Cardiology

DOACs for Thrombosis Prevention

Summary:

Over the last decade, direct oral anticoagulants (DOACs) have become the preferred anticoagulant for venous thromboembolism (VTE) prophylaxis, but they are still often under-utilized in clinical care. The 2026 American College of Cardiology report on DOACs provides a comprehensive overview of DOAC usage in the primary and secondary prevention of VTE.

DOACs

Apixaban | edoxaban | rivaroxaban
- Directly inhibit factor Xa in the coagulation cascade
Dabigatran
- Directly inhibits factor IIa (thrombin)
Predictable pharmacokinetic profile allows DOACs to be dispensed at fixed doses without routine monitoring

Primary Prevention of VTE and Stroke

DOAC therapy, oral anticoagulation (OAC) is the preferred medication for VTE and stroke prophylaxis in patients with history of atrial fibrillation and/or VTE.

An important exception is valvular heart disease. In these cases, anticoagulation with warfarin is preferred:

severe rheumatic mitral stenosis
mechanical heart valve in place

Atrial Fibrillation (AF)

AF increases stroke risk by a multiple of 2 to 5; 15 to 20% of all ischemic strokes are due to AF
Life-long OAC is indicated
Multiple risk calculators are available to determine need for primary prophylaxis with anticoagulation therapy:
- CHA₂DS₂-VASc
  - score of ≥2 in men and ≥3 in women
- Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA)
- Global Anticoagulant Registry in the Field-Atrial Fibrillation (GARFIELD-AF)
  - incorporates renal function in the score
HTN is most significant known risk factor for AF
- degree of blood pressure control is an important risk factor for stroke and should be used to determine need for anticoagulation
Unclear if anticoagulation is indicated:
- s/p catheter ablation of AF (recent evidence calls into question previous practice of continuing anticoagulation post ablation)
- subclinical device-detected AF
- atrial myopathy
In high-risk patients with CAD or PAD, who also require anticoagulation, the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial demonstrated benefit to adding low-dose rivaroxaban (2.5mg BID) to aspirin:
- significantly reduces major adverse cardiac events and total mortality
- More effective than aspirin alone or full-dose DOAC alone

Management and Secondary VTE Prevention

DVT and PE

Treatment can be in outpatient setting except for:
- symptomatic PE with elevated clinical severity score
- acute DVT leading to: cardiopulmonary or renal failure | phlegmasia cerulea dolens
DOACs are generally first line:
- non-inferior to warfarin and heparin for preventing VTE recurrence
- better in terms of adverse outcomes, such as intracranial or fatal bleeding
Important exceptions when warfarin is preferred:
- severe renal insufficiency (creatinine clearance <30 mL/min)
- severe liver disease
- antiphospholipid syndrome
- mechanical heart valves
Apixaban is generally preferred over Rivaroxaban
- Less bleeding (3.3%) with apixaban as compared to rivaroxaban (7.1%)
Loading doses are typically different than maintenance doses
Length of DOAC treatment depends on whether DVT/PE is considered provoked or not:
- Unprovoked DVT:
  - 3-6 months of OAC initially
  - Possible life-long OAC based on bleeding risk
- Provoked DVT/PE:
  - Risk factors can be removed: 3 months of treatment
  - Risk factors are ongoing:
    - 3 to 6 months of treatment initially
    - Consider longer-term OAC based on bleeding risk
  - Cancer-associated
    - 6 months of OAC initially
    - Consider life-long OAC
Often DOAC dose can be reduced for long-term maintenance

Acute Stroke

DOAC should be initiated within 4 days for patients with acute ischemic stroke and comorbid AF
If breakthrough stroke while on OAC
- no evidence for changing OAC type
- no benefit to adding antiplatelet therapy
- if relevant, left atrial appendage closure may be beneficial
OAR should typically be reinitiated in cases of intracranial hemorrhage (ICH)
- wait 4 to 8 weeks after ICH occurrence
- carefully balance risk of ischemia vs risk of bleeding

Assessing Bleeding Risk

HAS-BLED (2010) estimates risk of major bleeding based on:
- HTN
- Renal disease
- Liver disease
- Stroke history
- Prior history of major bleeding
- Labile INR
- Age >65
- Concomitant use of aspirin, clopidogrel, NSAIDs
- Alcohol use
HEMORR₂HAGES (2006) estimates risk of hemorrhage based on:
- Uncontrolled HTN
- Hepatic or renal disease
- Alcohol use
- Malignancy history
- Age >75
- Reduced platelet count or function
- History of prior bleeding
- Anemia
- Genetic factors
- Excessive falls
- Stroke history
RIETE (2008) estimates the risk of major bleeding based on:
- Recent major bleeding
- Creatinine >1.2 mg/dL
- Anemia
- Malignancy history
- Clinically-over PE
- Age >75
DOAC (2023) predicts bleeding risk on a DOAC based on:
- Age
- Creatinine clearance
- Liver disease
- Underweight
- History of stroke or TIA
- Diabetes
- HTN
- Antiplatelet use
- NSAID use
- Bleeding history
VTE-BLEED (2017) assess risk of bleeding while on anticoagulation using:
- Age ≥ 60
- Active cancer
- Male with uncontrolled HTN
- Anemia
- History of bleeding
- Renal dysfunction
ATRIA (2011) predicts major hemorrhage with warfarin
GARFIELD-AF (2017) predicts bleeding risk using race, which is no longer considered evidenced-based

Special Considerations

Older Adults

Frailty is not a contraindication to OAC
Studies support OAC in adults >80 years old
Apixaban has shown the most consistent benefit in older adults

Obesity

DOACs might have preferred outcomes over warfarin
BMI <40 kg/m²
- any DOAC is okay
BMI ≥40 kg/m²
- rivaroxaban or apixaban are preferred
- dabigatran and edoxaban are not recommended due to insufficient data
History of bariatric surgery
- consider use of warfarin due to possibility of impaired DOAC absorption and insufficient evidence to monitor effectiveness with lab studies

High Bleeding Risk

Many studies show net clinical benefit of DOACs for stroke prevention even in patients at high risk of bleeding.
As compared to warfarin:
- Lower risk of intracranial hemorrhage (ICH)
- Apixaban and low-dose dabigatran (110mg twice daily) have less risk of GI bleeding
After a bleeding event, review the following before restarting OAC:
- Bleeding location
- Bleeding severity
- Patient characteristics
In cases of GI bleed, ok to resume OAC after 7 to 14 days.
Okay to stop OAC if:
- Low stroke risk
- VTE history is remote
- Remote history of bioprosthetic heart valve replacement

History of Cancer

VTE in a frequent complication of cancer but routine thomboprophylaxis is not recommended
Prophylactic OAC or LMWH might be indicated in select cases
A personalized strategy should be developed for each patient

Monitoring and Follow-up

Nonadherence rates might be as high as 30%
Cost of OACs is a significant barrier
Unlike Warfarin, which can be monitored via INR, there is no equivalent blood test to monitor adherence or bleeding risk on OAC
Patients receiving DOAC therapy should undergo periodic monitoring of renal and hepatic function | concomitant medications | bleeding risk:
- One study supports monitoring the HAS-BLED score 4 times a year to reduce bleeding risk
OAC should be discontinued is major bleeding occurs:
- Severe bleeding that requires blood transfusion
- Bleeding into a critical closed space (intracranial | intraocular | retroperitoneal | compartment syndrome)
- Bleeding requiring invasive ablation: surgery | endoscopy | interventional radiology
Proton pump inhibitors can protect against bleeding risk for all OACs
Possibly some increased risk of bleeding with co-prescription of diltiazem
Reversal of factor Xa inhibitors can be achieved with:
- 4-factor prothrombin complex concentrate (4F-PCC)
- Activated PCC
- Idarucizumab can be used for dabigatran-associated ICH