Review: When Direct Oral Anticoagulants Should Not Be Standard Treatment

Direct oral anticoagulants (DOACs—apixaban, dabigatran, edoxaban, and rivaroxaban) are now preferred to vitamin K antagonists (VKAs) in several indications: for stroke prevention in atrial fibrillation and acute treatment and extended-duration secondary prevention of venous thromboembolism (VTE) in most patients.

However, several recent randomized controlled trials (RCTs) have shown DOACs may be less efficacious or safe or not confer net benefit compared with standard of care in a number of other conditions. These are described in a JACC State-of-the-Art Review by Behnood Bikdeli, MD, MS, of the Thrombosis Research Group and Division of Cardiovascular Medicine at Brigham and Women’s Hospital, Antoine Bejjani, MD, and Candrika D. Khairani, MD, MMSc, former fellows in the Research Group, and colleagues.

Mechanical Heart Valves

In patients with mechanical aortic or mitral valves, recent RCTs show that DOACs are less efficacious than warfarin and should be avoided except in future clinical trials. This is consistent with prior American College of Cardiology/American Heart Association (ACC/AHA) guidelines that recommend VKAs as the standard of care in such patients.

Rheumatic Atrial Fibrillation (AF)

Results from recent RCTs, including INVICTUS, indicate that DOACs are less efficacious than VKAs for these patients. The ACC/AHA and European Society of Cardiology recommend VKAs for stroke prevention in patients with rheumatic AF.

Thrombotic Antiphospholipid Syndrome (APS)

In a meta-analysis of randomized controlled trials (n=472 patients) published in JACC, the odds of myocardial infarction, stroke, and major acute limb events were higher in patients with thrombotic APS who were assigned to DOACs than those on warfarin, primarily driven by an excess risk of stroke (OR, 10.74). This occurred irrespective of whether the initial thrombotic event was a VTE or arterial thrombosis.

DOACs should not be used as first-line therapy in patients with thrombotic APS because of this significantly increased risk of arterial thrombosis. For patients with a history of VTE and thrombotic APS, EULAR guidelines recommend long-term VKA treatment.

Transcatheter Aortic Valve Replacement (TAVR)

The potential use of DOACs for preventing thromboembolic events after TAVR has been extensively studied, and DOACs do not seem to benefit patients in sinus rhythm. There are no trial data about apixaban, dabigatran, or rivaroxaban for patients with AF undergoing TAVR.

For patients post-TAVR with no other indications for oral anticoagulants, ACC/AHA guidelines advise aspirin combined with clopidogrel for three to six months, followed by aspirin alone. Emerging evidence suggests single antiplatelet therapy may be reasonable in many patients.

Embolic Stroke of Undetermined Source (ESUS)

DOACs do not offer significant benefits over aspirin for patients with ESUS and have been associated with an increased risk of bleeding. Accordingly, joint guidelines from the AHA and American Stroke Association do not recommend oral anticoagulation for patients with ESUS.

Left Ventricular Assist Device (LVAD)

A trial published in Circulation: Heart Failure investigated the safety and efficacy of dabigatran plus aspirin compared with phenprocoumon plus aspirin for the prevention of thromboembolism in 16 patients with an LVAD. The trial was stopped early because of a higher rate of thromboembolic events in the dabigatran arm.

The International Society for Heart and Lung Transplantation and the Heart Failure Association of the European Society of Cardiology advise using VKAs combined with low-dose aspirin for all patients with an LVAD.

Heart Failure With Reduced Left Ventricular Systolic Function Without AF

Routine use of anticoagulation is not recommended in this setting. In a trial published in NEJM, rivaroxaban reduced the rate of stroke compared with placebo but did not significantly reduce the rate of a composite of death from any cause, myocardial infarction, or stroke. Moreover, patients taking rivaroxaban had a higher rate of major bleeding (HR, 1.68).

Areas of Uncertainty

The safety and efficacy of DOACs are still uncertain in some conditions and patient subgroups. The paper reviews the limited evidence about:

  • Left ventricular thrombus
  • Catheter-associated deep vein thrombosis
  • Splanchnic vein thrombosis
  • Cerebral venous sinus thrombosis
  • End-stage renal disease
  • Adult congenital heart disease
  • Chronic thromboembolic pulmonary hypertension
  • Pregnant and breastfeeding individuals: DOACs should be generally avoided in pregnancy and their safety remains uncertain during breastfeeding
  • Individuals with body mass index >45 kg/m2 or post-bariatric surgery
  • Heparin-induced thrombocytopenia and thrombosis

The recommendations in this paper are based on evidence review and consensus among international experts. However, they are not the result of a formal clinical practice guideline process and are not meant to substitute for a clinical practice guideline by any professional society.

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