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CHICAGO -- Oral rivaroxaban (Xarelto) performed comparably to standard pulmonary embolism therapy for preventing recurrent venous thromboembolic events, the large randomized EINSTEIN-PE trial showed.

The rate of recurrent events was 2.1% in the rivaroxaban group and 1.8% in the group that received enoxaparin followed by a vitamin K antagonist (HR 1.12, 95% CI 0.75 to 1.68), according to Harry Buller, MD, of Academic Medical Center in Amsterdam.

Because the upper limit of the confidence interval was below 2, rivaroxaban met criteria for noninferiority, Buller reported at the American College of Cardiology meeting here. The results were published simultaneously in the New England Journal of Medicine.

A composite of major bleeding and clinically relevant nonmajor bleeding occurred in 10.3% of patients taking rivaroxaban and 11.4% of those receiving standard therapy (P=0.23), although the rate of major bleeding was cut in half in the rivaroxaban group (1.1% versus 2.2%, P=0.003).

The results were similar to those of a sister study in patients with deep vein thrombosis.

"If we look at them together, they're very consistent, and I think they reassure us that for patients with venous thromboembolism we now can offer both physicians and patients an attractive alternative with a single-drug approach," Buller said at a press briefing, pointing out that rivaroxaban does not require monitoring of coagulation status or dose adjustments.

Rivaroxaban, an oral factor Xa inhibitor, has been approved for stroke prevention in atrial fibrillation and for the prophylaxis of deep vein thrombosis in patients undergoing knee and hip replacement surgery, and Patrick O'Gara, MD, of Brigham and Women's Hospital in Boston, said that "the potential availability of an oral agent for management of patients with pulmonary emboli ... is a very important development in patient care."

O'Gara, who moderated the press briefing, said he looks forward to additional information about cost and about nonbleeding adverse events.

But, he said, "I don't think you should underestimate the potential value of being able to manage patients like this with oral medications, and I could envision a future where length of stay would drop by more than 50% for patients admitted with this particular disease and no adverse risk factors at time of presentation."

EINSTEIN-PE was a randomized, open-label, noninferiority trial of 4,832 patients (mean age 58, roughly half male) who had acute symptomatic pulmonary embolism with or without deep vein thrombosis. It was conducted at 263 sites in 38 countries.

Patients received one of two treatment regimens:

• Standard therapy consisting of enoxaparin 1 mg per kilogram body weight twice daily followed by adjusted-dose vitamin K antagonist (either warfarin or acenocoumarol) for 3, 6, or 12 months. Enoxaparin was stopped after the international normalized ratio (INR) was 2.0 or more for at least two consecutive days and the patient had received the drug for at least five days.
• Oral rivaroxaban 15 mg twice daily for the first three weeks followed by 20 mg once a day.

The median duration of enoxaparin treatment was 8 days, and the INR was 2.0 or higher in 83% of the patients. The percentage of time spent within the therapeutic range of 2.0 to 3.0 was 62.7%. O'Gara noted that the less-than-ideal time spent in the therapeutic range is a reality of treating these patients.

Combining the comparable rates of recurrent venous thromboembolic events in the two groups and the lower rate of major bleeding in the rivaroxaban group yielded a neutral net clinical outcome (3.4% for rivaroxaban versus 4% for standard therapy, P=0.28).

Rates of recurrent events and bleeding were similar across various subgroups. There was no signal of liver toxicity in the rivaroxaban group.

In their paper, Buller and colleagues acknowledged some limitations of the study, including the open-label design and the possibility of greater diagnostic suspicion bias in the rivaroxaban group. There was, in fact, a greater number of patients with suspected recurrence in the rivaroxaban group, even though the number of confirmed events was similar.

"This finding suggests that the open design may have caused a slight bias against rivaroxaban," the researchers wrote. "Careful follow-up revealed similarly low rates of both acute coronary events and changes in liver-function tests in the two study groups."

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