WHAT THIS STUDY ADDS:

• Fondaparinux is as effective as unfractionated heparin for initial PE treatment in hemodynamically stable patients. • Ximelagatran is as good as or better than warfarin in preventing VTE and death in patients undergoing knee replacement; it is better than placebo for long-term secondary VTE prophylaxis.

AMSTERDAM—Fondaparinux and ximelagatran, two anticoagulants currently under development, could be viable alternatives to established medications for preventing venous thromboembolism (VTE) and managing pulmonary embolism (PE). In a recent randomized trial, fondaparinux appeared to be as safe and effective as unfractionated heparin for the initial treatment of PE in hemodynamically stable patients.[1] Two other randomized studies demonstrated that ximelagatran is better than warfarin or placebo for the primary or secondary prevention of VTE.[2,3]

Harry R. Büller, MD, who chaired the writing and steering committee for the fondaparinux study, stressed that an advantage of this drug is that it requires only once-daily, fixed-dose, subcutaneous injections; no special patient monitoring is needed. Ximelagatran is an oral drug that is given twice a day, but it too does not require special monitoring. As all clinicians are aware, unfractionated heparin necessitates continuous intravenous infusion and close monitoring of the activated partial thromboplastin time (APTT); warfarin requires assessment of the international normalized ratio (INR) and, often, multiple dosage adjustments. Thus, both new agents would be markedly easier to administer.

FONDAPARINUX VERSUS HEPARIN

In the fondaparinux trial, 2,213 hemodynamically stable adults with acute symptomatic PE were randomly assigned to treatment with unfractionated heparin or fondaparinux, which is a synthetic antithrombotic agent with specific anti–factor Xa activity.[1] The daily dose of fondaparinux was determined by the patient’s body weight: 5 mg for those who weighed less than 50 kg, 7.5 mg for those between 50 and 100 kg, and 10 mg for those above 100 kg.

Unfractionated heparin was delivered as an initial intravenous bolus of at least 5,000 IU, followed by a continuous infusion of 1,250 IU/hr; the infusion rate was then adjusted to maintain the appropriate APTT.

Both fondaparinux and unfractionated heparin were administered for at least five days. Neither treatment was stopped until the INR exceeded 2.0 for two consecutive days. Vitamin K antagonist therapy was continued until the end of the three-month study.

During the study, recurrent VTE was diagnosed in 3.8% of the 1,103 patients given fondaparinux and in 5.0% of the 1,110 patients receiving unfractionated heparin. The two groups’ respective rates of major bleeding were 1.3% and 1.1% during initial treatment and 2.0% and 2.4% during the study as a whole. Their respective mortality rates during the study were 5.2% and 4.4%. Thrombocytopenia occurred in 0.9% of the patients given fondaparinux and in 1.2% of those receiving unfractionated heparin.

“Because we studied such a large, representative patient sample, we are certain beyond doubt that single subcutaneous fondaparinux injections can replace the more complicated unfractionated heparin infusions for the initial treatment of pulmonary embolism,” said Dr. Büller, Chairman of the Department of Vascular Medicine at the Academic Medical Center in Amsterdam.

XIMELAGATRAN AFTER KNEE REPLACEMENT?

Charles W. Francis, MD, and colleagues reported similarly impressive findings when they studied the direct thrombin inhibitor ximelagatran in patients undergoing total knee replacement.[2] Compared to warfarin, ximelagatran produced lower rates of VTE and similar rates of bleeding complications.

In this study, 2,301 patients were randomized in double-blind fashion to seven to 12 days of postoperative anticoagulation with one of the two study drugs. The warfarin dose was administered each evening beginning on the day of surgery; it was then adjusted to maintain an INR between 1.8 and 3.0. Ximelagatran was given in tablet form at a dose of either 24 or 36 mg twice daily (morning and evening); the first tablet was administered once adequate hemostasis had been achieved (at least 12 hours postoperatively). Treatment was continued until a venogram confirmed that no VTE was present.

Although the trial included two ximelagatran regimens, its main goal was to assess the higher dose, because an earlier study had shown that the lower dose was similar in efficacy and safety to warfarin. “So, we felt that we could safely increase the dose to 36 mg,” said Dr. Francis, Director of the Thrombosis Program at the University of Rochester Medical Center in New York. The higher dose might increase the drug’s effectiveness in preventing VTE, he added.

The study’s primary end point was a composite of total (distal and proximal) VTE, PE, and all-cause mortality. The secondary end point was similar but excluded distal VTE.

In the efficacy analysis, which included 1,851 patients, the composite primary end point was found in 20.3% of the patients in the higher-dose ximelagatran group, 24.9% of those in the lower-dose group, and 27.6% of those in the warfarin group. These results confirm previous findings that 24 mg of ximelagatran is comparable in efficacy to warfarin; however, they also demonstrate that 36 mg of the drug is markedly superior to warfarin in its ability to prevent VTE.

The composite secondary end point was seen in 2.7%, 2.5%, and 4.1% of the patients, respectively; these differences were not significant. The three groups also had comparable rates of major bleeding (0.8%, 0.8%, and 0.7%, respectively) and any type of bleeding (5.3%, 4.8%, and 4.5%, respectively).

“The results for the 24-mg dose of ximelagatran were consistent with previous findings, whereas the 36-mg dose clearly beat warfarin—without causing significantly more bleeding,” Dr. Francis reported. “If ximelagatran were to be FDA approved, it would likely have a place in preventing and treating thrombosis in a number of settings,” he suggested.

SECONDARY VTE PREVENTION

In another recent trial, Sam Schulman, MD, and colleagues compared ximelagatran (24 mg twice daily) to placebo for secondary prevention in patients who have received standard anticoagulation for symptomatic VTE.[3] In this study, ximelagatran substantially decreased the rate of VTE recurrence without significantly raising the risk of bleeding complications. However, it did increase the frequency of transient alanine aminotransferase elevations.

These investigators randomized 1,233 adults who had undergone six months of standard anticoagulation for symptomatic VTE to ximelagatran or placebo. The patients discontinued standard anticoagulant therapy at the beginning of the study, but they did not begin treatment with the study drugs until their INR was below 1.5. The ximelagatran or placebo regimens were continued for 18 months.

During these 18 months, the patients were prohibited from using other anticoagulants except aspirin (up to about 500 mg/d). Fibrinolytic and antiplatelet agents were also forbidden, but the patients could use nonsteroidal anti-inflammatory drugs with a half-life of less than seven hours.

The primary end point, symptomatic recurrent VTE, occurred in 12 (1.9%) of the 612 patients given ximelagatran and in 71 (11.6%) of 611 placebo recipients. Furthermore, this reduction in risk continued over time; thus, the two groups’ estimated cumulative risks of a venous thromboembolic event during 18 months’ treatment were 2.8% and 12.6%, respectively. In contrast, the 18-month mortality rate was comparable in the two groups (1.0% vs 1.1%), as was the rate of major bleeding (1.0% vs 0.8%).

In 6% of the patients given ximelagatran but only 1% of the placebo recipients, alanine aminotransferase levels rose to more than three times the upper limit of normal. In the ximelagatran group, these elevations typically normalized with time; in fact, the median time to normalization was longer in the patients who stopped treatment than in those who continued on ximelagatran.

“We said at the outset that we could accept an increased bleeding risk with ximelagatran because the drug would not require coagulation monitoring,” remarked Dr. Schulman, Associate Professor of Internal Medicine at the Karolinska Institute in Stockholm. “But surprisingly, no such risk increase was evident.”

—Timothy Begany

References
1.Büller HR, Davidson BL, Decousus H, et al. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med. 2003;349:1695-1702.
2.Francis CW, Berkowitz SD, Comp PC, et al. Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. N Engl J Med. 2003;349:1703-1712.
3.Schulman S, Wahlander K, Lundstrom T, et al. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med. 2003;349:1713-1721.

Return to table of contents