Anticoagulant approved for heparin complication

 

by ELENA PORTYANSKY BEYZAROV, Pharm.D.

Paradoxical would be one way to describe a rare phenomenon known as heparin-induced thrombocytopenia (HIT). Clinically diagnosed by a 50% reduction in platelet count, the devastating complication arises from drug-related antibodies and can result in the development of life-threatening arterial thrombosis, which may lead to pulmonary embolism, acute myocardial infarction, strokes, limb amputation, and death. Ironically, HIT is caused by heparin, the drug most frequently used to prevent clots in the first place.

Diagnoses can be challenging because of factors such as similarities between the symptoms of HIT and other syndromes, limitations of existing laboratory assays, and the unexpected presentation of clotting instead of bleeding.

Management of HIT is further complicated by the scarcity of available treatments. Refludan (lepirudin) was the only Food & Drug Administration-approved anticoagulant for use in HIT until the recent introduction of argatroban. Manufactured by SmithKline Beecham, argatroban is a selective thrombin inhibitor indicated for both prevention and treatment of thrombosis associated with HIT.

The agent, part of a class of drugs that includes hirudin and modifications of hirudin, acts on the thrombin molecule to prevent it from converting fibrinogen to the clot-forming substance fibrin, noted Jeffrey Dubb, M.D., group director of the cardiopulmonary therapeutic unit at SmithKline Beecham. "Because it is a synthetic molecule bearing no resemblance to heparin, argatroban does not form neutralizing antibodies to itself or cross-react with heparin antibodies that cause HIT," he added.

In distinguishing argatroban from lepirudin, Dubb said he believes the "new product is different because physicians do not need to adjust the doses for patients with renal failure. This is important as patients with renal failure or renal insufficiency are commonly treated with anticoagulation therapy." Approximately 25% of an argatroban dose is known to be excreted in the urine.

Argatroban's safety profile and efficacy were demonstrated in studies involving HIT patients, presenting either with or without thrombosis. According to results, the composite endpoint of death, amputation, or new thrombosis occurred in 34% of argatroban-treated patients, compared with 43% of the historical controls. Argatroban therapy provided a 21% relative reduction in the risk of death, amputation, or new thrombosis and delayed the onset of these events.

Bleeding is the most common adverse effect associated with anticoagulation therapy. Major bleeding events observed with argatroban-treated patients included gastrointestinal and genitourinary bleeding. The product is contraindicated in patients with overt major bleeding.

So how can argatroban fit into the treatment strategy for HIT? "Since the turnaround time for HIT assays is often long, physicians usually stop treatment with heparin once there is a suspicion of HIT. However, since half of the patients who have the symptoms of HIT are at risk for a thrombotic event 30 days after the cessation of heparin, physicians should immediately provide their patients with an anticoagulant such as argatroban. After one to two days of treatment, patients can then be switched to long-term anticoagulation treatment with warfarin, until they are stabilized," explained Dubb.

 

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