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Dabigatran Etexilate is a brand name for Dabigatran Etexilate. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: 1 INDICATIONS AND USAGE Dabigatran etexilate capsules are a direct thrombin inhibitor indicated: • To reduce the risk of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation ( 1.1 ) • For the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) in adult patients who…
Verbatim from this product's FDA label. Tap a section to expand.
1 Important Dosage Information Dabigatran etexilate is available in different dosage forms and not all dosage forms are approved for the same indications and age groups. In addition, there are differences between the dosage forms with respect to dosing due to differences in bioavailability.
3)] . 2 Recommended Dabigatran Etexilate Capsules Dosage for Adults Indication Dosage Reduction in Risk of Stroke and Systemic Embolism in Non-valvular AF CrCl >30 mL/min: 150 mg twice daily CrCl 15 to 30 mL/min: 75 mg twice daily CrCl <15 mL/min or on dialysis: Dosing recommendations cannot be provided CrCl 30 to 50 mL/min with concomitant use of P-gp inhibitors: Reduce dosage to 75 mg twice daily if given with P-gp inhibitors dronedarone or systemic ketoconazole.
CrCl <30 mL/min with concomitant use of P-gp inhibitors:
Avoid coadministration Treatment of DVT and PE Reduction in the Risk of Recurrence of DVT and PE CrCl >30 mL/min: 150 mg twice daily CrCl ≤30 mL/min or on dialysis: Dosing recommendations cannot be provided CrCl <50 mL/min with concomitant use of P-gp inhibitors: Avoid coadministration Prophylaxis of DVT and PE Following Hip Replacement Surgery CrCl >30 mL/min: 110 mg for first day, then 220 mg once daily CrCl ≤30 mL/min or on dialysis: Dosing recommendations cannot be provided CrCl <50 mL/min with concomitant use of P-gp inhibitors: Avoid coadministration Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation in Adult Patients For patients with creatinine clearance (CrCl) >30 mL/min, the recommended dosage of dabigatran etexilate capsules are 150 mg taken orally, twice daily.
3)]. Dosing recommendations for patients with a CrCl <15 mL/min or on dialysis cannot be provided. Treatment of Deep Venous Thrombosis and Pulmonary Embolism in Adult Patients For patients with CrCl >30 mL/min, the recommended dosage of dabigatran etexilate capsules are 150 mg taken orally, twice daily, after 5 to 10 days of parenteral anticoagulation.
3)]. Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism in Adult Patients For patients with CrCl >30 mL/min, the recommended dosage of dabigatran etexilate capsules are 150 mg taken orally, twice daily after previous treatment.
3)]. Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism in Adult Patients Following Hip Replacement Surgery For patients with CrCl >30 mL/min, the recommended dosage of dabigatran etexilate capsules are 110 mg taken orally 1 to 4 hours after surgery and after hemostasis has been achieved, then 220 mg taken once daily for 28 to 35 days.
2)]. gov/medwatch . 1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
1)] . The numbers of patients and their exposures are described in Table 2. Limited information is presented on the 110 mg dosing arm because this dose is not approved. 3 Total patient-years 10,242 10,261 10,659 Drug Discontinuation in RE-LY The rates of adverse reactions leading to treatment discontinuation were 21% for dabigatran etexilate capsules 150 mg and 16% for warfarin.
, dyspepsia, nausea, upper abdominal pain, gastrointestinal hemorrhage, and diarrhea). 2)] Table 3 shows the number of adjudicated major bleeding events during the treatment period in the RE-LY study, with the bleeding rate per 100 subject-years (%).
Major bleeding is defined as bleeding accompanied by one or more of the following: a decrease in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells, bleeding at a critical site or with a fatal outcome. Intracranial hemorrhage included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds.
Table 3:
Adjudicated Major Bleeding Events in Treated Patients a Event Dabigatran Etexilate Capsules 150 mg N = 6,059 n (%/year b ) Warfarin N = 5,998 n (%/year b ) Dabigatran Etexilate Capsules 150 mg vs. 02) a Patients during treatment or within 2 days of stopping study treatment.
Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. b Annual event rate per 100 pt-years = 100 * number of subjects with event/subject-years.
1 Increased Risk of Thrombotic Events after Premature Discontinuation Premature discontinuation of any oral anticoagulant, including dabigatran etexilate, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events.
8)]. 2 Risk of Bleeding Dabigatran etexilate increases the risk of bleeding and can cause significant and, sometimes, fatal bleeding. , a drop in hemoglobin and/or hematocrit or hypotension). 4)]. , anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs).
2)].
Reversal of Anticoagulant Effect:
In adults, a specific reversal agent (idarucizumab) for dabigatran etexilate is available when reversal of the anticoagulant effect of dabigatran is needed: For emergency surgery/urgent procedures In life-threatening or uncontrolled bleeding In pediatric patients, the efficacy and safety of idarucizumab have not been established.
Hemodialysis can remove dabigatran; however the clinical experience supporting the use of hemodialysis as a treatment for bleeding is limited [see Overdosage (10)] . Prothrombin complex concentrates, or recombinant Factor VIIa may be considered but their use has not been evaluated in clinical trials.
Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of dabigatran. Consider administration of platelet concentrates in cases where thrombocytopenia is present or long-acting antiplatelet drugs have been used.
3 Spinal/Epidural Anesthesia or Puncture When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see Boxed Warning] .
3)] . Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of dabigatran is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.
4)] • Active pathological bleeding ( 4 ) • History of serious hypersensitivity reaction to dabigatran etexilate capsules ( 4 ) • Mechanical prosthetic heart valve ( 4 )
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If dabigatran etexilate capsules is not started on the day of surgery, after hemostasis has been achieved initiate treatment with 220 mg once daily. 3)] . 3 Recommended Dabigatran Etexilate Capsules Dosage for Pediatrics Dabigatran etexilate capsules can be used in pediatric patients aged 8 to less than 18 years of age who are able to swallow the capsules whole.
Other age-appropriate pediatric dosage forms of dabigatran etexilate are available for pediatric patients less than 8 years of age. For the treatment of VTE in pediatric patients, initiate treatment following treatment with a parenteral anticoagulant for at least 5 days.
For reduction in risk of recurrence of VTE, initiate treatment following previous treatment. Dabigatran etexilate capsules are dosed orally twice daily, one dose in the morning and one dose in the evening, at approximately the same time every day.
The dosing interval should be as close to 12 hours as possible. The recommended dosage of dabigatran etexilate capsules for the treatment of or reducing the risk of VTE in pediatric patients 8 to less than 18 years of age is based on the patient’s actual weight as shown in Table 1 below.
Administer dabigatran etexilate capsules twice daily. 5)] . 4 Dosage Adjustments Adult patients with renal impairment Assess renal function prior to initiation of treatment with dabigatran etexilate capsules. , more frequently in clinical situations that may be associated with a decline in renal function) and adjust therapy accordingly.
Discontinue dabigatran etexilate capsules in patients who develop acute renal failure while on dabigatran etexilate and consider alternative anticoagulant therapy. Generally, in adult patients, the extent of anticoagulation does not need to be assessed.
2)] . Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation In patients with moderate renal impairment (CrCl 30 to 50 mL/min), concomitant use of the P-gp inhibitor dronedarone or systemic ketoconazole can be expected to produce dabigatran exposure similar to that observed in severe renal impairment.
3)] . Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism Dosing recommendations for patients with CrCl ≤30 mL/min cannot be provided. 3)] . Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism Following Hip Replacement Surgery Dosing recommendations for patients with CrCl ≤30 mL/min or on dialysis cannot be provided.
3)] . 73 m 2 and the risk of increased exposure, avoid use of dabigatran etexilate capsules in these patients. 413 x height in cm) / serum creatinine in mg/dL. 3)] . 5 Administration Dabigatran etexilate capsules should be swallowed whole.
Dabigatran etexilate capsules should be taken with a full glass of water. 3)] . If a dose of dabigatran etexilate capsules are not taken at the scheduled time, the dose should be taken as soon as possible on the same day; the missed dose should be skipped if it cannot be taken at least 6 hours before the next scheduled dose.
The dose of dabigatran etexilate capsules should not be doubled to make up for a missed dose. Consider administration with food if gastrointestinal distress occurs with dabigatran etexilate capsules. 6 Converting from or to Warfarin When converting patients from warfarin therapy to dabigatran etexilate capsules, discontinue warfarin and start dabigatran etexilate capsules when the INR is below 2.
When converting from dabigatran etexilate capsules to warfarin, adjust the starting time of warfarin as follows: Adults For CrCl ≥50 mL/min, start warfarin 3 days before discontinuing dabigatran etexilate capsules. For CrCl 30 to 50 mL/min, start warfarin 2 days before discontinuing dabigatran etexilate capsules.
For CrCl 15 to 30 mL/min, start warfarin 1 day before discontinuing dabigatran etexilate capsules. For CrCl <15 mL/min, no recommendations can be made. 73 m 2 , start warfarin 3 days before discontinuing dabigatran etexilate capsules.
73 m 2 have not been studied. Avoid use of dabigatran etexilate capsules in these patients. 2)]. , intravenous unfractionated heparin). 3)] . For pediatric patients currently taking dabigatran etexilate capsules, wait 12 hours after the last dose before switching to a parenteral anticoagulant.
8 Discontinuation for Surgery and Other Interventions If possible, discontinue dabigatran etexilate capsules in adults 1 to 2 days (CrCl ≥50 mL/min) or 3 to 5 days (CrCl <50 mL/min) before invasive or surgical procedures because of the increased risk of bleeding.
3)] . 73 m 2 ). 73 m 2 have not been studied, avoid use of dabigatran etexilate capsules in these patients. 2)] . 3)] . Use a specific reversal agent (idarucizumab) in case of emergency surgery or urgent procedures when reversal of the anticoagulant effect of dabigatran is needed in adults.
2)] . Refer to the idarucizumab prescribing information for additional information. Restart dabigatran etexilate capsules as soon as medically appropriate.
25. In case of recurrent events of the same category, the first event was considered. c Defined as bleeding accompanied by one or more of the following: a decrease in hemoglobin of ≥2 g/dL, a transfusion of 2 or more units of packed red blood cells, bleeding at a critical site or with fatal outcome.
d Intracranial bleed included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds. e On-treatment analysis based on the safety population, compared to ITT analysis presented in Section 14 Clinical Studies. f Fatal bleed: Adjudicated major bleed as defined above with investigator reported fatal outcome and adjudicated death with primary cause from bleeding.
g Non-intracranial fatal bleed: Adjudicated major bleed as defined above and adjudicated death with primary cause from bleeding but without symptomatic intracranial bleed based on investigator’s clinical assessment. 2%, respectively).
5) for patients ≥75 years of age.
Figure 1:
Adjudicated Major Bleeding by Baseline Characteristics Including Hemorrhagic Stroke Treated Patients Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified.
The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.
Gastrointestinal Adverse Reactions Patients on dabigatran etexilate capsules 150 mg had an increased incidence of gastrointestinal adverse reactions (35% vs 24% on warfarin). These were commonly dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) and gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, and gastrointestinal ulcer).
1% of patients receiving dabigatran etexilate capsules. Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism Dabigatran etexilate capsules was studied in 4,387 patients in 4 pivotal, parallel, randomized, double-blind trials.
Three of these trials were active-controlled (warfarin) (RE-COVER, RE-COVER II, and RE-MEDY), and one study (RE-SONATE) was placebo-controlled. The demographic characteristics were similar among the 4 pivotal studies and between the treatment groups within these studies.
1 years. 6 mL/min. 24 mmol/L or more, or leading to transfusion of 2 or more units of whole blood or red cells). RE-COVER and RE-COVER II studies compared dabigatran etexilate capsules 150 mg twice daily and warfarin for the treatment of deep vein thrombosis and pulmonary embolism.
Patients received 5 to 10 days of an approved parenteral anticoagulant therapy followed by 6 months, with mean exposure of 164 days, of oral only treatment; warfarin was overlapped with parenteral therapy. Table 4 shows the number of patients experiencing bleeding events in the pooled analysis of RE-COVER and RE-COVER II studies during the full treatment including parenteral and oral only treatment periods after randomization.
79) Note: MBE can belong to more than one criterion. a Patients with at least one MBE. b Bleeding site based on investigator assessment. Patients can have more than one site of bleeding. 4% on warfarin). The RE-MEDY and RE-SONATE studies provided safety information on the use of dabigatran etexilate capsules for the reduction in the risk of recurrence of deep vein thrombosis and pulmonary embolism.
RE-MEDY was an active-controlled study (warfarin) in which 1,430 patients received dabigatran etexilate capsules 150 mg twice daily following 3 to 12 months of oral anticoagulant regimen. Patients in the treatment studies who rolled over into the RE-MEDY study had a combined treatment duration of up to more than 3 years, with mean exposure of 473 days.
Table 5 shows the number of patients experiencing bleeding events in the study. 83) Note: MBE can belong to more than one criterion. a Patients with at least one MBE. b Bleeding site based on investigator assessment. Patients can have more than one site of bleeding.
2% on warfarin). RE-SONATE was a placebo-controlled study in which 684 patients received dabigatran etexilate capsules 150 mg twice daily following 6 to 18 months of oral anticoagulant regimen. Patients in the treatment studies who rolled over into the RE-SONATE study had combined treatment duration up to 9 months, with mean exposure of 165 days.
Table 6 shows the number of patients experiencing bleeding events in the study. 61) Note: MBE can belong to more than one criterion. a Patients with at least one MBE. b Bleeding site based on investigator assessment. Patients can have more than one site of bleeding.
3% on placebo). 17 per 100 patient-years)]. 34 per 100 patient-years)]. 7% on warfarin). 7%, respectively. 1% of patients receiving dabigatran etexilate capsules. Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism Following Hip Replacement Surgery Dabigatran etexilate capsules was studied in 5,476 patients, randomized and treated in two double-blind, active-controlled non-inferiority trials (RE-NOVATE and RE-NOVATE II).
The demographic characteristics were similar across the two studies and between the treatment groups within these studies. 2 years. 3% were black with a mean CrCl of 92 mL/min. 24 mmol/L) or more, or leading to transfusion of 2 or more units of whole blood or red cells, requiring treatment cessation or leading to re-operation.
The RE-NOVATE study compared dabigatran etexilate capsules 75 mg taken orally 1 to 4 hours after surgery followed by 150 mg once daily, dabigatran etexilate capsules 110 mg taken orally 1 to 4 hours after surgery followed by 220 mg once daily and subcutaneous enoxaparin 40 mg once daily initiated the evening before surgery for the prophylaxis of deep vein thrombosis and pulmonary embolism in patients who had undergone hip replacement surgery.
The RE-NOVATE II study compared dabigatran etexilate capsules 110 mg taken orally 1 to 4 hours after surgery followed by 220 mg once daily and subcutaneous enoxaparin 40 mg once daily initiated the evening before surgery for the prophylaxis of deep vein thrombosis and pulmonary embolism in patients who had undergone hip replacement surgery.
In the RE-NOVATE and RE-NOVATE II studies, patients received 28 to 35 days of dabigatran etexilate capsules or enoxaparin with median exposure of 33 days. Tables 7 and 8 show the number of patients experiencing bleeding events in the analysis of RE-NOVATE and RE-NOVATE II.
9% for enoxaparin. 5%, respectively. 1% vs. 6% vs 1%, respectively. 3% of patients receiving dabigatran etexilate capsules 220 mg. 3%) of patients who received enoxaparin. Pediatric Trials Treatment of VTE in Pediatric Patients The safety of dabigatran etexilate capsules in the treatment of VTE in pediatric patients was studied in one phase III trial (DIVERSITY).
The DIVERSITY study was a randomized, open-label, active-controlled, parallel-group trial comparing dabigatran etexilate capsules with standard of care – SOC (vitamin K antagonists, low molecular weight heparin, or fondaparinux). There were 266 pediatric patients who received study treatment, 176 patients treated with dabigatran etexilate capsules and 90 patients treated with SOC.
Patients on dabigatran etexilate capsules received age- and weight-adjusted dosages of an age-appropriate formulation of dabigatran etexilate (capsules, pellets, or oral solution) twice daily. Patients had a median age of 14 years (range: 0 to 17 years), 92% were white, and half the patients were male (50%).
Following at least 5 days of parenteral anticoagulant therapy, the median duration of treatment with dabigatran etexilate capsules was 85 days (range: 1 to 105). 73m 2 were excluded from the trial. Bleeding Data on adjudicated major bleeding, clinically relevant non-major (CRNM) bleeding and minor bleeding events, for the dabigatran etexilate group and the SOC group in the DIVERSITY study, are reported in Table 9.
There was no statistically significant difference in the time to first major bleeding event. 24 mmol/L) or more, or leading to transfusion of 2 or more units of whole blood or red cells. 8% in SOC arm). Gastrointestinal Adverse Reactions The incidence of gastrointestinal adverse reactions for patients on dabigatran etexilate capsules and SOC was 32% and 12%, respectively, with the following occurring in ≥ 5% of patients taking dabigatran etexilate capsules: dyspepsia (including term gastro-esophageal reflux disease, gastric pH decreased and esophagitis) in 9% (vs 2%), upper abdominal pain in 5% (vs 1%), vomiting in 8% (vs 2%), nausea 5% (vs 4%), and diarrhea 5% (vs 1%).
Reduction in Risk of Recurrence of VTE in Pediatric Patients The safety of dabigatran etexilate capsules in the reduction in the risk of recurrence of VTE in pediatric patients was studied in one open-label single-arm trial (Study 2).
Study 2 enrolled patients who required further anticoagulation due to the presence of a clinical risk factor after completing the initial treatment for confirmed VTE (for at least 3 months) or after completing the DIVERSITY study and received dabigatran etexilate capsules until the clinical risk factor resolved, or up to a maximum of 12 months.
There were 213 pediatric patients treated with dabigatran etexilate capsules, in a similar fashion as in the DIVERSITY trial. Patients had a median age of 14 years (range: 0 to 18 years), 91% were white, and 55% of patients were male.
Patients previously enrolled on DIVERSITY accounted for 43% of patients enrolled on Study 2 (29% from dabigatran etexilate capsules arm and 14% from SOC arm). The median duration of treatment with dabigatran etexilate capsules in Study 2 was 42 weeks (range: 0 to 56 weeks), with 45% of patients completing the 12-month planned duration, 17% stopping due to resolution of VTE risk factors, 12% stopping due to failure to attain target dabigatran concentration and 6% had an adverse event leading to discontinuation.
4%) had a clinically relevant non-major bleeding event, and 44 patients (20%) had a minor bleeding event. 8%). The adverse reaction profile in pediatric patients was generally consistent with that of adult patients. 2 Postmarketing Experience The following adverse reactions have been identified during post approval use of dabigatran etexilate.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and Lymphatic System Disorders :
Agranulocytosis, neutropenia, thrombocytopenia Gastrointestinal Disorders : Esophageal ulcer Immune System Disorders : Angioedema Renal and Urinary Disorders : Anticoagulant-related nephropathy Skin and Subcutaneous Tissue Disorders : Alopecia
Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently to detect any signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), bowel and/or bladder dysfunction.
Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.
4 Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves The safety and efficacy of dabigatran etexilate capsules in adult patients with bileaflet mechanical prosthetic heart valves was evaluated in the RE-ALIGN trial, in which patients with bileaflet mechanical prosthetic heart valves (recently implanted or implanted more than three months prior to enrollment) were randomized to dose adjusted warfarin or 150 mg, 220 mg, or 300 mg of dabigatran etexilate capsules twice a day.
RE-ALIGN was terminated early due to the occurrence of significantly more thromboembolic events (valve thrombosis, stroke, transient ischemic attack, and myocardial infarction) and an excess of major bleeding (predominantly postoperative pericardial effusions requiring intervention for hemodynamic compromise) in the dabigatran etexilate capsules treatment arm as compared to the warfarin treatment arm.
These bleeding and thromboembolic events were seen both in patients who were initiated on dabigatran etexilate capsules post-operatively within three days of mechanical bileaflet valve implantation, as well as in patients whose valves had been implanted more than three months prior to enrollment.
Therefore, the use of dabigatran etexilate is contraindicated in all patients with mechanical prosthetic valves [see Contraindications (4)]. The use of dabigatran etexilate for the prophylaxis of thromboembolic events in patients with atrial fibrillation in the setting of other forms of valvular heart disease, including the presence of a bioprosthetic heart valve, has not been studied and is not recommended.
3)] . 3)]. Concomitant use of P-gp inhibitors in patients with renal impairment is expected to produce increased exposure of dabigatran compared to that seen with either factor alone. Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation in Adult Patients Reduce the dosage of dabigatran etexilate capsules to 75 mg twice daily when dronedarone or systemic ketoconazole is co-administered with dabigatran etexilate capsules in patients with moderate renal impairment (CrCl 30 to 50 mL/min).
6)] . 6)] . 6)] . Treatment and reduction in risk of recurrence of VTE in pediatric patients The concomitant use of dabigatran etexilate capsules with P-gp-inhibitors has not been studied in pediatric patients but may increase exposure to dabigatran.
6 Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome Direct-acting oral anticoagulants (DOACs), including dabigatran etexilate, are not recommended for use in patients with triple-positive antiphospholipid syndrome (APS).
For patients with APS (especially those who are triple-positive [positive for lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.