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
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
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
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
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.
