Risk of VTE recurrence higher for patients with nonsurgical risk factors

May 12, 2011

A roundup of reports on risk of recurrent venous thromboembolism; direct factor Xa inhibitors; and managing clopidogrel hypersensitivity.

A patient with a first episode of symptomatic venous thromboembolism (VTE) provoked by a transient risk factor (TRF) usually receives anticoagulation for 3 months. Recurrence risk after end of anticoagulation is low but poorly characterized by specific risk factor (e.g., surgery, pregnancy, oral contraceptive use, air or auto travel, trauma- or illness-related immobility).

In a recent meta-analysis, researchers examined 11 prospective cohort studies or randomized controlled trials that followed patients for 24 months after anticoagulant therapy ended (2,268 patients; 150 recurrent VTEs). The rates of VTE recurrence when first episodes were provoked by surgery or by nonsurgical TRFs, or were unprovoked were 0.7%, 4.2%, and 7.4% per patient-year, respectively. These results raise questions about how long to anticoagulate patients who have nonsurgical TRFs, as well as questions relative to risk differences in the class of nonsurgical provoking factors (e.g., estrogen therapy vs. serious medical illness). More data are needed to further define length of therapy in patients with TRFs unrelated to surgery.

Source: Iorio A, Kearon C, Filippucci E, et al. Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: A systematic review. Arch Intern Med. 2010;170:1710-1716.

Direct factor Xa inhibitors show promise

Recently released data on new oral direct factor Xa inhibitors rivaroxaban and apixaban show efficacy for patients with VTE and atrial fibrillation. In the EINSTEIN-DVT, 1,731 patients with acute symptomatic deep vein thrombosis (DVT) received oral rivaroxaban 15 mg twice daily for 3 weeks, followed by 20 mg daily, and 1,718 patients received enoxaparin for at least 5 days, transitioning to a vitamin K antagonist (warfarin or acenocoumarol; INR 2.0-3.0). Patients were treated for 3, 6, or 12 months. An extension study of patients completing 6 to 12 months of treatment for DVT, randomized patients to either rivaroxaban (n=602) or placebo (n=594) for 6 or 12 months. Rivaroxaban was shown to be noninferior (36 vs. 51 events) to standard of care (enoxaparin/vitamin K antagonist) with similar rates of bleeding (8.1%). In the extension study, rivaroxaban was shown to be superior to placebo, but with a higher incidence of bleeding.

In the ADVANCE-2 and -3 trials, apixaban 2.5 mg twice daily was compared with enoxaparin 40 mg once daily in patients who had undergone knee- or hip-replacement surgery, respectively. Study medications were given for 10 to 14 days postoperatively in knee patients and 32 to 38 days for hip-replacement patients. A pooled analysis of the 2 phase 3 trials showed more than double the number of major VTE events in the enoxaparin group compared to apixaban (51 vs. 23). Bleeding events were similar.

These studies are an important step toward availability of anticoagulant drugs that require no monitoring and have no dietary interactions. Both are given at fixed doses. These drugs are expected to come to market within the next year.

Sources: 1. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499-24510. 2. Lassen MR, Raskob GE, Gallus A, et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): A randomised double-blind trial. Lancet. 2010;375:807-815. 3. Lassen MR, Gallus A, Raskob EG, et al; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010;363:2487-2498. 4. Phase 3 trials compare apixaban and enoxaparin in treating VTE.http://www.firstreportnow.com/articles/phase-3-trials-compare-apixaban-and-enoxaparin-treating-vte.

Managing clopidogrel hypersensitivity

Clopidogrel is widely used to prevent thrombosis after stent placement. Up to 6% of patients treated with clopidogrel after a percutaneous coronary intervention (PCI) develop a hypersensitivity reaction. The percentage is relatively small, but in light of the number of clopidogrel prescriptions written, it is a problem that healthcare providers are likely to encounter. The reaction usually occurs in the first week or 2 of treatment, but stopping the drug is not a good option because it puts patients at major risk of stent thrombosis.

A small study recently published in the American Journal of Cardiology suggests that the allergic reaction can be managed with corticosteroids and antihistamines. The study involved 25 patients who developed clopidogrel hypersensitivity an average of 6 days after PCI. The researchers treated 5 of them with corticosteroids, another 5 with antihistamines, and 15 with both corticosteroids and antihistamines. Treatment was successful, with sustained symptom resolution in 22 of 25 patients (88%). In successfully desensitized patients, clopidogrel therapy was continued for a mean of 417 days, which exceeds the minimum target duration recommended in guidelines by the American College of Cardiology and American Heart Association.

Source: Campbell KL, Cohn JR, Fischman DL, et al. Management of clopidogrel hypersensitivity without drug interruption. Am J Cardiol. 2011;107:812-816.

Anna D. Garrettis manager, Outpatient Clinical Pharmacy Programs, Mission Hospital, Asheville, N.C., and president and founder of the National Association of Women in Health Care (www.nawhc.com). She also is a Drug Topics board member. She can be reached at anna.garrett@msj.org.