Anticoagulation Therapies for Thromboembolic Disorders

Minneapolis—Approved by the US Food and Drug Administration (FDA) in 1954, warfarin has been the standard of care for decades for many patients with thromboembolic disorders. Still, some physicians are reluctant to prescribe warfarin because of side effects, including the risk of major bleeding. Recently, new oral anticoagulants have become an alternative to warfarin, and their increased use is expected in the next decade and beyond, according to presenters at a satellite symposium at the AMCP meeting titled The Evolving Paradigm of Anticoagulation Therapy: Optimizing Managed Care Outcomes for Thromboembolic Disorders. James B. Groce, III, PharmD, CACP, professor in the department of pharmacy practice at Campbell University in North Carolina, said atrial fibrillation (AF) affects >2.6 million people in the United States. AF is the most common arrhythmia requiring hospitalizations and leads to 461,000 hospital discharges and >90,000 deaths per year. Dr. Groce cited the ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) study that projected the number of adults in the United States with AF. By 2050, the trial predicted, there will be 5.61 million adults with AF. “Atrial fibrillation will continue to grow,” Dr. Groce said. “It’s going to be a healthcare crisis, one of many we have to address.” People with AF have a 5 times higher risk for ischemic stroke, which is the leading cause of serious disability in the United States. Of the people who survive strokes, 50% to 70% regain functional independence, although 15% to 30% become permanently disabled, according to a 2010 study from Circulation that Dr. Groce cited. Three months after the onset of a stroke, 20% of the patients required institutional care. A separate study of AF patients published in the Archives of Internal Medicine found that 91% of patients were concerned with having a stroke compared with 38% who were concerned with death and 13% who were concerned with major bleeding. The costs associated with AF are high. A 2006 Value Health article that Dr. Groce discussed estimated it cost $6.65 billion in 2005 for AF treatment in inpatient, emergency department, and hospital outpatient settings. “From a health economics perspective, this has tremendous impact,” Dr. Groce said. Dr. Groce also mentioned warfarin, an oral vitamin K antagonist. Dr. Groce cited a 2001 article from Chest that included several problems associated with warfarin, such as delayed onset/offset, unpredictable dose response, narrow therapeutic range, drug–drug and drug–food interactions, problematic monitoring, and slow reversibility. Albert L. Waldo, MD, professor of cardiology, medicine, and biomedical engineering at Case Western Reserve University in Cleveland, Ohio, agreed with Dr. Groce’s assessment that warfarin is underutilized for patients with AF who are at risk for a stroke. He emphasized that although physicians may suggest patients take acetaminophen instead of warfarin, acetaminophen is “a very, very, very bad alternative.” Rather, Dr. Waldo said there is a need for safe and effective oral anticoagulants to replace warfarin. According to Dr. Waldo, several randomized controlled trials have proven the effectiveness of anticoagulants such as dabigatran etexilate, rivaroxaban, apixaban, and endoxaban. The RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) study took place between December 2005 and March 2009 and examined 18,000 patients with AF at 951 centers in 44 countries. Patients received warfarin, 110 mg of dabigatran etexilate, or 150 mg of dabigatran etexilate. There were 6000 patients in each group. Dabigatran etexilate is a competitive inhibitor of thrombin. The authors found that patients taking 150 mg of dabigatran etexilate had a significant reduction in strokes and a similar risk of major bleeding compared with patients taking warfarin. Patients taking 110 mg of dabigatran etexilate had a significant reduction in major bleeding and a similar rate of strokes compared with patients taking warfarin. Both doses of dabigatran etexilate reduced intracerebral, life-threatening, and total bleeding. The drug had no major toxicity, although the study found dabigatran etexilate increased dyspepsia and gastrointestinal bleeding. “This was a major, major breakthrough,” Dr. Waldo said. Dr. Waldo then spoke about the ROCKET-AF (Randomized, Double-Blind Study Comparing Once Daily Oral Rivaroxaban with Adjusted-Dose Oral Warfarin for the Prevention of Stroke in Subjects with Non-Valvular Atrial Fibrillation) trial. Patients were assigned to take 15 mg of rivaroxaban, 20 mg of rivaroxaban, or warfarin. Rivaroxaban is a direct specific competitive inhibitor of factor Xa. According to Dr. Waldo, the study found that rivaroxaban was a proven alternative to warfarin in patients with AF. Compared with warfarin, rivaroxaban was noninferior in preventing strokes and non–central nervous system embolism and superior hen patients were taking the drug. When assessed by intention to treat, rivaroxaban was noninferior but did not achieve superiority. In addition, the drugs had similar rates of bleeding and adverse events, but warfarin had less intracranial hemorrhage and fatal bleeding. The FDA approved dabigatran etexilate in October 2010 for stroke prevention in patients with AF; it has not approved rivaroxaban, although the drug’s manufacturer submitted a new drug application to the FDA in January 2011. Although the new oral anticoagulants have proven effective in some trials, they also have potential clinical challenges, according to Dr. Waldo. A therapeutic range has not been established, there are no validated tests to measure the anticoagulation effect, the safety profile for the drugs is unknown, and there are a lack of studies comparing the new agents. Jeffrey D. Dunn, PharmD, MBA, formulary and contract manager for SelectHealth Inc in Murray, Utah, reiterated that warfarin use is limited because physicians fear complications such as bleeding, drug interactions, and complex pharmacokinetics. Continuously monitoring patients taking warfarin is also inconvenient and costly, causing some physicians to not prescribe warfarin. According to data from SelectHealth, branded warfarin has an average wholesale price per unit of $1.35 compared with $0.13 for generic warfarin, $90 for branded enoxaparin, $65 for generic enoxaparin, and $4.05 for dabigatran etexilate. However, Dr. Dunn said it is difficult to compare the costs of warfarin and other agents. He said some costs associated with warfarin, such as monitoring, can be easily measured, but quality-of-life issues, dose adjustments, and other costs are difficult to measure. Meanwhile, the new agents have higher acquisition costs but will not require monitoring and have fewer drug–drug interactions, according to Dr. Dunn. Dr. Dunn said that warfarin reduces the risk and costs associated with a stroke, but patients do not always adhere to their regimen. He added that oral anticoagulants may be effective at fixed doses, have limited drug–drug interactions, and be more cost-effective in preventing strokes. “I don’t think warfarin is going away,” Dr. Dunn said. “But some of these new anticoagulants are potentially attractive.”