unmet need for guidance on how to manage antithrombotic therapy after bleeding has occurred. Patients with recent bleeding have been excluded from most randomized trials of antithrombotic therapy and rigorous evidence to inform decisions is scarce. While waiting for observational and randomized data to accrue, this consensus paper offers a European perspective on managing antithrombotic therapy after bleeding in patients with CAD and/or AF, including which drugs to stop, which to restart, and when. For the purpose of this document, major bleeding has been defined according to the Bleeding Academic Research Consortium (BARC)25 as BARC type ≥ 3, minor bleeding as BARC type 2 and minimal as BARC type 1. Cessation of antithrombotic therapy has been defined according to Mehran et al.19 as discontinuation (recommended, physician-directed withdrawal), interruption (temporary cessation of antiplatelet treatment due to surgical necessity with reinstitution within 14 days), or disruption (cessation of antiplatelet treatment due to bleeding or non-compliance). Tables 1 and 2 present the authors’ consensus definitions of thrombotic and haemorrhagic risks for CAD and AF patients who develop a bleeding event. Risks are stratified into five categories: low, low-to-moderate, moderate, high, and very high. Definitions are based on simple clinical parameters and validated scores.26,27 Although the value of platelet function testing for predicting ischaemic and bleeding risks was recently demonstrated in a cohort of >20 000 patients,28 personalized treatment based on platelet function and/or genetic testing cannot be recommended in routine clinical practice due to insufficient prospective data.29,30 Ongoing studies further investigate this issue (e.g. NCT01538446, NCT01959451). Consensus definitions of thrombotic risk categories ACS, acute coronary syndrome; AF, atrial fibrillation; BVS, biovascular scaffolds; CAD, coronary artery disease; CHA2DS2-VASc, Cardiac failure, Hypertension, Age ≥75 (2 points), Diabetes, Stroke (2 points)—Vascular disease, Age 65–74, Sex category; DES, drug eluting stent; PCI, percutaneous coronary intervention. Consensus definitions of thrombotic risk categories ACS, acute coronary syndrome; AF, atrial fibrillation; BVS, biovascular scaffolds; CAD, coronary artery disease; CHA2DS2-VASc, Cardiac failure, Hypertension, Age ≥75 (2 points), Diabetes, Stroke (2 points)—Vascular disease, Age 65–74, Sex category; DES, drug eluting stent; PCI, percutaneous coronary intervention. Consensus definitions of recurrent bleeding risk categories To be in the low-risk category for recurrent bleeding, both bleeding source/severity, clinical setting and patient risk factors for bleeding must be low. To be in the high-risk category, it is sufficient that one variable is high risk. HAS-BLED, Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65), Drugs/alcohol concomitantly; PCI, percutaneous coronary intervention. Consensus definitions of recurrent bleeding risk categories To be in the low-risk category for recurrent bleeding, both bleeding source/severity, clinical setting and patient risk factors for bleeding must be low. To be in the high-risk category, it is sufficient that one variable is high risk. HAS-BLED, Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65), Drugs/alcohol concomitantly; PCI, percutaneous coronary intervention. The concomitance of very high thrombotic and very high haemorrhagic risks in a patient with bleeding poses the most difficult treatment decisions. Given the increased risk of thrombotic events after premature cessation of antithrombotic drugs, our consensus is to consider resumption of oral antithrombotic therapy in all situations where there is a clear indication, even in case of major bleeding, as long as the bleeding event is not a life-threatening intracranial or extracranial bleed. When the thrombotic risk is higher than the risk of recurrent bleeding (according to Tables 1 and 2), we suggest continuing antithrombotic therapy. When thrombotic risk is in equipoise with bleeding risk, we suggest only brief or temporary interruption of antithrombotic therapy. When bleeding risk outweighs thrombotic risk, we suggest considering, on a case to case basis, reducing the number and/or dose of antithrombotic drug(s). Whenever possible we strongly suggest recruiting patients into randomized trials or registries designed to address the many dilemmas discussed below. When this is not possible, we suggest applying the guidance provided by this consensus paper. The risk for new cardiovascular events is increased in patients with a recent ACS, especially during the first 3 months, and remains elevated up to 1 year after the acute event.31 The importance of dual antiplatelet treatment (DAPT) with aspirin and a P2Y12 inhibitor up to 1 year for these patients is well established.32 After bleeding, no randomized trials have assessed whether stopping or restarting one or both antiplatelet agents is the best choice. In patients with a recently implanted coronary stent, premature disruption of one or both antiplatelet agents (especially the P2Y12 inhibitor) has been shown to be the strongest predictor of stent thrombosis.33–35 The risk of stent thrombosis increases with longer time off treatment, particularly more than 5 days, and if treatment is stopped within the 1st month after the procedure.33,34,36,37 One-year mortality rates for stent thrombosis remain as high as 10–14%.38,39 In a contemporary registry of over 5000 patients treated with PCI, cardiovascular risk was significantly increased when DAPT cessation was due to non-compliance or bleeding.19 The risk was highest for the first 7 days after the start of disruption, but still high within 30 days.19 Thus, it is important for clinicians to clearly appreciate the heightened risk of ischaemic events following premature cessation of antiplatelet therapy in patients with coronary stents. Recent randomized trials using newer-generation (everolimus- or zotarolimus-eluting) drug-eluting stents (DES) support shortening DAPT duration in patients at high risk of bleeding; in some of these studies, there was no evidence of lower efficacy with 3–6 months of DAPT than with 12 months.32,40,41 Thus, when major bleeding occurs after 3–6 months of DAPT, these studies lend support to discontinuing the P2Y12 inhibitor and continuing aspirin alone, particularly in patients without a prior history of ACS.32 Furthermore, the Prospective Randomized Comparison of the BioFreedom Biolimus A9 Drug-Coated Stent vs. the Gazelle Bare-Metal Stent in Patients at High Bleeding Risk (LEADERS FREE) trial suggested that a polymer-free biolimus-coated stent may allow even shorter duration of DAPT (1 month).42 Therefore, decisions of whether and when to resume antiplatelet treatment after bleeding should also consider the type of stent(s). While the overall risk of stent thrombosis is lowest with the newest generation DES, the thrombotic risk appears higher with the new bioresorbable vascular scaffolds (BVS), owing to thrombogenicity related to strut thickness and extent of blood contact surface.43,44 Therefore, a longer DAPT duration and a more urgent need for resuming antiplatelet agents after bleeding may be needed with BVS,45 although further studies specifically with this device are required to explore the optimal DAPT duration. In ACS patients treated with the newer P2Y12 inhibitors prasugrel or ticagrelor, there are no data available for resumption after bleeding. The risk of non-CABG related bleeding with these agents is significantly higher compared to clopidogrel. Although the evidence is weak, clopidogrel (which results in less platelet inhibition and a lower risk of spontaneous bleeding) may be used as P2Y12 inhibitor after bleeding has occurred during treatment with prasugrel or ticagrelor, as soon as re-initiation of antiplatelet therapy is possible. The irreversible binding of prasugrel and the reversible binding of ticagrelor should be taken into consideration when deciding when to restart P2Y12 inhibitors in these patients. Dose reduction from 10 to 5 mg od prasugrel or from 90 mg to 60 mg bid ticagrelor is not recommended due to lack of evidence of efficacy in patients with a recent ACS. Of note, however, the two doses of ticagrelor provided similarly high levels of platelet inhibition.46 The bleeding risk is also increased with the thrombin receptor antagonist vorapaxar,47 having an extremely prolonged half-life. Our consensus is that this drug should be discontinued permanently in patients after bleeding has occurred. Trials and registries show that a significant proportion of patients with ACS are treated medically without revascularization for various reasons.48 Such patients on average have worse cardiovascular outcomes compared to those that undergo revascularization.49 The suggestions for antithrombotic therapy after bleeding, outlined for patients treated invasively, largely apply also to patients receiving medical treatment alone, except for the lack of stent thrombosis risk. Two meta-analyses, based mainly on observational data, suggest that single antiplatelet therapy prescribed for secondary prevention in stable CAD patients should be reinitiated within a few days after bleeding. The first analysis includes 50 279 patients receiving aspirin: cessation of, or non-adherence to, aspirin were associated with a three-fold higher risk of major adverse cardiac events compared to its continued use [OR = 3.14 (1.75–5.61), P = 0.0001].50 The risk was magnified in patients with coronary stents.50 The second meta-analysis evaluated patients with perioperative aspirin interruption.51 The mean time to coronary events after withholding aspirin was 8.5 days, with events occurring as early as 5 days after withdrawal. On the other hand, a large randomized trial (POISE-2),52 comparing perioperative aspirin vs. placebo among patients considered at risk of cardiovascular events and undergoing non-cardiac surgery, showed no significant effect of aspirin on the 30-day rate of death or non-fatal myocardial infarction but an increased risk of major bleeding vs. placebo. Of note, less than one third of the POISE-2 population had prior vascular disease and only 23% had CAD. Algorithm for the management of patients with upper gastrointestinal haemorrhage who are using antiplatelet agent(s); modified with permission from Gralnek et al.55 APT, antiplatelet therapy; ASA, aspirin; DAPT, dual antiplatelet therapy; GI, gastrointestinal. For patients at high or very high thrombotic risk (see Table 1: ACS or coronary stenting <30 days) who develop minor or major bleeding, we suggest continuation of low-dose aspirin without interruption. Restarting of the second antiplatelet agent should be considered as soon as possible after stabilization. For patients at moderate thrombotic risk (see Table 1: ACS or PCI with a second generation DES 1–12 months ago) who develop minor or major bleeding, we suggest resumption of low-dose aspirin as soon as bleeding is controlled, preferably within 3 days. Restarting a second antiplatelet agent should be considered if thrombotic risk outweighs recurrent bleeding risk. For patients who develop bleeding while on DAPT within 3 months of new generation DES implantation, we suggest resuming DAPT up to 3 months. If patients develop bleeding more than 3 months after new generation DES implantation and remain at risk of recurrent bleeding, we suggest resumption of only one antiplatelet agent (either aspirin or clopidogrel). In patients with bleeding after BVS implantation, DAPT may be necessary up to 12 months after implantation. Clopidogrel, as less effective but also with a tendency for less bleeding rates, may be used as P2Y12 inhibitor of choice after bleeding has occurred on prasugrel or ticagrelor. The duration of the effect of prasugrel (7–10 days) or ticagrelor (3–5 days)32 should be taken into consideration when deciding when to restart P2Y12 inhibitors in these patients. In patients who develop major bleeding under vorapaxar, we suggest permanent discontinuation of the latter. In medically managed ACS patients who develop major bleeding on DAPT, single antiplatelet therapy may be considered, given the lack of stent thrombosis risk. For patients with stable CAD or ACS who develop upper GI (non-variceal) bleeding, antiplatelet therapy (single or dual) can be continued without interruption if endoscopy identifies low-risk bleeding stigmata (Figure 2). If high-risk bleeding stigmata are identified and bleeding has been controlled by interventional endoscopy, aspirin can be restarted within 3 days.55 If high-risk stigmata are identified in patients on DAPT, resuming the second antiplatelet agent should be on an individual basis after careful weighing potential thrombotic and bleeding risks. Addition of a PPI is recommended in all cases of upper GI bleeding.55,56 PPI should also be used in patients on DAPT at higher than average risk of GI bleeds.32 The pharmacodynamic interaction between PPIs (especially omeprazole) and clopidogrel has not so far been clearly associated with worse clinical outcome, but it is preferred to use PPIs with weaker CYP2C19 inhibition (e.g. pantoprazole).56 Treatment with OACs reduces the risk of stroke and systemic embolism in patients with AF. Cessation of OACs has been shown to be associated with an increased risk of stroke even after short interruptions.57,58 A recent meta-analysis of studies in patients on long-term VKA demonstrated that resumption of warfarin following interruption due to GI bleeding was associated with a reduction in thromboembolic events and mortality without any significant increase in recurrent GI bleeding.59 In a retrospective study of patients with non-valvular AF, restarting warfarin after major GI bleeding was independently associated with decreased mortality as compared to permanent warfarin cessation.60 No significant difference in the incidence of new GI bleeding was found when warfarin was resumed after 1 week vs. 1 month; however, when warfarin was restarted before the 1st week after GI bleeding had passed, the risk of recurrent bleeding was significantly enhanced. Based on these data, in the presence of a clear indication, VKA therapy should be resumed within 1 week following major GI bleeding.60–62 In patients with mechanical heart valves, discontinuation of VKA is associated with a high risk of thrombosis and is generally discouraged. The NOACs have not been tested in AF patients with recent bleeds and the optimal time for restarting NOAC after bleeding is unknown. In a recent study with the antidote idarucizumab for patients on dabigatran presenting a life-threatening bleed or requiring urgent surgery, thrombotic events occurred within 6 days after idarucizumab administration when anticoagulation was not reinitiated.17 It may be reasonable to follow the same advice as for VKA, being aware that the full anticoagulant effect of NOAC occurs sooner (within 1–4 h)63 than with VKA (several days). When (re)starting a NOAC, renal function should be carefully assessed and monitored to avoid drug accumulation. The recommended time interval during follow-up for monitoring of renal function depends on the level of renal function: If creatinine clearance (CrCl) is less than 60 mL/min, then recheck renal function every x months, where x = CrCl/10.63 After major bleeding, however, this interval should be reduced. Some of the NOACs are associated with an increased risk of GI bleeding compared to warfarin.16,64 Switching to warfarin or to a NOAC without an increased risk of GI bleeding compared to warfarin (e.g. apixaban)16,64 may be considered. After extracranial bleeding, OAC should be reinitiated as soon as the cardiovascular thrombotic risks associated with discontinuation are thought to outweigh the risk of re-bleeding with reinitiation, in most cases within 1 week. When (re)starting a NOAC, renal function should be carefully assessed and monitored to avoid drug accumulation. If an antidote (idaruzicumab) has been used to reverse the anticoagulant effect of a NOAC, it is suggested to restart OAC as soon as possible, preferably within 3–4 days if the individual bleeding risk allows. In patients with mechanical heart valves, discontinuation of VKA is associated with a high risk of thrombosis and is discouraged, particularly for valves in the mitral position. NOACs are currently for patients with mechanical heart A in of antithrombotic treatment is patients who present with both AF and most of having an for both DAPT and A of therapy is recommended in most by therapy single up to one OAC is considered DAPT with OAC or significantly increases bleeding of any of the large of possible The is the and anticoagulant therapy in patients with OAC and coronary trial of patients demonstrated that therapy was with to BARC bleeding compared to therapy clopidogrel and and registries have shown The recent in Patients on After Stent study patients receiving VKA who DES implantation and showed that outcomes were if on of VKA and was for 6 or 6 these trials were to ischaemic and the patients were stable and had not a bleed. as an from these studies, we suggest stopping aspirin or clopidogrel when a patient major bleeding during oral antithrombotic therapy. In patients who develop major bleeding on therapy single discontinuation of the antiplatelet agent may be considered before 1 year has passed, as long as the risk is moderate or less is no randomized study comparing VKA vs. NOAC in the setting of AF with and the suggest that can be used in with antiplatelet to choice of antiplatelet the the use of prasugrel or ticagrelor as of The use of ticagrelor in with a NOAC is currently being tested in prospective randomized trials When NOACs are with antiplatelet drugs, the lowest effective dose for stroke prevention should be dabigatran mg bid mg mg or 30 mg only when for dose are The efficacy of bid has not been demonstrated for stroke prevention in AF patients and cannot be recommended for this When patients with non-valvular AF develop bleeding during oral antithrombotic we suggest stopping aspirin or clopidogrel not within the first month of For we suggest a of with VKA and the lowest effective dose for stroke prevention for In patients who develop major bleeding on therapy single discontinuation of the antiplatelet agent may be considered before 1 year has suggest DAPT for 1 year after when a patient with non-valvular AF and a risk of stroke 1 for 2 for bleeding during or antithrombotic therapy. of ACS patients develop intracranial haemorrhage while on antiplatelet is evidence on whether to or resume antiplatelet therapy. consideration of thrombotic and bleeding risk is In restarting therapy after temporary discontinuation should be considered if thrombotic risk, as defined in Table is very high or high. randomized controlled trial of restarting vs. antiplatelet drugs after is is one of the most of occurring in of patients In patients the is whether to restart A of observational studies of patients with heart valves an in patients with mechanical heart valves, anticoagulation with can be restarted as early as 3 days after and to VKA at 7 days without major of For patients without mechanical valves, the is whether to OAC at all after of that a to several observational studies have compared (re)starting vs. OAC after The most studies with various of and a of for OAC and the risks of recurrent or ischaemic events for patients who or restarted from these studies suggest a reduction in ischaemic in recurrent and in death rates associated with restarting although by is given the for the or re-initiation of oral anticoagulation after intracranial AF, atrial fibrillation; intracranial atrial NOAC, antagonist oral oral VKA, = any that not oral anticoagulation no antithrombotic at antiplatelet agent(s); of the evidence The NOACs because of the lower risks of than warfarin in trials of patients with non-valvular AF, but these drugs have not been tested in patients with prior NOACs are currently in the presence of mechanical heart valves given the results of the in Patients with In AF patients with and/or and/or atrial is an randomized trial of vs. no anticoagulation after is and when to restart OAC after an should be on an individual basis, on the thrombotic risk and the risk of recurrent bleeding (Figure between and is needed to decisions. In the of mechanical valves, NOACs may be to warfarin after given lower incidence of among non-valvular AF patients in but efficacy and have still to be in this If one of the NOACs is the lowest effective dose for stroke prevention in AF should be function, and drug should be carefully considered to avoid is a of observational data, and even more so of randomized the risks and of when and how to resume antithrombotic drugs after bleeding in patients with CAD and/or AF. antithrombotic management is largely from randomized trials in patients without a history of bleeding. 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