Arterial Thrombotic Events a Hazard With Off-Label Use of Factor VIIa

November 04, 2010

November 4, 2010 (Amsterdam, the Netherlands) — Use of recombinant activated factor VII (rFVIIa) (NovoSeven, Novo Nordisk) on an off-label basis significantly increases the risk of arterial thromboembolic events, especially among the elderly, a new report shows [1].

The analysis of data from 35 randomized placebo-controlled trials, published in the November 4, 2010 issue of the New England Journal of Medicine, was conducted by a team led by Dr Marcel Levi (Academic Medical Center, Amsterdam, the Netherlands).

They explain that rFVIIa is approved for the treatment of bleeding in patients with hemophilia A or B who have inhibiting antibodies to coagulation factor VIII or IX and for the treatment/prevention of bleeding related to surgical or invasive procedures in patients with congenital and acquired hemophilia, factor VII deficiency, or Glanzmann's thrombasthenia. But it is also used off label in preventing or treating severe or life-threatening bleeding in patients with other clinical conditions.

They point out that the primary concern surrounding the use of rFVIIa is its potential as a hemostatic agent to induce thromboembolic events. As it acts by generation of thrombin on thrombin-activated platelets, it is theoretically localized to the site of vessel-wall injury, but systemic activation of coagulation may still occur.

To look into this risk, Levi and colleagues analyzed rates of thromboembolic events in 35 placebo-controlled trials of off-label indications for rFVIIa, all of which involved using the product for the treatment or prevention of bleeding.

Results showed that of the 4468 subjects included, 498 had thromboembolic events (11.1%). Rates of arterial thromboembolic events and coronary arterial events were higher among those who received rFVIIa than those who received placebo, but rates of venous thromboembolic events were similar among rFVIIa and placebo patients. Rates of arterial thromboembolic events were particularly high in elderly patients who received rFVIIa.

Incidence of Thromboembolic Events With Off Label Use of RFVIIa in Placebo-Controlled Trials

Outcome rFVIIa (%) Placebo (%) p
Arterial thromboembolic event 5.5 3.2 0.003
Venous thromboembolic event 5.3 5.7 NS
Coronary arterial thromboembolic event 2.9 1.1 0.002
Arterial thromboembolic event in patients >65 y 9.0 3.8 0.003
Arterial thromboembolic event in patients >75 y 10.8X 4.1X 0.02X

The authors emphasize the difference between these results and those seen with the use of rFVIIa in approved indications, where the rate of thromboembolic events is less than 1%. Noting that their data are reliable as they come from placebo-controlled trials, they conclude that the risk/benefit considerations should be evaluated before administering any hemostatic agent.

In an accompanying editorial [2], Dr Louis Aledort (Mount Sinai School of Medicine, New York) says that in patients with bleeding disorders, the challenge is to establish hemostasis without incurring thromboembolic events, but he points out that as studies of an agent in off-label indications have not been evaluated by regulatory agencies, it is difficult to learn about adverse events.

Aledort continues: "The thrombotic sequelae reported here are not inconsequential," and "the risk is particularly notable among older patients." He adds: "This article should serve as a template for pharmaceutical companies to report all studies involving the use of a given drug, on-label and off-label, so that physicians can fully appreciate the benefits and risks when making therapeutic decisions."

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