Will heparin eventually be phased out with expanded use of DOACs for VTE?
Unfractionated heparin has been in use as an anticoagulant for nearly a century and LMWH for more than 3 decades. Over the last decade, we have seen an explosion in alternatives to heparin analogues, and now it appears that a heparin-free future is not inconceivable. As we continue our quest for the ideal anticoagulant, emerging safety and efficacy data make a compelling case for DOACs to replace heparins for many indications, not only because DOACs can be orally administered in fixed doses, but also because they have a rapid onset of action, predictable therapeutic effect, and limited food and drug interactions. Also, they do not require monitoring and are affordable.
Over the years, unfractionated heparin has been increasingly replaced with LMWH or other anticoagulants due to concern for the higher immunogenic potential of unfractionated heparin, leading to HIT. McGowan and colleagues showed that an “avoid heparin initiative” reduced incidence of HIT by 63% at a tertiary care hospital in Canada. Similar hospital-wide HIT-prevention strategies have been implemented in other institutions.
DOACs have replaced heparin analogues for thromboprophylaxis in major orthopedic surgeries. Also, DOACs have been shown to be safe and effective and are now the drugs of choice for the initial treatment of thromboembolic disease and for stroke prevention among patients with nonvalvular atrial fibrillation. Most recently, apixaban, edoxaban (Savaysa, Daiichi Sankyo) and rivaroxaban (Xarelto, Janssen) have been shown to be equally efficacious to LMWH for management of cancer-associated VTE. Betrixaban (Bevyxxa, Portola Pharmaceuticals) is approved for prophylaxis of VTE in adult hospitalized patients.
Heparin analogues are still preferred for some patients and indications, but these exceptions are becoming increasingly rare. Direct factor Xa inhibitors have been shown to be safe for patients with obesity or moderate renal failure, and studies are underway in patients with end-stage renal disease. Unfractionated heparin remains the anticoagulant of choice when immediate anticoagulation with the need for quick reversal is required, especially for patients undergoing cardiothoracic surgeries and for patients needing cardiac bypass. However, there is increasing evidence for the IV use of the direct thrombin inhibitors bivalirudin and argatroban for patients with HIT undergoing these procedures.
As we continue to gain experience using nonheparin anticoagulants in complex situations, the use of heparin is certainly going to decline and there may come a time when heparin may be phased out.
McGowan KE, et al. Blood. 2016;doi:10.1182/blood-2015-07-660001.
Usha S. Perepu, MBBS, MRCP, is clinical associate professor of internal medicine at University of Iowa Carver College of Medicine. She can be reached at 200 Hawkins Drive, Iowa City, IA 52242. Disclosure: Perepu reports no relevant financial disclosures.
Despite the expanding role of direct oral anticoagulants, I do not foresee heparin being phased out as treatment for VTE.
Heparin products have a short half-life compared with DOACs allowing for their safe and effective use in the perioperative setting. DOACs are stopped at least 4 to 5 days before high-risk surgeries, which leaves patients at risk for VTE.
Having a short half-life also means that an antidote for reversal in emergency situations is rarely needed. Antidotes for DOACs, meanwhile, are expensive and not readily available.
Most cardiac procedures, such as transcatheter aortic valve replacement and coronary artery bypass grafting, utilize intraoperative heparin. DOACs can’t be used in this setting because of the rapid onset action, long half-life and continuous need for monitoring.
There are limited data on valvular heart disease, so a heparin bridge with coumadin remains the standard choice.
Oral agents are also not feasible for intubated, immediate postoperative patients.
For patients who are critically ill, parenteral treatment with heparin is beneficial because it is easy to monitor.
There have been no prospective trials with DOACs for patients who are pregnant or have antiphospholipid syndrome, cirrhosis or unusual sites of VTE, such as in the splanchnic veins or cerebral veins. Hence, heparin/LMWH and VKA remains standard of care.
DOACs also lack safety and efficacy data on patients with extreme body weights of more than 120 kg or less than 50 kg.
Whether DOACs can be used for the initial management of PE with hemodynamic instability remains controversial. The trial of Hokusai and colleagues showed noninferiority of combination heparin/edoxaban compared with conventional treatment; however, it still utilized heparin. Most trials featuring patients with PE who took DOACs did not include patients with right ventricular dysfunction or unstable hemodynamics.
Except for the RECOVER trial with dabigatran (Pradaxa, Boehringer Ingelheim), no other studies testing DOACs included patients with thrombophilia. Hence, heparin products remain first line for this population.
There has been no prospective trial testing DOACs in patients with chronic kidney disease or who are on dialysis with VTE. Most data on hemodialysis patients are extrapolated from atrial fibrillation studies, and safety and efficacy are not established.
Cancer subgroups have also been underrepresented in DOAC studies, so LMWH remains the drug of choice in this population. This remains true despite a new noninferiority study showing comparable efficacy but with increased bleeding risk.
Lastly, DOACs are an expensive choice for inpatient DVT prophylaxis. Their outpatient use for prophylaxis in patients with high-risk cancer remains investigational.
Raskob GE, et al. New Engl J Med. 2013;doi:10.1056/NEJMoa1306638.
Schulman S, et al. New Engl J Med. 2009;doi:10.1056/NEJMoa0906598.
Rashmi Khanal, MD, is division chief of hematology and oncology at Jeanes Hospital. She can be reached at Fox Chase Cancer Center, Jeanes Physicians Office Building, Suite 110, 7500 Central Ave., Philadelphia, PA 19111. Disclosure: Khanal reports no relevant financial disclosures.