A practical guide on how to handle patients with bleeding events while on oral antithrombotic treatment

Bleeding is a frequent complication both in patients treated with oral anticoagulation (OAC) and in patients with antiplatelet therapy, in which major bleeding occurs in roughly 5% within one year in both groups [1‐8]. Despite the bleeding risk, dual antiplatelet therapy (DAPT), consisting of aspirin with a P2Y12 inhibitor, remains the cornerstone of treatment in patients with acute coronary syndrome (ACS) and those undergoing percutaneous coronary intervention (PCI) with stenting. Moreover, the more potent P2Y12 inhibitors, ticagrelor and prasugrel, are preferred over clopidogrel, further increasing the risk of bleeding [9]. The preferred duration of DAPT after ACS is 12 months, but in patients with a high bleeding risk a shorter duration should be considered, with a minimum of one month in medically managed patients and 6 months in patients who underwent PCI, based on the literature [10, 11]. OAC is indicated in most patients with non-valvular atrial fibrillation (AF). The non-vitamin K oral anticoagulants (NOACs) are recommended in preference to vitamin K antagonists (VKAs) because of the reduced bleeding risk [12]. Major bleeding is associated with a significant increase in the risk of death (11%), myocardial infarction and stroke, possibly because predictors of bleeding have much overlap with predictors of ischaemic events and due to discontinuation of effective antithrombotic drugs when bleeding occurs [13, 14]. Therefore, resuming antithrombotic therapy poses a clinical dilemma: restarting antithrombotic therapy prematurely could lead to recurrent bleeding while delaying reinitiation puts the patient at an increased thrombotic risk.

The purpose of this review is to provide recommendations to enhance clinical decision making regarding the treatment of patients with a bleeding event while on antithrombotic therapy, based on the literature and expert opinion. Our search is shown in the Appendix.

First, we will discuss the recommendations from the guidelines regarding the treatment of mild, moderate, severe and life-threatening bleeding, using the same definitions for the bleeding categories. Where possible, we will provide the guideline’s class of recommendation and level of evidence (LoE). Fig. 1 and 2 show flow charts summarising the treatment options stratified by bleeding severity.

There are no randomised data on restarting medication after gastrointestinal bleeding. The meta-analysis of Chai-Adisaksopha et al. examined the benefit and risks of resuming anticoagulant therapy following gastrointestinal bleeding [28]. Three studies were selected, including patients using warfarin for various reasons (AF, deep vein thrombosis, pulmonary embolism or prosthetic heart valve), of which 17–83% also used anti-platelet therapy. Resumption of warfarin (in 53% of patients) was associated with a significant reduction in thromboembolic events 9.9% versus 16.4% (hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.52–0.88; p = 0.004) and mortality 24.6% versus 39.2% (HR 0.76; 95% CI 0.66–0.88; p = 0.0002). However, a numerically increased rate of recurrent gastrointestinal bleeding was observed in patients resuming warfarin (10.1% vs 5.5%, HR 1.20; 95% CI 0.97–1.48; p = 0.10). This risk was significantly higher when restarting warfarin within 7 days compared with restarting later [29, 30]. Accordingly, the European Society of Gastrointestinal Endoscopy (ESGE) guideline recommends in patients on (N)OAC with a moderate gastrointestinal bleeding or worse, to stop (N)OAC and restart between 7–15 days after the gastrointestinal bleeding event [17]. Patients with a very high thrombotic risk, e. g. mechanical heart valve, cardiac assist device, CHA₂DS₂-VASc score ≥4 may benefit from earlier (first week) resumption [11, 17].

The aforementioned studies all have an observational design and are, therefore, subject to bias through confounding by indication; patients who did not restart OAC had more severe bleeding events and were older compared with restarters.

Specific data regarding restarting NOAC after gastrointestinal bleeding is lacking. Therefore, it seems reasonable to extrapolate data regarding warfarin to the NOACs, keeping in mind the faster therapeutic onset of NOACs compared with warfarin. The four phase III trials comparing the different NOACs with warfarin, showed an increased risk of gastrointestinal bleeding with rivaroxaban, high-dose dabigatran and high-dose edoxaban. Apixaban, low-dose dabigatran and low-dose edoxaban showed comparable gastrointestinal bleeding risk with warfarin [3‐6]. Therefore, patients with a gastrointestinal bleeding while using a NOAC should be considered for a lower dose or for apixaban (class IIa, LoE B) [12].

A double-blinded, randomised controlled trial (RCT) included 156 patients with upper gastrointestinal bleeding on aspirin for secondary prevention and randomised to continuing aspirin or placebo. Recurrent upper gastrointestinal bleeding occurred more frequently in the group treated with aspirin, 10.3% vs. 5.4% (HR 1.9; 95% CI 0.6–6.0). But the number of blood transfusions was equal between both groups, implying relatively mild recurrent bleeding events. Mortality after 8 weeks was, however, significantly lower in patients treated with aspirin, 1.3% vs. 12.9% (HR 0.2; 95% CI 0.06–0.60) [31]. Data regarding gastrointestinal bleeding while on DAPT are scarce.

In accordance, the ESGE guideline and expert consensus paper of the ESC, advises in patients on aspirin or DAPT for secondary prevention with upper gastrointestinal bleeding, to continue aspirin or DAPT if endoscopy shows no active bleeding [16, 17]. Consider a three-day interruption of aspirin in patients with active bleeding by endoscopy (strong recommendation, moderate quality evidence), in case of DAPT, continue the P2Y12 inhibitor and interrupt aspirin for three days [16, 17]. Likewise, the American College of Gastroenterology guideline regarding acute lower gastrointestinal bleeding recommends continuing aspirin for secondary prevention [32]. But, in patients on DAPT, it is advised to interrupt the P2Y12 inhibitor for a maximum of 7 days, aspirin should be continued. However, if the patient suffered from an ACS within 90 days or received a coronary stent within 30 days DAPT should be continued (strong recommendation, low quality evidence) [32]. The ESC DAPT guideline also advises to consider shortening the DAPT duration and switching to DAPT consisting of aspirin with clopidogrel [11].

In addition to the measures mentioned above, the ESGE guideline recommends in patients with upper gastrointestinal bleeding, immediate initiation of high-dose intravenous proton pump inhibitors (PPIs) (strong recommendation, high quality evidence) [17] and to continue infusion until 72 hours post endoscopy [17]. PPIs reduce the risk of upper gastrointestinal bleeding significantly in patients treated with antiplatelet therapy, and numerically in patients treated with OAC. Therefore, it is recommended to continue treatment with oral PPIs after discharge when antiplatelet therapy is reinitiated [11, 16, 33‐35], and we advise to consider this when OAC is reinitiated [35].

A meta-analysis by Murthy et al. summarised the results of eight retrospective cohort studies, including patients with nontraumatic intracranial haemorrhage (intraparenchymal, subdural and/or subarachnoid haemorrhages) while on OAC [36]. Indication for OAC (mainly VKA) was most often AF, followed by prosthetic heart valve, venous thromboembolism and previous ischaemic stroke; in addition, 5–33% also used antiplatelet therapy. After intracranial haemorrhage, 35.8% resumed VKA, with a mean of one month after intracranial haemorrhage. The results showed a thromboembolic complication rate of 6.7% in patients restarting OAC versus 17.6% in those who did not (rate ratio [RR] 0.34; 95% CI 0.25–0.45), while recurrence of intracranial haemorrhage was numerically higher in patients restarting therapy, 8.7% vs. 7.8% (RR 1.01; 95% CI 0.58–1.77). These data should be interpreted with caution as all studies were subject to confounding by indication restarting VKA in patients with smaller haematomas and a less critical location of bleeding. Data regarding the treatment of intracranial haemorrhage while using NOAC is not available, however, the studies RE-LY, ENGAGE-AF, ARISTOTLE and ROCKET-AF all showed a significantly reduced risk of intracranial haemorrhage with NOACs compared with VKA. Moreover, NOAC-related intracranial haemorrhages were smaller and had a better clinical outcome [3‐6]. The ESC AF guideline advises to withhold OAC if bleeding occurred while adequately dosed, in case of uncontrolled hypertension, if the bleeding is located cortically, if there are multiple microbleeds (>10) or if DAPT is needed. Factors supporting reinitiating OAC are: bleeding occurred on VKA or in the setting of overdose; bleeding was traumatic or has a treatable cause; bleeding is located in the basal ganglia; when the white matter lesions are mild; in case of removed subdural haematoma or clipped/coiled aneurysm [12]. Switching to a NOAC after intracranial haemorrhage should be considered (class IIb, LoE B) [12, 15, 16, 37‐40]. If it is decided to restart antithrombotic treatment the advice is to start one month after intracranial haemorrhage (class IIb, LoE B) [12, 21, 36].

A meta-analysis including six observational studies, reviewed the treatment decisions made in patients with a primary intracranial haemorrhage while on single antiplatelet therapy [41]. In total, 1916 patients were included of which 825 (43%) resumed antiplatelet therapy. Timing of resumption after intracranial haemorrhage varied widely and data were not always available. In the largest included study (n = 759), the median time to restart was 24 days, however, only patients with AF were included [42]. The meta-analysis showed equal recurrence of intracranial haemorrhage or haematoma expansion in both groups [RR 0.84; 95% CI 0.47–1.51; p = 0.56], but thromboembolic events were significantly lower in patients restarting antiplatelet therapy [RR 0.61; 95% CI 0.48–0.79; p < 0.01].

One study from the meta-analysis included 109 Chinese patients with a first-time aspirin-related primary intracerebral haemorrhage surviving >90 days after admission. All patients used aspirin for secondary prevention. After intracerebral haemorrhage, 19% restarted aspirin after a median of 87 days. Patients who resumed aspirin had less disabilities and a higher rate of ischaemic heart disease (56.8% vs. 23.6%). Importantly, ischaemic events were 2–3 times more common than recurrent intracerebral haemorrhage, which was comparable between both groups. A systolic blood pressure of >140 mm Hg and cerebral amyloid angiopathy were independent predictors of recurrent intracerebral haemorrhage. After intracerebral haemorrhage it takes a few weeks to restore the blood-brain barrier [43], and for the perihaemorrhagic oedema to decrease [44]. Therefore, antiplatelet resumption should be safe after approximately 4 weeks.

Confounding by indication is of particular importance in patients after intracranial haemorrhage because different locations of bleeding are associated with different recurrent rates and disabilities. The most common distinction made in intracerebral haemorrhage is lobar (cerebral cortex and underlying white matter) versus deep (basal ganglia, thalamus, brainstem) with recurrence rates of 15.7% vs. 3.4% (p = 0.011) respectively [45].

Intracranial haemorrhage while on DAPT is reported in only 0.3% of patients [7, 8]. We can only speculate on when to restart medication in these patients and presume that DAPT could also be reinitiated after approximately 4 weeks.

The Dutch guideline for blood transfusions advises in patients with a recent (<3 months) myocardial infarction or ongoing ischaemia to consider a liberal blood transfusion regimen, transfusing patients with haemoglobin levels of ≤6 mmol/L [47]. However, the ESC NSTEMI guideline recommends transfusion only in haemoglobin levels <4.5 mmol/L (class IIb, LoE C) [9]. And the American College of Physicians clinical practice guideline and the American College of Cardiology expert consensus document on management of bleeding recommend a target haemoglobin level of >5 mmol/L [48].

The largest RCT addressing restrictive versus liberal transfusion in ischaemic heart disease patients included 838 patients, admitted to the intensive care unit, with haemoglobin levels of 5.5 mmol/L or less, without active bleeding or chronic anaemia [49]. Of these, 257 had ischaemic heart disease, 111 received restrictive and 146 liberal transfusion. In the total study population, a restrictive red-cell transfusion (<4.5 mmol/L) proved non-inferior to a liberal transfusion (<6 mmol/L). However, subgroup analysis of patients with ischaemic heart disease showed a nonsignificant decrease in overall survival in the restrictive transfusion group [50]. The authors conclude that patients with ACS might not benefit from the restrictive transfusion strategy. A smaller RCT, including 110 patients with symptomatic coronary artery disease allocated patients to a restrictive (<5 mmol/L) or liberal (<6 mmol/L) strategy and found also a trend towards fewer major cardiac events and deaths in the liberal transfusion group [51].

This article summarises the current literature and recommendations from the guidelines about the management of patients with a bleeding while on antithrombotic therapy. Furthermore, we reviewed and interpreted the data, and based our specific advice to guide the clinician upon this. However, the available guidance is primarily based on observational cohort studies with a high risk of confounding. Overall, it is advised to restart antithrombotic treatment after the bleeding event except for patients suffering from a lobar cerebral haemorrhage. However, the decision to restart antithrombotic therapy should be evaluated per patient and needs multidisciplinary consultation. In addition, we would advise to treat anaemic ACS patients according to a liberal transfusion strategy (<6 mmol/L).