For decades, physicians have prescribed the anti-coagulant warfarin (coumadin) to prevent stroke and systemic embolism in patients with atrial fibrillation, also called irregular heartbeat.
Warfarin prevents blood from clotting but that same attribute also poses a threat when massive bleeding follows even a minor injury in some people. Patients must also undergo frequent blood draws, accept dietary restrictions and be wary of harmful interactions with other drugs while taking warfarin.
Nearly all the large pharmaceutical companies are developing new types of drugs that do not require the same restrictions or carry the same risks for uncontrolled bleeding as warfarin to compete in the stroke prevention market. The global market for anticoagulants, (including warfarin and heparins) was estimated at $6.2 billion in 2008 and is projected to reach $9.1 billion by 2014, according to a report in Nature Reviews. Atrial fibrillation affects about 2.5 million people in the United States and 4.5 million in the European Union.
Irena Melnikova, PhD, an analyst with TVM Capital in Boston, Massachusetts, wrote in Nature Reviews that the growth in anti-coagulants is being driven by the aging population, increased incidence of cardiovascular disease, and the availability of new medications. She predicted the approval of these new agents will make warfarin obsolete.
An FDA panel voted September 8, 2011, to recommend approval of Bayer AG's and Johnson & Johnson's rivaroxaban, brand name Xarelto, a new type of anti-clot medication for atrial fibrillation.
The US Food and Drug Administration (FDA) could make a final decision on Xarelto by Nov. 4. However, an FDA staff analysis found flaws in how the medicine trial was conducted and the agency may bypass the panel's 9-2 recommendation and call for additional safety studies. Johnson & Johnson would distribute the drug in the United States while Bayer plans to market the drug in outside the United States. Xarelto has already been approved for the prevention of deep vein thrombosis (DVT) following knee or hip replacement therapy.
Results from a trial of apixaban, developed by Bristol-Myers Squibb Co. and Pfizer under the brand name Eliquis, were announced in the New England Journal of Medicine in August 2011. Following a nearly two-year study of 18,201 patients with atrial fibrillation, Duke University researchers found that apixaban reduced stroke risk by 21 percent; lowered the incidence of bleeding by 31 percent, and cut risk of death by 11 percent, which reflected minor but still significant improvement when compared to warfarin.
Mark S. Link, MD, a cardiac electrophysiologist and associate professor of medicine at New England Medical Center and Tufts University School of Medicine in Boston, commented in Journal Watch that direct head-to-head comparison trials of the drugs will need to be completed before physicians can know which drug is best for individual patients.
The FDA approved the anticoagulant dabigatran etexilate, marketed as Pradaxa by Boehringer Ingelheim, in October 2010.
There are many other trials underway and it seems likely there will be new warfarin alternatives coming to market soon if manufacturers can convince the FDA of their safety and efficacy. Some manufacturers hope to recoup revenues lost when their blockbuster drugs go off patent through the development of new medications for treating cardiovascular disease.
The American Heart Association stated in the June 11, 2011 issue of its journal Circulation, that "Combinations of antiarrhythmic medications, such as amiodarone and ranolazine or dronedarone and ranolazine, are a promising avenue of investigation."
Merck & Co. returned rights of betrixaban, an anti-clot drug it had been developing with Portola Pharmaceuticals Inc. back to Portobla which said it intends to continue to develop the drug.
New Drugs Not Without Risks
Upon receiving approval of its drug Multaq (dronedarone) for atrial fibrillation in 2009, Sanofi-Aventis's head of R&D, Marc Cluzel, released a statement. "We are pleased that the FDA has granted approval of Multaq for patients in a therapeutic area that has seen few new treatment options in the last twenty years," said Cluzel.
However, in January 2011, Sanofi-Aventis and the FDA issued a letter to US healthcare professionals warning that Multaq was associated with severe liver injuries and liver failure. Both the FDA and the European Medicines Agency, which also approved Multaq for European markets in 2009, are reviewing the drug's safety history in regard to both liver and cardiovascular damage.
Ximelagatran, which AstraZeneca planned to market as Exanta, was the first warfarin alternative to undergo a major trial. It was approved by France in 2003 for preventing stroke in atrial fibrillation and was approved by the European Union for the prevention of venous thromboembolism in orthopedic surgery in 2004. However, the FDA recommended against its approval due to toxic damage to the liver. In 2006, AstraZeneca pulled Exanta from the European market.