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Rivaroxaban may effectively treat heparin-induced thrombocytopenia
Rivaroxaban effectively treated patients with heparin-induced thrombocytopenia, according to results of a multicenter, single-arm prospective cohort study published in Journal of Thrombosis and Haemostasis.
Further, rivaroxaban (Xarelto, Janssen) could be a safe alternative for patients with a prior history of heparin-induced thrombocytopenia (HIT) who require anticoagulation, according to the researchers.
“The purpose of our study was to determine if rivaroxaban could be used to treat patients suspected or confirmed to have the serious drug allergy, HIT,” Lori-Ann Linkins, MD, MSc, associate professor in the division of hematology and thromboembolism of the department of medicine at McMaster University in Hamilton, Ontario, told HemOnc Today.
HIT is a life- and limb-threatening adverse drug reaction caused by the binding of platelet-activating immunoglobulin G antibodies to platelet factor 4 heparin complexes on the surface of platelets triggered by exposure to heparin.
Currently, the approved nonheparin anticoagulants to treat HIT are parenteral, costly and require laboratory coagulation monitoring.
Researchers sought to prove that rivaroxaban is an ideal potential alternative to nonheparin anticoagulants, such as fondaparinux, because it is administered orally by fixed dosing, requires no routine coagulation monitoring, and has been proven to be effective in the treatment of venous and arterial thromboembolism in other settings.
The analysis included 22 adults with suspected or confirmed HIT who received rivaroxaban (15 mg twice daily) until results of local HIT assay were available. The 12 participants with HIT–positive assay results continued rivaroxaban at the same dosage until platelet recovery — or until day 21 if the patient had acute thrombosis at baseline — then stepped down to 20 mg per day until day 30. Patients with negative assay results discontinued treatment.
The incidence of new symptomatic, objectively confirmed venous and arterial thromboembolism at 30 days served as the primary outcome measure.
Researchers reported platelet recovery in nine out of 10 HITpositive patients with thrombocytopenia, with a median recovery of 7 days. The participant who did not achieve platelet recovery had received only two doses of rivaroxaban before it was discontinued due to a transient rise in liver enzymes. That patient developed a major gastrointestinal bleed 9 days after rivaroxaban was held, from a known gastric tumor while receiving fondaparinux.
One HIT–positive patient had symptomatic recurrent VTE (4.5%; 95% CI, 0-23.5). Another HIT–positive patient achieved platelet recovery but still required limb amputation.
The thrombotic event rate in HIT–positive patients was 8.3% (95% CI, 0.1-37.5).
None of the 10 HIT–negative participants had a thrombotic or major bleeding event during the study.
Linkins and colleagues noted that because rivaroxaban does not appear to produce or enhance HIT antibody formation, patients with a prior history of HIT who require anticoagulation may also benefit from its use.
“We were pleasantly surprised to see that rivaroxaban was effective even in severe cases of HIT,” Linkins said. “We were excited by this finding because rivaroxaban has distinct advantages over the drugs currently used to treat HIT because it can be given orally, without monitoring of drug levels and is comparatively inexpensive.”
The primary limitation of the study was its size; the study was terminated early due to poor recruitment. Researchers noted enrollment was poor because of low frequency of HIT, difficulty identifying patients with suspected HIT, and failure to meet study enrollment criteria, specifically the 4Ts score and creatinine clearance requirements.
“Ideally, the next step would be a randomized controlled trial comparing rivaroxaban to argatroban — approved for HIT — or fondaparinux, not approved for HIT,” Linkins said. “However, due to feasibility issues, such a trial may never be conducted.” – by Chuck Gormley
For more information:
Lori-Anne Linkins , MD, MSc , can be reached at linkinla@mcmaster.ca.
Disclosure: Linkins reports lecture honoraria from Bayer and Pfizer Canada. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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A. Koneti Rao
Heparin-induced thrombocytopenia (HIT) is associated with major complications, including life- and limb-threatening thrombosis. An estimated 30% to 50% of patients with HIT not treated with a non-heparin alternative anticoagulant develop a thrombotic event — either venous or arterial. It is a self-limiting immune disorder caused by platelet-activating immunoglobulin G antibodies that develop on heparin exposure. These antibodies bind to a complex consisting of platelet factor 4 — a protein in platelet alpha granules — and heparin on platelets. HIT is associated with one of the most intense hypercoagulable states resulting from activation of platelets, the coagulation system, monocytes and endothelial cells, and intense thrombin generation.
The treatment of HIT involves discontinuing heparin and replacing it with a non-heparin anticoagulant. Two drugs, argatroban and bivalirudin, are approved in the United States for this purpose. Both need to be administered intravenously. Another agent, fondaparinux (GlaxoSmithKline), administered by the subcutaneous route, is gaining increasing use in acute HIT, with accumulating evidence of being effective and safe in this context. However, it is not approved in the United States for the treatment of HIT. Warfarin is contraindicated in acute HIT because of the association with the devastating complication of venous limb gangrene and attendant risk for limb loss.
Thus, major treatment revolves around the usage of intravenously administered agents, argatroban and bivalirudin, which require monitoring with coagulation tests and substantial expense. Therefore, the availability of an oral agent that does not require monitoring would be a huge step forward in the management of this complex and difficult disease, encumbered with high mortality and morbidity. This is where the studies published by Linkins and colleagues may become a game changer in the management of HIT.
Linkins and colleagues reported results of a multicenter, single-arm, prospective cohort study designed to evaluate the safety and efficacy of oral rivaroxaban (Xarelto, Janssen), an oral Factor Xa inhibitor, for the treatment of HIT. Researchers studied 22 consecutive adults with suspected or confirmed HIT who received rivaroxaban 15 mg twice daily until the local results of a HIT assay were available. Those with a positive assay result continued rivaroxaban 15 mg twice daily until platelet recovery, or until day 21 if they had acute thrombosis at study entry. Rivaroxaban dose then was switched to 20 mg daily until day 30.
Initial plans were to study 200 patients, but the study was terminated early after 22 patients because of difficulty in recruitment. The primary outcome measure was incidence of new symptomatic, objectively confirmed venous and arterial thromboembolism at 30 days.
Of the 22 patients enrolled, 12 patients were HIT positive, with a mean serotonin release of 95%. Six of them had thrombosis at entry. Platelet recovery was achieved in nine of 10 HIT–positive patients with thrombocytopenia. The primary outcome measure — a new objectively confirmed venous or arterial thrombotic event at 30 days — occurred in one person (4.5%; 95% CI, 0-23.5), an extension of an upper-extremity thrombosis in a vein that had been vascular access. One HIT–positive patient required limb amputation. The researchers concluded that rivaroxaban was effective for treating patients with confirmed HIT.
This is a small but important and carefully conducted study. It was the first prospective study of rivaroxaban in well-characterized patients with HIT, half of whom had thrombosis at enrollment and many of whom had other complicating comorbidities, including malignancy. It extends the information from several small case reports on the use of rivaroxaban for HIT. Rivaroxaban is an oral agent with already well-established efficacy in the treatment of venous thromboembolism, and in the prevention of embolic events in patients with atrial fibrillation. No monitoring is needed, which enhances its ease of use, as well as the cost benefit. The small numbers of patients is a limitation. Larger studies designed to compare it to one of the IV agents would provide the needed evidence to solidify its role in HIT, but they are unlikely to be on the horizon any time soon. The study by Linkins and colleagues enrolled 22 patients over 2.5 years. As is happening with the off-label use of fondaparinux for treating HIT, rivaroxaban may gain usage on the strength of cumulative observational data over time. When established, rivaroxaban has the potential of having a major impact on treatment approaches for acute HIT.
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Disclosure: Rao reports no relevant financial disclosures.