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Research · Medication

Direct oral anticoagulants (DOACs)

Pooled trials of about 72,000 people with atrial fibrillation found DOACs cut stroke or systemic embolism by 19% and brain bleeds by about half against warfarin, with more stomach bleeding. For leg and lung clots they matched warfarin with less major bleeding. Labels carry boxed warnings on stopping early and spinal hematoma.

Add to Bio HackChecked 2026-11-13
Status
Prescription drugs in the US. All four are FDA-approved to reduce stroke and systemic embolism in nonvalvular atrial fibrillation and to treat deep vein thrombosis and pulmonary embolism. Apixaban, rivaroxaban and dabigatran are also approved to reduce the recurrence of these clots and to prevent them after hip replacement, and apixaban and rivaroxaban after knee replacement. Rivaroxaban is also approved with aspirin in coronary and peripheral artery disease. All four labels carry FDA boxed warnings.
Also called
apixaban, Eliquis, rivaroxaban, Xarelto, dabigatran, Pradaxa, edoxaban, Savaysa, DOAC, NOAC, novel oral anticoagulants, factor Xa inhibitors, direct thrombin inhibitor, blood thinners
Taken for
stroke prevention in atrial fibrillation, blood clots, deep vein thrombosis, pulmonary embolism, preventing clots after hip or knee replacement, replacing warfarin, heart attack and stroke prevention in artery disease

Strong several reviews agree · Moderate one review or consistent trials · Limited one or a few small studies · Untested no study in people, listed with what it rests on

Shown to help6

Reported risks15

What people take it for, and what was found

Shown to help6

Strong

Stroke prevention in atrial fibrillation, against warfarin

Shown to cut stroke or systemic embolism by about 19% and death by about 10% against warfarin in adults with atrial fibrillation.

The numbers and sources
Effect
Across the four pivotal trials, DOACs lowered stroke or systemic embolism by 19% against warfarin (RR 0.81, 95% CI 0.73 to 0.91), mainly through fewer hemorrhagic strokes (RR 0.49, 95% CI 0.38 to 0.64), and lowered death from any cause (RR 0.90, 95% CI 0.85 to 0.95) [1]. In patient-level data from the same trials, stroke or systemic embolism occurred in 3.01% on a standard-dose DOAC against 3.69% on warfarin (HR 0.81, 95% CI 0.74 to 0.89) and death in 7.76% against 8.42% (HR 0.92, 95% CI 0.87 to 0.97) [2]. By trial, the yearly rate of stroke or systemic embolism was 1.11% on dabigatran 150 mg against 1.69% on warfarin [3], 1.7% on rivaroxaban against 2.2% [4], 1.27% on apixaban against 1.60% [5] and 1.18% on high-dose edoxaban against 1.50% [6].
Population
71,683 participants in four trials, 42,411 on a DOAC and 29,272 on warfarin [1][2]; 18,113 patients [3]; 14,264 patients [4]; 18,201 patients [5]; 21,105 patients [6].
Sources
[1], [2], [3], [4], [5], [6]
Caveats
Lower-dose regimens did not lower stroke or systemic embolism against warfarin (HR 1.06, 95% CI 0.95 to 1.19) [2] and were followed by more ischemic strokes (RR 1.28, 95% CI 1.02 to 1.60) [1]. Both meta-analyses pool the same four manufacturer-funded trials. The trials enrolled nonvalvular atrial fibrillation.
Strong

Treating deep vein thrombosis and pulmonary embolism

Shown to prevent repeat clots about as well as warfarin-based treatment in adults with acute venous clots, with about 40% less major bleeding.

The numbers and sources
Effect
Across six phase 3 trials, recurrent venous thromboembolism occurred in 2.0% on a DOAC and 2.2% on a vitamin K antagonist (RR 0.90, 95% CI 0.77 to 1.06), and major bleeding was lower on a DOAC (RR 0.61, 95% CI 0.45 to 0.83) [7]. A Cochrane review of 21 trials found no clear difference in recurrent clots for factor Xa inhibitors (OR 0.85, 95% CI 0.71 to 1.01) or for direct thrombin inhibitors (OR 1.17, 95% CI 0.83 to 1.65) against conventional anticoagulation, with less major bleeding on both (OR 0.63 and 0.58) [8]. With apixaban, recurrent clots or related death occurred in 2.3% against 2.7% on conventional therapy, and major bleeding in 0.6% against 1.8% (RR 0.31, 95% CI 0.17 to 0.55) [9].
Population
27,023 patients in six trials [7]; 30,895 participants in 21 trials [8]; 5,244 patients with acute venous thromboembolism [9].
Sources
[7], [8], [9]
Caveats
The trials were designed to show DOACs were not worse than warfarin-based treatment. No placebo group was used.
ModerateCommon

Preventing repeat clots after the first months of treatment

Shown to cut repeat venous clots to 1.7% against 8.8% on placebo over a year with apixaban, and to 1.2% to 1.5% against 4.4% on aspirin with rivaroxaban.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
After 6 to 12 months of earlier treatment, recurrent venous thromboembolism or related death occurred in 1.7% on apixaban 2.5 mg and 1.7% on 5 mg against 8.8% on placebo, a difference of about 7 percentage points. Major bleeding occurred in 0.2%, 0.1% and 0.5% [10]. With rivaroxaban, recurrence occurred in 1.5% on 20 mg and 1.2% on 10 mg against 4.4% on aspirin (HR 0.34 and 0.26), with major bleeding in 0.5%, 0.4% and 0.3% [11].
Population
2,482 patients who had completed 6 to 12 months of anticoagulation [10]; 3,365 patients with venous thromboembolism treated a median 351 days [11].
Sources
[10], [11]
Caveats
The band above is the absolute difference of about 7 in 100 in the apixaban trial. Both trials were funded by the manufacturers and enrolled people for whom continued treatment was an open question.
Moderate

Preventing clots after hip or knee replacement

Shown to prevent symptomatic clots after hip or knee replacement at least as well as enoxaparin injections, with rivaroxaban lower on clots and higher on bleeding.

The numbers and sources
Effect
Against enoxaparin, the risk of symptomatic venous thromboembolism was lower with rivaroxaban (RR 0.48, 95% CI 0.31 to 0.75) and similar with dabigatran (RR 0.71, 95% CI 0.23 to 2.12) and apixaban (RR 0.82, 95% CI 0.41 to 1.64). Clinically relevant bleeding was higher with rivaroxaban (RR 1.25, 95% CI 1.05 to 1.49), similar with dabigatran (RR 1.12, 95% CI 0.94 to 1.35) and lower with apixaban (RR 0.82, 95% CI 0.69 to 0.98) [12].
Population
38,747 patients in 16 trials [12].
Sources
[12]
Caveats
The treatments did not differ on the net clinical endpoint. Edoxaban was not included [12].
Limited

Stable coronary or peripheral artery disease, low-dose rivaroxaban with aspirin

One trial found cardiovascular death, stroke or heart attack in 4.1% on low-dose rivaroxaban plus aspirin against 5.4% on aspirin alone, with more major bleeding.

The numbers and sources
Effect
The primary outcome occurred in 4.1% on rivaroxaban 2.5 mg twice daily plus aspirin against 5.4% on aspirin alone (HR 0.76, 95% CI 0.66 to 0.86). Major bleeding occurred in 3.1% against 1.9% (HR 1.70, 95% CI 1.40 to 2.05), with no significant difference in intracranial or fatal bleeding. Deaths occurred in 3.4% against 4.1% (HR 0.82, 95% CI 0.71 to 0.96). Rivaroxaban 5 mg twice daily alone did not improve outcomes against aspirin and caused more major bleeding [13].
Population
27,395 participants with stable atherosclerotic vascular disease [13].
Sources
[13]
Caveats
The evidence is for rivaroxaban. The mortality result did not meet the trial's threshold for significance. Funded by the manufacturer [13].
Why limited
This rests on one trial, of 27,395 people. Strength counts independent studies that agree, so one trial is limited at any size.
Limited

Atrial fibrillation when warfarin is unsuitable, against aspirin

One trial found stroke or systemic embolism at 1.6% a year on apixaban against 3.7% on aspirin, with no significant rise in major bleeding.

The numbers and sources
Effect
Stroke or systemic embolism occurred at 1.6% a year on apixaban and 3.7% a year on aspirin (HR 0.45, 95% CI 0.32 to 0.62). Major bleeding occurred at 1.4% a year against 1.2% (HR 1.13, 95% CI 0.74 to 1.75), with 11 and 13 intracranial bleeds. Deaths occurred at 3.5% a year against 4.4% (HR 0.79, 95% CI 0.62 to 1.02) [14].
Population
5,599 patients with atrial fibrillation for whom vitamin K antagonist therapy was unsuitable [14].
Sources
[14]
Caveats
The evidence is for apixaban. The trial was stopped early for benefit [14].
Why limited
This rests on one trial, of 5,599 people. Strength counts independent studies that agree, so one trial is limited at any size.

Mixed results1

Moderate

Differences between the four drugs

Linked to less major and stomach bleeding with apixaban than with rivaroxaban or dabigatran in indirect comparisons and large cohorts. No randomized trial compared the drugs directly.

The numbers and sources
Effect
In a network meta-analysis of 23 trials, major bleeding was higher with dabigatran 150 mg twice daily (OR 1.33, 95% CI 1.09 to 1.62) and rivaroxaban 20 mg (OR 1.45, 95% CI 1.19 to 1.78) than with apixaban 5 mg twice daily. Stroke or systemic embolism was higher with rivaroxaban (OR 1.35) and edoxaban 60 mg (OR 1.33) than with dabigatran 150 mg [15]. In US Medicare patients, rivaroxaban was associated with more major ischemic or hemorrhagic events than apixaban (16.1 against 13.4 per 1,000 person-years, HR 1.18, 95% CI 1.12 to 1.24) [16]. In a multinational cohort, apixaban was associated with less gastrointestinal bleeding than dabigatran (HR 0.81), edoxaban (HR 0.77) or rivaroxaban (HR 0.72, 95% CI 0.66 to 0.79), with similar rates of ischemic stroke, intracranial bleeding and death [17].
Population
94,656 patients in 23 trials [15]; 581,451 Medicare beneficiaries aged 65 or older, mean age 77.0 [16]; 527,226 new DOAC users [17].
Sources
[15], [16], [17]
Caveats
The network meta-analysis compares drugs indirectly through warfarin, and the cohorts are observational, so differences between the people prescribed each drug may remain [17].

Not shown to help1

Moderate

Mechanical heart valves and rheumatic heart disease

Not shown to match warfarin with mechanical heart valves or rheumatic atrial fibrillation: two trials found more strokes, clots or deaths on a DOAC.

The numbers and sources
Effect
A trial of dabigatran in people with mechanical heart valves was stopped after 252 patients. Stroke occurred in 5% on dabigatran and none on warfarin, and major bleeding in 4% against 2% [18]. In rheumatic heart disease with atrial fibrillation, 560 patients on rivaroxaban and 446 on a vitamin K antagonist had a stroke, systemic embolism, heart attack or death, and survival time free of these was 76 days shorter on rivaroxaban (95% CI 31 to 121). Major bleeding did not differ [19]. The dabigatran label lists a mechanical prosthetic heart valve as a contraindication [20].
Population
252 patients with mechanical heart valves [18]; 4,531 patients with rheumatic heart disease and atrial fibrillation, mean age 50.5 [19].
Sources
[18], [19], [20]
Caveats
One trial each for dabigatran and rivaroxaban. The pivotal atrial fibrillation trials did not enroll these groups.

Doses studied

The atrial fibrillation trials used apixaban 5 mg twice daily [5], rivaroxaban 20 mg once daily [4], dabigatran 110 mg or 150 mg twice daily [3] and two once-daily edoxaban regimens [6], which the label gives as 60 mg and 30 mg [21]. Extended clot prevention trials used apixaban 2.5 mg or 5 mg twice daily [10] and rivaroxaban 10 mg or 20 mg once daily [11]. The artery disease trial used rivaroxaban 2.5 mg twice daily with aspirin 100 mg once daily [13].

The labels give lower doses or advise against use at set levels of kidney function, and the apixaban label halves the dose with certain interacting drugs [22][20].

Risks

Reported risks15

LimitedVery common

Indigestion and stomach upset on dabigatran

One trial found gut side effects such as indigestion and gastritis-like symptoms in 35% on dabigatran 150 mg against 24% on warfarin.

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
In the pivotal atrial fibrillation trial, gastrointestinal adverse reactions were reported by 35% on dabigatran 150 mg against 24% on warfarin, commonly dyspepsia and gastritis-like symptoms including reflux, esophagitis and erosive gastritis. Adverse reactions led 21% on dabigatran and 16% on warfarin to stop treatment [20].
Population
18,113 patients with atrial fibrillation [3][20].
Sources
[20], [3]
Caveats
The evidence is for dabigatran, against warfarin.
Why limited
This rests on one trial, of 18,113 people. Strength counts independent studies that agree, so one trial is limited at any size.
LimitedVery common

More clots than warfarin in antiphospholipid syndrome

One small trial found strokes or heart attacks in 12% on rivaroxaban and none on warfarin in high-risk antiphospholipid syndrome, and was stopped early.

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
In people with antiphospholipid syndrome positive on all three antibody tests, thromboembolic events occurred in 7 of 59 on rivaroxaban (12%), 4 ischemic strokes and 3 heart attacks, against none of 61 on warfarin. Major bleeding occurred in 7% against 3% [26]. The rivaroxaban label states that DOACs have been associated with more recurrent thrombotic events than vitamin K antagonists in this group [23].
Population
120 high-risk patients followed a mean 569 days [26].
Sources
[26], [23]
Caveats
A small open-label trial in one high-risk group. The evidence is for rivaroxaban.
LimitedVery common

Frail older adults switched from warfarin

One trial found more bleeding after frail older adults were switched from a vitamin K antagonist to a DOAC, 101 of 662 against 62 of 661.

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
Among frail older adults with atrial fibrillation, a major or clinically relevant nonmajor bleeding complication occurred in 101 of 662 people switched to a DOAC against 62 of 661 who continued a vitamin K antagonist (HR 1.69, 95% CI 1.23 to 2.32). Thromboembolic events did not differ (HR 1.26, 95% CI 0.60 to 2.61). The trial was stopped for futility [27].
Population
1,323 frail patients with atrial fibrillation, mean age 83, already managed on a vitamin K antagonist [27].
Sources
[27]
Caveats
One trial in people already stable on a vitamin K antagonist. It does not describe people starting an anticoagulant for the first time.
Why limited
This rests on one trial, of 1,323 people. Strength counts independent studies that agree, so one trial is limited at any size.
StrongCommon

Major bleeding

Shown to cause major bleeding in about 5% of people with atrial fibrillation over the trials, a rate similar to or below warfarin's 5.9%.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
In patient-level data from four atrial fibrillation trials, major bleeding occurred in 5.05% on a standard-dose DOAC against 5.94% on warfarin (HR 0.86, 95% CI 0.74 to 1.01) and in 4.34% on a lower dose (HR 0.63, 95% CI 0.45 to 0.88) [2]. The yearly rate was 2.13% on apixaban against 3.09% on warfarin [5], 3.11% on dabigatran 150 mg against 3.36% [3] and 2.75% on high-dose edoxaban against 3.43% [6]. On rivaroxaban, major and clinically relevant nonmajor bleeding occurred at 14.9% a year against 14.5% [4]. In venous clot treatment, major bleeding was lower on a DOAC than on a vitamin K antagonist (RR 0.61, 95% CI 0.45 to 0.83) [7].
Population
71,683 participants in four atrial fibrillation trials [2]; 27,023 patients in six venous thromboembolism trials [7].
Sources
[2], [5], [3], [4], [6], [7]
Caveats
The comparator is warfarin, not placebo. The reduction against warfarin was larger at trial centers where warfarin control was poorer [1].
StrongCommon

Stomach and gut bleeding

Shown to raise stomach and gut bleeding by about 25% against warfarin across the class, with the rise seen on rivaroxaban and not on apixaban.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
Across the four atrial fibrillation trials, DOACs increased gastrointestinal bleeding against warfarin (RR 1.25, 95% CI 1.01 to 1.55) [1]. In the rivaroxaban trial, 221 of 7,111 people on rivaroxaban had a gastrointestinal bleed against 140 of 7,125 on warfarin (HR 1.61, 95% CI 1.30 to 1.99) [23]. In the apixaban trial it was 128 of 9,088 against 141 of 9,052 (HR 0.89, 95% CI 0.70 to 1.14) [22]. A network meta-analysis found gastrointestinal bleeding higher with some DOACs than with warfarin [15]. In a cohort of 527,226 users, apixaban was associated with less gastrointestinal bleeding than the other three drugs (HR 0.72 to 0.81) [17].
Population
71,683 participants in four trials [1]; 14,236 people in the rivaroxaban trial [23]; 18,140 in the apixaban trial [22]; 527,226 new users [17].
Sources
[1], [23], [22], [15], [17]
Caveats
The band above is the 3.1% with a gastrointestinal bleed on rivaroxaban in its trial. The comparator is warfarin.
ModerateCommon

Bleeding when taken with NSAIDs, aspirin or other blood thinners

Linked to about 2.4 times the major bleeding when an NSAID was taken alongside an anticoagulant, and to 3.1% against 1.9% when rivaroxaban was added to aspirin.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
Among people treated for venous clots with rivaroxaban or enoxaparin and a vitamin K antagonist, major bleeding occurred at 6.5 per 100 patient-years during NSAID use against 2.0 without (HR 2.37, 95% CI 1.51 to 3.75), and clinically relevant bleeding at 37.5 against 16.6 (HR 1.77). With aspirin, clinically relevant bleeding occurred at 36.6 against 16.9 per 100 patient-years (HR 1.70, 95% CI 1.38 to 2.11). The increases were similar for both anticoagulant regimens [24]. Adding rivaroxaban to aspirin raised major bleeding to 3.1% against 1.9% on aspirin alone [13]. The labels state that aspirin, other antiplatelet drugs, other anticoagulants and chronic NSAID use increase the risk of bleeding [22][23].
Population
8,246 patients in two rivaroxaban venous thromboembolism trials [24]; 27,395 participants with stable vascular disease [13].
Sources
[24], [13], [22], [23]
Caveats
The NSAID analysis is observational within trials and gives rates per patient-years. The band above is the share with major bleeding on rivaroxaban plus aspirin [13].
ModerateCommon

Heart attack on dabigatran

Shown to raise heart attack or acute coronary events on dabigatran, to 1.19% against 0.79% on comparators across seven trials.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
Across seven trials, heart attack or acute coronary syndrome occurred in 237 of 20,000 people on dabigatran (1.19%) against 83 of 10,514 on warfarin, enoxaparin or placebo (0.79%) (OR 1.33, 95% CI 1.03 to 1.71) [25].
Population
30,514 participants in seven trials across atrial fibrillation, venous clots and acute coronary syndrome [25].
Sources
[25]
Caveats
The evidence is for dabigatran. Using revised trial results the estimate was borderline (OR 1.27, 95% CI 1.00 to 1.61). In its atrial fibrillation trial, death rates on dabigatran were not higher than on warfarin [3].
StrongUncommon

Bleeding in the brain

Shown to cause bleeding inside the skull in 0.63% of people with atrial fibrillation over the trials, about half the 1.40% on warfarin.

The numbers and sources
How common
Uncommon: between 1 in 1,000 and 1 in 100 people.
Effect
Intracranial bleeding occurred in 0.63% on a standard-dose DOAC against 1.40% on warfarin (HR 0.45, 95% CI 0.37 to 0.56) and in 0.42% on a lower dose (HR 0.28, 95% CI 0.21 to 0.37) [2]. The trial-level meta-analysis gave a similar result (RR 0.48, 95% CI 0.39 to 0.59) [1]. Hemorrhagic stroke occurred at 0.10% a year on dabigatran 150 mg against 0.38% on warfarin [3] and 0.24% a year on apixaban against 0.47% [5].
Population
71,683 participants in four atrial fibrillation trials [2][1].
Sources
[2], [1], [3], [5]
Caveats
The comparator is warfarin. Against aspirin, intracranial bleeds were 11 on apixaban and 13 on aspirin in one trial [14].
LimitedHow often is not known

FDA boxed warning: stopping early raises the risk of clots and stroke

FDA states that stopping any oral anticoagulant early, without another anticoagulant in its place, increases the risk of thrombotic events.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The boxed warning on all four labels states that premature discontinuation of any oral anticoagulant increases the risk of thrombotic events [22][23][20][21]. The rivaroxaban label reports that an increased rate of stroke was observed during the transition from rivaroxaban to warfarin in atrial fibrillation trials [23].
Population
Boxed warnings in labeling. The stroke observation comes from atrial fibrillation trials of rivaroxaban [23].
Sources
[22], [23], [20], [21]
Caveats
The label sections read here give no rate.
LimitedHow often is not known

FDA boxed warning: bleeding around the spine

FDA states that epidural or spinal hematomas may occur with spinal anesthesia or spinal puncture in people on these drugs, and may cause long-term or permanent paralysis.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The boxed warning on all four labels describes epidural or spinal hematomas in people receiving neuraxial anesthesia or undergoing spinal puncture, which may result in long-term or permanent paralysis. The listed risk factors include indwelling epidural catheters and use of other drugs that affect clotting, such as NSAIDs, platelet inhibitors and other anticoagulants [22][23][20][21].
Population
Boxed warnings in labeling, with no study counts [22][23].
Sources
[22], [23], [20], [21]
Caveats
The labels give no rate.
LimitedHow often is not known

FDA boxed warning on edoxaban: less protection with high kidney clearance

FDA states that people with atrial fibrillation and creatinine clearance above 95 mL/min had more ischemic strokes on edoxaban 60 mg than on warfarin.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
In the pivotal edoxaban trial, the rate of ischemic stroke in people with creatinine clearance above 95 mL/min was higher on edoxaban 60 mg than on warfarin (HR 2.16, 95% CI 1.17 to 3.97). In people with clearance above 50 and up to 80 mL/min the rate was lower on edoxaban (HR 0.63, 95% CI 0.44 to 0.89). The label states that people with high clearance had lower edoxaban blood levels [21].
Population
Subgroups by kidney function within a trial of 21,105 patients [21][6].
Sources
[21], [6]
Caveats
A subgroup finding from one trial. The evidence is for edoxaban.
LimitedHow often is not known

Bleeding with SSRI and SNRI antidepressants

The labels list SSRI and SNRI antidepressants among drugs that increase the risk of bleeding when taken with apixaban or rivaroxaban. They give no rate.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The apixaban label states that drugs affecting hemostasis increase the risk of bleeding, and lists selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors alongside aspirin, other antiplatelet agents, heparin and NSAIDs [22]. The rivaroxaban label carries the same list [23].
Population
Statements in labeling, with no study counts [22][23].
Sources
[22], [23]
Caveats
The labels give no numbers.
LimitedHow often is not known

Medicines that raise or lower DOAC blood levels

The labels warn that ketoconazole, itraconazole and ritonavir raise blood levels of these drugs, and that rifampin, carbamazepine, phenytoin and St. John's wort lower them.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The apixaban label states that combined P-glycoprotein and strong CYP3A4 inhibitors such as ketoconazole, itraconazole and ritonavir increase apixaban blood levels, and that combined inducers reduce them [22]. The rivaroxaban label advises against use with ketoconazole and ritonavir, and with inducers such as carbamazepine, phenytoin, the antibiotic rifampin and St. John's wort [23]. The dabigatran label states that rifampin reduces dabigatran exposure, and that dronedarone or systemic ketoconazole with moderate kidney impairment raises exposure to the level seen in severe kidney impairment [20].
Population
Interaction studies summarized in labeling [22][23][20].
Sources
[22], [23], [20]
Caveats
Changes in blood levels, with no rate of bleeding or clots given.
LimitedHow often is not known

Reduced kidney function

The labels state that reduced kidney function raises blood levels of dabigatran and edoxaban. They give no bleeding rate for this.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The dabigatran label states that P-glycoprotein inhibition and impaired renal function are the major independent factors that increase exposure to dabigatran, and that it cannot give dosing for creatinine clearance of 30 mL/min or below in some uses [20]. The edoxaban label states that the kidneys account for about 50% of edoxaban clearance, and that blood levels are higher with poor kidney function [21].
Population
Pharmacokinetic data summarized in labeling [20][21].
Sources
[20], [21]
Caveats
A change in drug exposure, with no rate of harm given.
LimitedHow often is not known

Pregnancy

The label states that human data are too limited to inform risks in pregnancy, and that treatment may increase bleeding during pregnancy and delivery.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The apixaban label states that limited available data in pregnant women are insufficient to inform drug-associated risks of major birth defects, miscarriage or adverse developmental outcomes, and that treatment may increase the risk of bleeding during pregnancy and delivery. No adverse developmental effects were seen in rats, rabbits and mice [22]. The rivaroxaban label warns of pregnancy-related hemorrhage [23].
Population
Limited human reports and animal studies summarized in labeling [22].
Sources
[22], [23]
Caveats
No controlled study in pregnant women was sourced.

Claims tested and not found

  1. That DOACs cause more brain bleeds than warfarin. Across four trials, intracranial bleeding was about half as frequent on a DOAC (RR 0.48, 95% CI 0.39 to 0.59) [1].
  2. That DOACs cause more major bleeding overall than warfarin. Major bleeding occurred in 5.05% on a standard-dose DOAC and 5.94% on warfarin in atrial fibrillation [2], and was lower on a DOAC in venous clot treatment (RR 0.61) [7].
  3. That a DOAC can replace warfarin for a mechanical heart valve. A dabigatran trial was stopped early with strokes in 5% on dabigatran and none on warfarin [18].
  4. That lower doses protect against stroke as well as warfarin with no trade-off. Lower-dose regimens were followed by more ischemic strokes than warfarin (RR 1.28, 95% CI 1.02 to 1.60) [1].
  5. That rivaroxaban alone outperforms aspirin in stable artery disease. Rivaroxaban 5 mg twice daily alone did not improve cardiovascular outcomes against aspirin and caused more major bleeding [13].
  6. That switching frail older adults from warfarin to a DOAC lowers bleeding. Bleeding complications were more frequent after switching (HR 1.69, 95% CI 1.23 to 2.32) [27].

Sources

  1. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. The Lancet. 2014. https://doi.org/10.1016/S0140-6736(13)62343-0
  2. Carnicelli AP, Hong H, Connolly SJ, et al. Direct Oral Anticoagulants Versus Warfarin in Patients With Atrial Fibrillation: Patient-Level Network Meta-Analyses of Randomized Clinical Trials With Interaction Testing by Age and Sex. Circulation. 2022. https://doi.org/10.1161/CIRCULATIONAHA.121.056355
  3. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. New England Journal of Medicine. 2009. https://doi.org/10.1056/NEJMoa0905561
  4. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. New England Journal of Medicine. 2011. https://doi.org/10.1056/NEJMoa1009638
  5. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. New England Journal of Medicine. 2011. https://doi.org/10.1056/NEJMoa1107039
  6. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. New England Journal of Medicine. 2013. https://doi.org/10.1056/NEJMoa1310907
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