Direct Oral Anticoagulants: Quick Primer on When to Use and When to Avoid

Abstract

Direct oral anticoagulants (DOACs) have transformed the landscape of antithrombotic therapy in the past two decades. However, there is uncertainty about when they should or should not be used for treatment or prevention of thromboembolic events. DOACs have largely replaced warfarin for many patients with atrial fibrillation or venous thromboembolism who require anticoagulant therapy. In addition to noninferior efficacy, fewer drug–drug and food–drug interactions and improved convenience; DOACs have been shown to reduce the risk of intracranial hemorrhage. They have also received new indications compared with warfarin, such as cardiovascular risk reduction in patients with stable atherosclerotic diseases. However, there are some scenarios in which DOACs are associated with inferior efficacy or worse safety compared with standard treatment, such as warfarin. These include patients with mechanical heart valves, thrombotic antiphospholipid syndrome, and others. Although DOACs offer a streamlined and convenient option for the management of many patients with or at risk of thromboembolic events, their use should be avoided in certain high-risk scenarios. This minireview summarizes such conditions and those in which there is uncertainty for use of DOACs for particular diseases or particular patient subgroups.

Keywords

direct oral anticoagulant - anticoagulant - warfarin - thromboembolism - thrombosis

Introduction

Direct oral anticoagulants (DOACs), including factor Xa inhibitors and direct thrombin inhibitors, offer benefits such as fixed dosing, and no routine monitoring, and were reassuringly found in clinical trials to have a lower risk of intracranial bleeding,[1] [2] [3] compared with vitamin-K antagonists (VKAs). They are preferred for stroke prevention in atrial fibrillation (SPAF)[2] [3] [4] [5] [6] [7] [8] and for treating venous thromboembolism (VTE)[9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] in most patients and can be used safely and effectively for most such patients, if they meet criteria for durable anticoagulation.[29] However, they may be less effective or safe in specific conditions such as thrombotic antiphospholipid syndrome (APS)[30] [31] [32] [33] [34] [35] and mechanical heart valves,[36] [37] with uncertainties in other conditions, or patients with end-stage renal disease (ESRD).[38] [39] [40] This primer provides a succinct summary about when to use and when to be cautious about DOACs.

Conditions where Direct Oral Anticoagulants are Standard of Care

Current guidelines endorse DOACs for SPAF based on landmark trials.[4] [5] [6] [7] For stable patients with atrial fibrillation who have had acute coronary syndromes or recent percutaneous coronary intervention,[41] [42] [43] [44] [45] [46] a DOAC combined with a single antiplatelet agent like clopidogrel is recommended for the first 12 months.[47] In stable patients with chronic coronary disease (i.e., without percutaneous coronary intervention or acute coronary syndromes in the prior 12 months) who have an indication for anticoagulation, discontinuing antiplatelet therapy and continuing only a DOAC may be considered.[47] [48] [49] [50] DOACs are also reasonable to use in patients with atrial fibrillation and many types of valvular heart disease, including bioprosthetic valves,[51] [52] [53] with the exception of rheumatic heart disease (including moderate to severe mitral stenosis[54] [55]) and mechanical heart valves, which will be discussed subsequently. For VTE, DOACs are recommended for both acute management (after early use of heparin-based regimens, in case of using dabigatran or edoxaban),[9] [10] [11] [12] [13] including in cancer-associated thrombosis (except for dabigatran),[56] [57] [58] [59] [60] [61] [62] [63] and extended secondary prevention.[64] Additionally, in stable atherosclerotic cardiovascular disease[65] or after peripheral artery revascularization,[66] very low-dose rivaroxaban (2.5 mg twice daily) combined with aspirin has been shown to reduce cardiovascular events.

Conditions where Direct Oral Anticoagulants Should be Avoided

These benefits in the majority of patients notwithstanding, results of several recent randomized controlled trials (RCTs) have shown that DOACs may be less efficacious or safe compared with standard of care in scenarios such as mechanical heart valves, rheumatic atrial fibrillation (AF), thrombotic APS, post-transcatheter aortic valve replacement (TAVR) in those without another indication for anticoagulation, and embolic stroke of undetermined source (ESUS) ([Fig. 1]). Among patients with mechanical heart valves (including aortic, mitral and On-X valves), the use of DOACs was associated with a significantly higher risk of thromboembolic events and concern for higher risk of major bleeding compared with warfarin.[36] [37] Current guidelines recommend VKAs as a standard of care in patients with mechanical heart valves.[67] In turn, in patients with rheumatic heart disease and AF, DOACs led to an increased rate of a composite of stroke, systemic embolism, myocardial infarction, or death compared with VKAs, without a significant difference in the rate of major bleeds.[68] Several RCTs investigated the safety and efficacy of DOACs in patients with thrombotic APS compared with VKAs. However, individual results were limited by small samples and few events.[31] [32] [33] [34] [35] A prespecified meta-analysis of results from these RCTs showed that DOACs, compared with VKAs, resulted in a 5-fold excess risk of arterial thrombosis, including a 10-fold excess risk of stroke.[30] The results were consistent among patients with or without triple-positive APS, with or without history of arterial thrombosis, and in female and male patients alike.[30] In a pilot trial of patients with a left ventricular assist device, the use of dabigatran was associated with a higher rate of thromboembolic events.[69] Guidelines accordingly advise the use of VKAs compared with aspirin for all patients with left ventricular assist device.[70] Use of DOACs, compared with dual antiplatelet therapy, among patients in sinus rhythm who undergone TAVR has failed to show ischemic benefit, while in some studies (particularly with rivaroxaban) suggested harm with excess bleeding events and excess in death and thromboembolism.[71] [72] [73] [74] In patients with AF and recent TAVR, the use of edoxaban was noninferior to warfarin for the prevention of cardiovascular events; however, edoxaban was associated with higher risk of major bleeding, largely driven by gastrointestinal bleeds.[71] [75] Overall, in patients post-TAVR and no other indications for oral anticoagulants, existing guidelines recommend dual antiplatelet therapy for 3 to 6 months, followed by single antiplatelet therapy, with emerging evidence suggesting that early antiplatelet monotherapy being an attractive alternative. There is likely a role, however, for DOACs in patients undergoing TAVR who have a preexisting indication for anticoagulants.[75] The existing RCTs in patients with ESUS,[76] [77] [78] [79] including those that enrolled a broad population of patients with ESUS,[76] [77] or those targeted patients with predictive risk factors for AF,[78] or atrial cardiopathy defined as P-wave terminal force >5,000 µV.msecond⁻¹ in electrocardiogram lead V₁, serum N-terminal pro-B-type natriuretic peptide level >250 pg/mL, or left atrial diameter index ≥3 cm/m² on echocardiogram,[79] there has been no demonstrable benefit for DOACs compared with antiplatelet monotherapy. While future studies may identify a small subgroup that benefits from anticoagulation, the current best evidence is not supportive of their routine use.[80]

Fig. 1 Considerations of DOACs use across a spectrum of conditions and subgroups. *Other indications where DOACs should not be used include patients with TAVR and in sinus rhythm as well as patients with ESUS. ^†Apixaban has high levels in breast milk, but rivaroxaban and dabigatran have lower levels (see cited illustrated review for details[104]). ^‡In the absence of conditions summarized in the red zone and cautioning in the orange zone. ACHD, adult congenital heart disease; AF, atrial fibrillation; APS, antiphospholipid syndrome; CVST, central venous sinus thrombosis; DOACs, direct oral anticoagulants; DVT, deep vein thrombosis; ESRD, end-stage renal disease; ESUS, embolic stroke of undetermined source; LV, left ventricular; LVAD, left ventricular assist device; SPAF, stroke prevention in atrial fibrillation; TAVR, transcatheter aortic valve replacement; VTE, venous thromboembolism.

Uncertainties around Direct Oral Anticoagulants Use

Additionally, there are several indications and subgroups where the efficacy and safety of DOACs are uncertain.[81] [82] Recently, two large, randomized trials compared the role apixaban versus aspirin,[83] and edoxaban versus placebo,[84] in patients with atrial high rate episodes (also known as subclinical AF, lasting 6 minutes to 24 hours) detected by implantable cardiac monitors such as pacemakers. Results from both studies were directionally similar and reached significance for the apixaban trial,[83] and the pooled analysis of the two trials[85] for the reduction of the risk of ischemic stroke. However, the absolute event rates were low, precluding a practical use of DOACs in unselected patients. Ongoing studies from these trials can better inform practice about subgroups who may benefit from anticoagulation in this setting: in a subgroup analysis of the apixaban trial, patients with a CHA₂DS₂-VASc score >4 had a more favorable benefit-to-risk ratio, than those with CHA₂DS₂-VASc score <4.[86] While there has been concern about use of DOACs for preventing and treating left ventricular thrombus,[35] emerging data from multiple randomized trials,[87] [88] [89] [90] including the recently completed REWARF-STEMI trial and a resultant pooled analysis[91] [92] indicate that DOACs may be reasonable in this situation, until further data emerge. In a recent RCT comparing edoxaban versus warfarin in patients with chronic thromboembolic pulmonary hypertension who had undergone reperfusion treatment, edoxaban met criteria for noninferiority for a primary outcome of preventing worsening of pulmonary hemodynamics, and rates of recurrent VTE were not significantly different between both arms, although additional confirmatory data with other DOACs can further strengthen the evidence base.[93] Emerging evidence on DOACs use for cerebral venous sinus thrombosis suggest that their use may be reasonable: in a meta-analysis of randomized trials comparing DOACs (dabigatran and rivaroxaban) with VKAs for cerebral venous sinus thrombosis, there were similar rates of recurrent VTE, all-cause death, and recanalization in both groups.[94] [95] [96] [97] Several published and ongoing trials have investigated the use of DOACs for catheter-associated deep vein thrombosis[98] and splanchnic vein thrombosis,[99] but definitive evidence is lacking.

Pivotal RCTs for VTE management and SPAF have excluded patients with advanced renal disease or ESRD: limited data have shown that apixaban did not confer benefit, whereas dose-reduced rivaroxaban had hypothesis-generating impressive results in patients with AF and on dialysis.[38] [39] [40] The safety and efficacy of DOACs remain poorly studied among patients with a body mass index >45 kg/m², those weighing >150 kg, and those postbariatric surgery.[100] DOACs are also contraindicated in patients with advanced liver disease (Child-Pugh stage C), because of their partial hepatic clearance.[100] [101] In addition, the very elderly (patients older than 80 years) are underrepresented in most clinical trials of DOACs[103]—much like many other disease conditions. Recent evidence suggests that switching from VKAs to DOACs in patients with AF ≥ 75 years old who were stable on VKAs increased the risk of major bleeding compared with continuing with VKAs, without conferring additional benefits.[55] [104]

Similarly, given the limited data and concern for DOACs crossing the placenta, their use should be avoided in pregnancy. During breastfeeding, apixaban should be avoided, since it will have high levels in breast milk. While rivaroxaban and dabigatran are generally not advisable, they may have lower breast milk levels.[105]

Updates from the Major Guidelines in 2024

There are not currently any all-encompassing guidelines on the use of DOACs versus alternative treatment options in various conditions such as AF and VTE. The European Society of Cardiology recently published guidelines for the diagnosis and management of atrial fibrillation, recommending their use over VKAs for stroke prevention in AF, as well as in patients with AF and recent acute coronary syndrome or percutaneous intervention, and patients with AF and chronic coronary disease;[55] key exceptions include mechanical heart valves and rheumatic AF. They also include a IIb recommendation for considering DOACs in patients with subclinical AF and elevated thromboembolic risk, excluding patients at high risk of bleeding.[55] The European Society of Cardiology also recently released guidelines on the management of patients with peripheral arterial disease, where they suggest the use of very low-dose rivaroxaban (2.5 mg twice daily) with aspirin 75 to 100 mg daily for patients with chronic symptomatic peripheral arterial disease with or without revascularization,[106] recommendations shared as well by the American College of Cardiology/American Heart Association recent guide on the management of peripheral artery disease.[107]

In conclusion, DOACs are the cornerstone of therapy for SPAF and VTE prevention and treatment; however, they should be avoided in conditions such as thrombotic APS, mechanical heart valves, and rheumatic AF. Further research is needed to elucidate the potential mechanisms underlying their variable efficacy and safety in these scenarios and to find efficacious and safe treatment options for understudied populations such as those with cerebral vein thrombosis, splanchnic vein thrombosis, chronic thromboembolic pulmonary hypertension, and particularly those with cirrhosis,[108] advanced kidney disease[109] and ESRD.

Conflict of Interest

B.B. was supported by the Scott Schoen and Nancy Adams IGNITE Award and is supported by the Mary Ann Tynan Research Scientist award from the Mary Horrigan Connors Center for Women's Health and Gender Biology at Brigham and Women's Hospital, and the Heart and Vascular Center Junior Faculty Award from Brigham and Women's Hospital. B.B. reports that he was a consulting expert on behalf of the plaintiff for litigation related to two specific brand models of IVC filters. B.B. has not been involved in the litigation in 2022–2024, nor has he received any compensation in 2022–2024. B.B. reports that he is a member of the Medical Advisory Board for the North American Thrombosis Forum and serves in the Data Safety and Monitory Board of the NAIL-IT trial funded by the National Heart, Lung, and Blood Institute and Translational Sciences. B.B. is a collaborating consultant with the International Consulting Associates and the U.S. Food and Drug Administration in a study to generate knowledge about the utilization, predictors, retrieval, and safety of IVC filters. B.B. receives compensation as an Associated Editor for the New England Journal of Medicine Journal Watch Cardiology, as an Associate Editor for Thrombosis Research, and as an Executive Associate Editor for JACC, and is a Section Editor for Thrombosis and Haemostasis (no compensation). A.B. has no disclosures.

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Publication History

Received: 14 September 2024

Accepted: 24 October 2024

Article published online:
18 November 2024