Two Studies of Once-Promising Idraparinux in New England Journal of Medicine Highlight Necessity of Large, Randomized Trials, Weill Cornell Researcher Says
DOHA, QATAR (October 8, 2007) — Patients hoping for an easier alternative to conventional blood thinners may be disheartened by the results of two collaborative phase III clinical trials of an experimental agent, idraparinux.
As reported Sept. 12 in the New England Journal of Medicine, an international team—including Dr. Bruce Davidson, professor of medicine at Weill Cornell Medical College in Doha, Qatar—found that, despite promising results in smaller trials, idraparinux's safety profile was unexpectedly weak.
"The drug did drive down rates of recurrent clotting in patients with a prior history of deep vein thrombosis (DVT)—clots typically originating in the veins of the leg," notes Dr. Davidson, who is also senior associate dean for clinical affairs at Qatar.
"Unfortunately, it was not as effective in preventing a more serious form of clots in the lungs, called pulmonary embolism," he adds. "Patients taking idraparinux over the long term also had a significantly higher risk for dangerous bleeding—something we had not seen in smaller, earlier trials."
Even though the results are disappointing for this particular agent, the two trials reinforce some valuable lessons for researchers, Dr. Davidson says.
"First of all, they suggest that DVT is not the same clinical entity as pulmonary embolism, and that anticoagulant treatment satisfactory for DVT can be ineffective for pulmonary embolism," he says.
"And the surprising finding regarding the excess bleeding risk with idraparinux reinforces the importance of testing all new agents in randomized phase III trials," the researcher says. "Without these large, comparative studies, we simply would not catch many of these risks before a drug made its way to patients."
Both of the studies were funded by Sanofi-Aventis, the developer of idraparinux, and were conducted by a collaborative research group known collectively as the Van Gogh Investigators. The group is chaired by Dr. Harry Buller, of the Academic Medical Center, Amsterdam. Dr. Davidson's work enrolling patients and coordinating the trials was done while he was at the University of Washington School of Medicine, Seattle.
Millions of patients worldwide take anticoagulants such as warfarin (Coumadin) or heparin to lower their risk of dangerous clots, Dr. Davidson explains.
"The trouble is, the chronic use of vitamin K antagonists like warfarin requires regular monitoring and dose re-adjustments to make sure we keep clots at bay while not increasing the patient's risk of bleeding," he says. "That can be tough on patients, especially the frail elderly."
For that reason, drug companies have been hard at work developing safe, effective alternatives to warfarin, heparin and similar drugs.
Enter idraparinux, a once-a-week injectable drug that in early, smaller trials appeared to be up to the task. Idraparinux is from a newer class of anticoagulant drugs called pentasachharides.
"In earlier trials, idraparinux was able to keep clotting down while maintaining a good safety profile," Dr. Davidson says.
But surprises arose in both phase III studies.
In one trial published in NEJM, the Van Gogh Investigators enrolled 2,904 patients with a prior history of DVT, and 2,215 patients with a prior incident of pulmonary embolism, to receive either 2.5 mg of injected idraparinux once weekly or standard heparin therapy for three or six months.
"We found that idraparinux equaled heparin in terms of preventing another DVT in patients who'd already experienced this type of clot," Dr. Davidson says. Just over 3 months into therapy, 2.9 percent of those on idraparinux had experienced a recurrent DVT versus 3 percent of those taking heparin.
But those numbers were not repeated in patients with pulmonary embolism—in that group, 3.4 percent of patients on the experimental drug suffered another lung clot, compared to just 1.6 percent of those taking heparin.
"That idraparinux failed to be as effective against pulmonary embolism as it was against DVT came as a surprise," Dr. Davidson says. "It suggests that treating these two related conditions is not a 'one-size-fits-all' proposition."
Six-month rates of serious bleeding were similar between the two treatment arms, the investigators found. About 2 percent of patients died in each group.
In the second Van Gogh trial, researchers compared the idraparinux regimen against placebo for six months in 1,215 patients with a prior history of either confirmed DVT or pulmonary thrombosis.
All of the patients had already been treated for at least 6 months prior to the study with either warfarin or a related anti-clotting drug, acenocoumarol.
"This time it was idraparinux's safety profile that surprised us," Dr. Davidson says.
The experimental agent did reduce patients' risk of recurrent DVT—just one percent of those taking idraparinux experienced a recurrence versus 3.7 percent of those on placebo.
But major bleeding occurred in 11 of 594 patients (1.9 percent) taking idraparinux compared to none of the 621 patients on placebo.
That gap was magnified among patients who had taken idraparinux before they entered the trial compared to those who had been on a drug such as warfarin (3.1 percent incidence of bleeding vs. 0.9 percent, respectively).
The heightened risk of major bleeding linked to idraparinux use appeared to continue for at least 20 weeks after discontinuation of the drug, the team found. Overall, 16 patients taking indraparinux and none taking placebo suffered a "major hemorrhagic episode." Three of these bleeding events involved fatal brain hemorrhages, the researchers noted.
"This excess bleeding risk was unexpected and underscores why phase III research is so critical to giving us a fuller picture of a drug's risks and benefits," Dr. Davidson says.
The Van Gogh team also discovered that indraparinux levels didn't "wash out" of the body, but gradually accumulated in patients' blood over time. "That also renders the drug insufficiently safe for long-term use at the dosage tested," Dr. Davidson says.
The bottom line? Based on these phase III findings, indraparinux is of "marginal" clinical benefit, at best, the researchers conclude.
But the news isn't all bad.
"This trial's negative findings have come alongside some positive new insights into both DVT and pulmonary embolism," Dr. Davidson says. "It's exactly those types of insights that will bring us the better, safer treatments we seek."
Other members of the Van Gogh Investigators Writing Group include Dr. Ander Cohen of King's College Hospital, London; Dr. Herve Decousus, Hospital Bellevue, Saint Etienne, France; Dr. Alex Gallus, Flinders Medical Center, Bedford Park, South Australia, Australia; Dr. Gerard Pillion, Sanofi-Aventis, Antony Cedex, France; Dr. Franco Piovella, Fondazione Istituto di Ricovero e Cura a Caraterre Scientifico Policlinico, San Mattea, Pavia, Italy; Dr. Martin Prins, University of Maastricht, The Netherlands; Dr. Gary Raskob, University of Oklahoma Health Sciences Center, Oklahoma City; and Michael Gent, Henderson Research Center, Hamilton, Ont., Canada.
Weill Cornell Medical College-Qatar
Established in partnership with the Qatar Foundation, Weill Cornell Medical College-Qatar (WCMC-Q) is part of Cornell University, the first American institution to offer its M.D. degree overseas. WCMC-Q shares the tripartite mission of Weill Cornell Medical College (WCMC): a dedication to excellence in education, patient care and biomedical research. Weill Cornell Medical College-Qatar offers an innovative program of pre-medical and medical studies leading to an M.D. degree from Cornell University. Teaching is by Cornell and Weill Cornell faculty, including physicians at Hamad Medical Corporation (HMC) who hold Weill Cornell appointments. Faculty and staff of WCMC-Q and WCMC are building the research capacity of Qatar in partnership with Qatar Foundation, HMC, the Qatar Ministry of Health and other organizations, with a focus on high-quality research in genetic and molecular medicine, women's and children's health, gene therapy and vaccine development. For more information, visit qatar-weill.cornell.edu.
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