DOAC Uses Rapidly Expand

Dabigatran, apixaban, edoxaban and rivaroxaban all have FDA approval for use to reduce the risk of stroke and blood clots in patients with nonvalvular atrial fibrillation and treatment of deep vein thrombosis and pulmonary embolism. Dabigatran, apixaban and rivaroxaban are also indicated for the prevention of blood clots after hip or knee replacement surgery.

New indications continue to emerge for DOACs.

Hospitalized patients: Betrixaban and, as of mid-October, rivaroxaban are also approved for use in the prevention of VTE in hospitalized acutely ill medical patients at risk for thromboembolic complications who are not at high risk of bleeding. Patients can continue on both for several weeks after discharge.

Cardiovascular events: Rivaroxaban is the only DOAC to date with an indication to reduce the risk of cardiovascular death, myocardial infarction and stroke in patients with coronary artery disease or peripheral artery disease. For this indication, the DOAC must be taken with aspirin. The FDA based its approval on the COMPASS trial, which enrolled 27,395 patients and terminated early because the rivaroxaban/aspirin combination demonstrated superiority at 23 months.¹

“The COMPASS trial was groundbreaking. It was one of the most important cardiology trials of the decade and showed so much benefit,” said Turakhia. “For other drugs to receive the same approval, they would have to do the same kind of trial and I don’t think they are. It’s a huge indication that affects many more people in the VA than atrial fibrillation.”

Dialysis: The use of DOACs in patients with renal impairment has been a matter of ongoing debate. All DOACs are renally cleared to some extent. Dose reductions are recommended when using dabigatran, edoxaban, and rivaroxaban in patients with moderate renal impairment and they should not be used in patients with severe renal impairment or those on dialysis.

Apixaban can be used in patients with end-stage renal disease and patients on dialysis, at a full or reduced dose, according to its package insert. A recent study raised questions about using the full 5 mg dose in these patients and the two prospective studies done to date have had only 15 patients combined.² Two ongoing studies, RENAL-AF and AXADIA, are evaluating the risks and benefits of apixaban and warfarin in these challenging patients.

“So far, the studies are underenrolled,” noted Turakhia. The bigger issue, though, is identifying a real benefit for anticoagulation for patients on dialysis. “They are at risk for so many things, would they live long enough to sustain a benefit from anticoagulation?” he asked.

Recent and ongoing studies have also identified several promising potential indications for DOACs.

Cancer: The Phase 3 ADAM trial determined that apixaban was as safe and 80% more effective than dalteparin in reducing the risk of recurrence of venous thromboembolism associated with cancer.³ The CASSINI study showed a significant reduction in VTE and death in cancer patients initiating systemic treatment during the on treatment period with rivaroxaban, while the AVERT trial found that apixaban significantly reduced the rate of VTE in intermediate-to-high risk ambulatory cancer patients starting chemotherapy.^4,5

LVT: A small retrospective study indicated that patients with left ventricular thrombi had similar rates of systemic embolism as those on warfarin and a meta-analysis of 30 articles found a thrombus resolution success rate in LVT of 81%, 100% and 88.9% for rivaroxaban, apixaban and dabigatran.^6,7

Bleeding following stenting: The ENTRUST-AF PCI trial recently found edoxaban plus a P2Y12 inhibitor (clopidogrel) as effective as the standard triple therapy of a P2Y12 inhibitor plus aspirin and a vitamin K antagonist in preventing bleeding in patients with atrial fibrillation who have undergone coronary stenting.⁸ The results echoed previous trials that determined dual therapy with apixaban, rivaroxaban or dabigatran and a P2Y12 inhibitor reduced bleeding after percutaneous coronary intervention compared to the standard triple therapy with no increase in thromboembolic events.

#Edoxaban is not recommended for atrial fibrillation patients with excellent renal function (creatinine clearance >95 mL/min) as a subgroup analysis indicated it may be less effective than warfarin in these patients.

*Edoxaban and dabigatran are approved for the acute treatment of venous thromboembolism only following five to 10 days of treatment with a parenteral anticoagulant such as low molecular weight heparin, fondaparinux or heparin.

**Rivaroxaban is approved in combination with aspirin for reduction of risk of cardiovascular death, myocardial infarction or stroke in patients with PAD or CAD.

1. Eikelboom JW, Connolly SJ, Bosch J, et al; COMPASS Investigators. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. NEJM. 2017 Oct 5; 377:1319-1330.
2. Mavrakanas TA, Samer CF, Nessim SJ, Frisch G, Lipman ML. Apixaban Pharmacokinetics at Steady State in Hemodialysis Patients. J Am Soc Nephrol. 2017 Jul; 28(7):2241-2248.
3. McBane RD, Wysokinski WE, Le-Rademacher J, et al. Apixaban, dalteparin, in active cancer associated venous thromboembolism, the ADAM VTE trial. Abstract #421. Presented at the 2018 ASH Annual Meeting, Dec 2, 2018; San Diego, CA.
4. Khorana AA, Soff GA, Kakkar AK, et al; CASSINI Investigators. Rivaroxaban for Thromboprophylaxis in High-Risk Ambulatory Patients with Cancer. N Engl J Med. 2019 Feb 21; 380(8):720-728. doi:10.1056/NEJMoa1814630.
5. Carrier M, Abou-Nassar K, Mallick R, et al; AVERT Investigators. Apixaban to Prevent Venous Thromboembolism in Patients with Cancer. N Engl J Med. 2019 Feb 21; 380(8):711-719.
6. Robinson A, Ruth B, Dent J. Direct oral anticoagulants compared to warfarin for left ventricular thrombi: A single center experience. JACC. 2018 Mar; 71(11):S735.
7. Kajy M, Shokr M, Ramappa P. Use of Direct Oral Anticoagulants in the Treatment of Left Ventricular Thrombus: Systematic Review of Current Literature. Am J Ther. 2019 Jan 29.
8. Vranckx P, Valgimigli M, Eckardt L. Edoxaban-based versus vitamin K antagonist-based antithrombotic regimen after successful coronary stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a randomized, open-lable, Phase 3b trial. Lancet. 2019 Oct 12; 394(10206):P1335-1343.