Risk and Management of Bleeding Complications with Direct Oral Anticoagulants in Patients with Atrial Fibrillation and Venous Thromboembolism: a Narrative Review

Atrial fibrillation (AF), the most common cardiac arrhythmia, shows an escalating age-dependent prevalence [1], and is significantly associated with an increased risk of thromboembolic events, hospitalization, and mortality [2, 3]. Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third most frequent acute cardiovascular syndrome after myocardial infarction and stroke, ranking among the main causes of cardiovascular mortality [4]. Therefore, both AF and VTE carry a high healthcare financial and social burden.

Direct oral anticoagulants (DOACs), the first-line anticoagulant agents for stroke prevention in non-valvular AF (NVAF) and treatment of VTE, compared to vitamin K antagonists (VKAs), show similar or superior efficacy and better safety, significantly reducing the risk of major bleeding (MB), mainly intracerebral hemorrhage (ICH) [3‐5]. DOACs exert their anticoagulant activity through direct inhibition of thrombin (dabigatran) or activated factor X (FXa) (rivaroxaban, apixaban, edoxaban) and do not require routine laboratory monitoring to assess their antithrombotic activity [3]. The recommended doses of DOACs according to different therapeutic indications, including the relevant dose-reduction criteria, are reported in Table 1 [3].

VKAs, such as warfarin, are still widely used, playing an important therapeutic role in patients in whom DOACs are contraindicated: e.g., in those with estimated glomerular filtration rate (eGFR) < 15 ml/min, mechanical heart valves, valvular AF (moderate/severe mitral stenosis), VTE with triple-positive antiphospholipid syndrome, or in the presence of major drug interactions [2‐4]. Both DOACs and VKAs are contraindicated in pregnancy and lactation.

All anticoagulants are associated with a risk of bleeding complications, which can occur at different anatomical sites and with variable severity. This comprehensive review aims at critically discussing available evidence regarding the risk of bleeding complications and efficacy of DOACs compared to VKAs in patients with NVAF and VTE, including a focus on special patient populations. Furthermore, practical principles to help the clinician in assessing bleeding risk, managing bleeding complications, and choosing the appropriate anticoagulant based on patient profile are provided. To this end, we searched the PubMed database for publications up to June 2022, using the following MESH terms and their combination: direct oral anticoagulants, apixaban, dabigatran, edoxaban, rivaroxaban, venous thromboembolism, atrial fibrillation, bleeding, major, gastrointestinal, intracerebral, elderly, obesity, chronic kidney disease, liver disease, cancer, and COVID-19. Clinical trials, observational studies, systematic reviews, meta-analyses, editorials, expert consensus, and clinical guidelines were considered if relevant to the issue. This article is based on previously conducted studies and does not contain any new investigations involving human participants or animals performed by any of the authors.

Figure 1 summarizes the therapeutic management of bleeding complications on DOACs according to current guidelines [2, 3, 132]. The type of bleeding and patient/anticoagulant drug characteristics are key aspects to consider for successful bleeding management. Given the short half-life of DOACs, most non-MB complications can be safely managed only with discontinuation of the anticoagulant and supportive measures. Systolic blood pressure should be lowered to 140 mm Hg in all patients with ICH [133]. Specific coagulation tests that measure the anticoagulant activity of DOACs [diluted thrombin time (dTT) and anti-Xa chromogenic assay] play a key role in the management of MB that is not immediately life-threatening, in as much as they enable selecting only those patients who, having therapeutic plasma concentration of DOACs are truly in need of antifibrinolytic therapy and/or anticoagulant reversal agents [2, 3, 132]. Tranexamic acid should be considered in cases of MB, especially in trauma patients [2, 3, 132]. Conversely, high doses of this should be avoided in patients with GIB in whom it will not reduce mortality and may even increase the risk of VTE events, particularly in patients with liver disease or with suspected variceal bleeding [134]. Specific measures should be adopted in cirrhotic patients, as extensively reviewed elsewhere [99]. In the case of bleeding at a critical site (e.g., intracranial, ocular, thoracic, abdominal, pericardial, retroperitoneal)/life-threatening MB or MB not responding to the general control measures, specific (idarucizumab for dabigatran; andexanet alfa for FXa inhibitors) or unspecific [4-factor prothrombin complex concentrates (4-F PCC)] anticoagulant reversal agents can be indicated as a life-saving measure [2, 3, 132]. In patients receiving VKA treatment, the administration of 10 mg intravenous (IV) vitamin K and CCP-4F according to body weight and INR value is recommended [132]. Endoscopic, radiological, or surgical mechanical hemostasis procedures should be performed whenever necessary [2, 3, 132].

Assessment of resumption of anticoagulant therapy after bleeding complications should consider location/severity of bleeding, whether there is an identifiable cause, the profile of the individual patient’s thrombotic and hemorrhagic risk, the presence of modifiable bleeding risk factors (e.g., supratherapeutic INR, acute or worsening renal failure, concomitant antiplatelet agent), and the appropriateness of anticoagulant prescription based on patient characteristics/clinical indication [132]. In most cases, resuming anticoagulation after a bleeding event provides a net clinical benefit [132]. In case of bleeding due to secondary causes (e.g., post-trauma) or reversible (e.g., genitourinary due to cancer), anticoagulation can generally be resumed once the cause of the bleeding has been eliminated [3].

In the event of MB, particularly if life-threatening, a careful risk–benefit assessment for resuming anticoagulation should be conducted in collaboration with other specialists (e.g., neurologist, surgeon, endoscopist, interventional radiologists) and shared with the patient. None of the bleeding risk scores have been studied in the specific situation of active or very recent bleeding. In case of high thrombotic risk conditions (e.g., mechanical heart valve prosthesis, valvular AF, NVAF with CHA₂DS₂-VASc score ≥ 4, transient ischemic attack/ischemic stroke within 3 months, VTE within 3 months, or recurrent or cancer-associated VTE), restarting the anticoagulant will likely result in a benefit for the patient even if the risk of rebleeding is high, and should occur early once hemostasis and clinical stability have been achieved [132]. In patients at both high thrombotic and bleeding risk with relative or absolute contraindication to resume anticoagulation (e.g., severe and life-threatening bleeding without a clear secondary or reversible/treatable cause), nonpharmacological therapies may be considered, such as devices for closing the left atrial appendage to reduce the thrombotic risk in AF or retrievable inferior vena cava (IVC) filters in case of DVT and/or PE.

The choice of the proper anticoagulant should carefully consider the patient thrombotic and bleeding risk profile. In some patients (e.g., severe CKD, mechanical heart valves, valvular AF or major drug interactions, extreme body weights), only VKAs are indicated. In DOAC-eligible patients, based on the above reported literature evidence and expert opinions, it can be suggested to match the optimal DOAC to the patient profile, especially in those with AF, with the aim of reducing the risk of complications [66, 85, 148‐150] (Fig. 2).

In the elderly (≥ 75 years old) or frail NVAF patients, apixaban followed by edoxaban may be the first choice due to the excellent efficacy–safety profile demonstrated in these subpopulations, while dabigatran and rivaroxaban may be considered secondarily in those at low-bleeding risk [57, 63, 66]. All FXa inhibitors are viable options in elderly patients with VTE, while dabigatran 150 mg should not be the first choice, given the increased risk of MB reported in this subgroup in pooled data of RECOVER I and II [151].

Apixaban may be the first choice in AF as well as in VTE patients at high risk of GIB, while in those with AF, dabigatran 110 mg may also be a reasonable option [24, 48, 50, 148, 150]. In patients with dyspepsia/gastroesophageal reflux, dabigatran should be avoided; or treatment with PPI should be associated [148, 150].

In patients at risk of genitourinary bleeding there is no evidence supporting that any specific DOAC type is safer than warfarin [24]. Reduced risk of heavy menstrual bleeding, however, has been reported with dabigatran in a post-hoc analysis of the RE-COVER and RE-MEDY studies [152].

In AF patients with moderate-to-severe CKD (eGFR 15–49 ml/min) the first therapeutic choice may be apixaban 5 mg twice daily (2.5 mg twice daily if eGFR 15–29 ml/min or two dose reduction criteria are satisfied), edoxaban 30 mg once daily or rivaroxaban 15 mg daily; dabigatran 110 mg twice a day as a second choice in patients with moderate CKD (eGFR 30–49 ml/min), while it is contraindicated in patients with severe CKD (eGFR 15–30 ml/min) owing to its predominant renal elimination [3, 85, 148, 150]. Likewise, using DOACs less dependent on renal excretion may be preferred in VTE patients with moderate-severe CKD but DOAC dose reduction is not recommended in these patients, except for edoxaban [3, 22].

No evidence is available regarding the best efficacy and safety profile of individual DOAC in patients with liver disease [99]. Dabigatran may be preferred based on the prevailing renal excretion; while apixaban may appear preferable based on optimal GIB safety profile, it undergoes hepatic metabolism to a larger extent than other DOACs. Rivaroxaban is contraindicated in Child–Pugh class B patients and all DOACs should be avoided in Child–Pugh class C patients [3].

In severely obese patients (either BMI 40–49 kg/m² or weight 120–140 kg), DOACs may cautiously be used, preferring apixaban, edoxaban or rivaroxaban in those with AF and apixaban or rivaroxaban in those with VTE [71‐74, 78‐80].

In low body weight patients (60–40 kg) with AF or VTE, apixaban and edoxaban may be preferred [3, 70, 81, 84, 85].

DOACs with low incidence of MB (such as apixaban, dabigatran 110 mg, and edoxaban) should be considered in AF patients with high bleeding risk (HASBLED ≥ 3) [148], while in those with high thrombotic risk and a low bleeding risk, dabigatran at a dose of 150 mg would be preferable, given that it is the only DOAC more effective than warfarin in reducing ischemic stroke [6].

Drug interactions must always be evaluated before prescribing DOACs: certain antiarrhythmics require a dose reduction of DOACs (e.g., dabigatran and edoxaban in verapamil users); moreover, many antineoplastic, antiepileptic, and antifungal drugs contraindicate the use of DOACs [2, 3, 150].

In case of therapeutic compliance concerns, once daily dosing DOAC (rivaroxaban or edoxaban) should be preferred because this could improve treatment adherence [3, 148, 149].

Finally, a structured follow-up involving general practitioners/consultants (cardiologist, internist, or hematologist) with surveillance of renal–hepatic function, symptoms/signs of bleeding, and medication compliance should be considered for all patients to optimize management and reduce the risk of complications, such as recommended by current guidelines [2‐4]. A closer follow-up should be adopted for patients at high risk of bleeding, addressing all modifiable risk factors.

DOACs compared to VKAs have at least a comparable or better efficacy–safety profile for multiple indications, with significantly reduced of risk of ICH, while the risk of MB and GIB vary according to each individual DOAC.

Bleeding severity and intensity requested for its management are generally lower during therapy with DOACs than with VKAs. In most patients, supportive measures can be used as the therapeutic effect decreases due to the shorter half-life of DOACs than VKAs, while anticoagulant reversal agents are indicated for life-threatening bleeding complications. In most cases, resuming anticoagulation after a bleeding event will provide a net clinical benefit.

Correct patient selection, including careful assessment of bleeding risk profile and choice of appropriate DOAC type/dosing based on patient characteristics/comorbidities and presence of drug interactions is key to minimizing adverse events. Aimed at optimizing management efficacy while reducing the risk of complications, a closer, more structured follow-up should be considered for all patients at high risk of bleeding.