Sep. 6, 2001 STOCKHOLM, Sweden – An experimental agent that prevents the formation of blood clots earlier in the coagulation process than other agents has cleared its first hurdle in becoming a potential new treatment for patients with coronary artery disease, according to the results of a recently completed trial led by Duke University Medical Center cardiologists.
The new drug inhibits the action of Factor Xa (as in Roman numeral X), the most pivotal of the dozen known clotting factors involved in the complex cascade of biochemical events that ultimately leads to the formation of a blood clot. If larger trials continue to demonstrate the agent's benefit, it could offer a more effective and safer way to keep potentially life-threatening blood clots from forming.
While anti-coagulation therapy is widely used to keep clots from forming in patients at risk for heart attacks or those undergoing angioplasty procedures, their biggest drawback has been the potential for bleeding complications. Many of these agents have "narrow" windows for therapeutic effect – too little can lead to clot formation and too much can cause bleeding.
"This is the first reported clinical trial to provide some preliminary safety and clinical information on a novel class of agents for the treatment of coronary artery disease," said Dr. Christopher Dyke, senior cardiology fellow at the Duke Clinical Research Institute (DCRI). "Based on the results of this small Phase I trial, this new anticoagulant appears to effectively inhibit factor Xa while being well tolerated." Dyke prepared the results of the DCRI analysis for presentation Wednesday (Sept. 5) at the annual meeting of the European Society of Cardiology.
The trial, dubbed XaNADU (Xa Neutralization for Atherosclerotic Disease Understanding), was a Phase Ib clinical trial involving 73 patients with clinically stable coronary artery disease at 10 U.S. academic medical centers. Typically, Phase I trials test the safety of an agent on healthy volunteers, and while Phase Ib clinical trials also test an agent's safety, it does so with a group of patients having the medical condition under study.
On average, the patients were 63 years old, with 68 percent having had a prior heart attack and 86 percent having had a revascularization procedure, either an angioplasty or a coronary artery bypass surgery. In the double blind, placebo controlled study, the patients were randomized to either placebo, or one of four escalating doses of the Factor Xa inhibitor. The patients were followed in each academic center's General Clinical Research Center, National Institutes of Health-funded centers for specialized clinical research.
"We found no statistically significant difference in bleeding complications among all five groups," Dyke said. "Also, there were no adverse changes in kidney or liver function, and the hemoglobin and platelet counts remained stable across all groups."
When Factor Xa is activated, it responds by converting a precursor chemical circulating in the blood known as prothrombin into the enzyme thrombin. Once activated, thrombin then converts circulating fibrinogen (Factor I) into the protein fibrin, the primary building block of a blood clot. Thrombin also exhibits a number of additional properties that increase the ability of blood to clot, Dyke said.
The advantages of interrupting the clotting cascade at the point of Factor Xa activation is that sits at the intersection of the two classical pathways for blood clot formation and limits the generation of thrombin, Dyke said.
"Because of its location in the cascade, Factor Xa has long been seen as an attractive target for anti-coagulation therapy," Dyke said. "Currently available anti-coagulants that work by blocking other factors in the cascade, for example, target thrombin after it is generated, either directly or indirectly, the latter in the case of heparins."
Dr. Robert Harrington, another DCRI cardiologist and senior researcher for the trial, said the new agent has great potential in treating heart patients, but says enthusiasm should be tempered until the results of larger multi-center trials are completed.
"This is truly the first experience in real patients who have coronary artery disease with a novel class of drug, so it is a pretty important step moving along our knowledge of anti-coagulation therapy," Harrington said.
"Even if this proves to be a modest advance, modest steps forward in treating a disease that effects millions of people every year is pretty good. Larger trials will be required to give us the answer as to whether these are steps forward in reducing blood clotting while minimizing bleeding."
These answers could be forthcoming in the near future. Two Phase II trials, both being coordinated by the DCRI, are under way. The first trial is testing the agent in conjunction with angioplasty procedures and has already enrolled more than 100 patients. It should conclude this year.
The second trial, which will enroll more than 400 patients with unstable angina, begins later this month. This will be the first time a clinical trial involving cardiovascular agents will be conducted in both the United States and Japan. For cultural and regulatory reasons, Japan has in the past preferred to conduct their trials with Japanese participants, Harrington said.
The trial was funded by Daiichi Pharmaceutical Co., Ltd., Japan, which developed the Factor Xa inhibitor, known as DX-9065a.
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