Synthetic Anticoagulant Appears Safe, Effective
Initial reports from four Phase III trialsthe Ephesus, Pentathlon 2000, Penthifra, and Pentamaks studieswere presented in December at the annual American Society of Hematology meeting in San Francisco. According to meeting abstracts, orthopedic surgery patients who received the synthetic compound were 50 percent less likely to have a postsurgical VTE than were patients assigned to enoxaparin therapy.
The anticoagulant known variously as pentasaccharide, Org31540, and SR90107A is a synthetic, selective factor Xa inhibitor that blocks the generation of thrombin. The drug is manufactured by the European companies N.V. Organon and Sanofi-Synthelabo Inc. Organon announced before the hematology meeting that the companies expected to file for approval of the drug in the United States and Europe by the end of 2000.
In early January 2001, an Organon spokeswoman said her company and Sanofi-Synthelabo were in the process of filing a new drug application for their product, which is now known by the generic name fondaparinux sodium. The brand name cannot yet be disclosed, she said.
Specific data on the safety of the synthetic anticoagulant was not provided in the meeting abstracts, which stated only that the safety profile was similar to that of enoxaparin. However, a Dec. 5 press release from Organon reported that 0.33 percent of all recipients of the investigational drug and 0.25 percent of the patients in the enoxaparin groups required treatment for bleeding episodes during the four studies.
Transfusions of two or more units of blood were required by 2.3 percent of pentasaccharide recipients and 1.4 percent of enoxaparin recipients. Three percent of the pentasaccharide group and 2.7 percent of the enoxaparin group had minor bleeding episodes.
Fifteen people who received pentasaccharide injections and 21 who received enoxaparin injections died within 11 days of surgery. Organon did not state the percentage of patients these numbers represented among the different treatment groups.
Each clinical trial compared the efficacy of pentasaccharide with that of enoxaparin. A total of 7,347 patients enrolled in the four randomized trials, and data from 5,386 patients, or 73 percent, was analyzed. The four abstractsauthored by different researchers but bearing a marked similarity in languagedid not reveal why data from the remaining patients was not evaluated.
In the four studies, patients assigned to the pentasaccharide group received a subcutaneous 2.5-mg dose of the drug once a day for up to nine days. The first dose was given after surgery.
The Ephesus study, conducted at 73 medical centers in 16 European countries, enrolled patients undergoing elective hip-replacement surgery. Patients assigned to the enoxaparin group received the "standard European enoxaparin dosage"40 mg per day for up to nine days, with the first dose given before surgery. Efficacy data was available from 79 percent of the 2,309 patients who participated in the study. The risk of VTE developing during the first 11 days after surgery was 56 percent lower in the pentasaccharide group than in the enoxaparin group.
The Penthifra study, conducted at 100 medical centers, involved patients undergoing surgery to repair a fracture of the upper third of the femur. Enoxaparin was administered as in the Ephesus study. The researchers obtained efficacy data from 73 percent of the 1,714 study participants. Patients in the pentasaccharide group were 56 percent less likely than enoxaparin users to develop a VTE during the first 11 days after surgery.
Patients who participated in the Pentathlon 2000 study, which was conducted at 149 medical centers in North America and Australia, were hospitalized for elective hip-replacement surgery. In this study, patients in the enoxaparin group were given the "standard North American enoxaparin dosage"30 mg by subcutaneous injection every 12 hours, starting after surgery. Efficacy data was available from 1,585, or 70 percent, of the 2,275 study participants. Through day 11, the risk of postsurgical VTE was 25 percent lower in the pentasaccharide group than in the enoxaparin group.
Pentamaks study enrollees underwent elective major knee surgery at one of 64 medical centers in North America. Patients in the enoxaparin group were given the standard North American dosage of the drug. Data from 69 percent of the 1,049 study participants was available for efficacy analysis. In this study, the risk of postsurgical VTE through day 11 was 55 percent lower in the pentasaccharide group than in the enoxaparin group.
Before availability of the meeting abstracts, Aventis Pharmaceuticals Inc., manufacturer of the Lovenox brand of enoxaparin, voiced concerns about the preliminary findings of the clinical trials that pitted its product against pentasaccharide.
In a Nov. 9 message to shareholders, Aventis noted that study announcements issued by Organon and Sanofi-Synthelabo did not account for about a quarter of the enrollees in the four Phase III trials. The fate of these patients, said Aventis, could affect the interpretation of the final study results.
The Aventis message also noted that patients using pentasaccharide had more bleeding episodes and serious adverse events than patients who used enoxaparin. Though the frequency of such episodes did not differ statistically between the treatment groups, Aventis argued that the differences could be "clinically meaningful to practitioners."
Another issue raised by Aventis is the lack of an available antidote to pentasaccharide's anticoagulant effect, whereas enoxaparin can be neutralized by the drug protamine. However, Ibex Technologies Inc., a Canadian company, is now conducting clinical studies of Neutralase, a heparinase product that seems to neutralize the anticoagulant effects of pentasaccharide and low-molecular-weight heparins.
A report describing the safety and efficacy of pentasaccharide at daily dosages ranging from 0.75 to 8.0 mg appears in the Mar. 1, 2001, New England Journal of Medicine.