Pharmacology Watch

Rivaroxaban: Another Warfarin Replacement

In this issue: Rivaroxaban may be dabigatran's first competitor; a new way to measure non-adherence to medication therapy; FDA Actions.

Another Warfarin Replacement on Horizon

Just as Boehringer Ingelheim begins marketing dabigatran (Pradaxa®) as a replacement for warfarin, a competitor drug may be on the horizon. As reported at the American Heart Association (AHA) meetings in November, rivaroxaban, an oral drug factor Xa inhibitor, is as effective as warfarin at preventing stroke and blood clots in patients with nonvalvular atrial fibrillation.

The ROCKET AF study (Stroke Prevention Using the Oral Direct Factor Xa Inhibitor Rivaroxaban Compared With Warfarin in Patients with Nonvalvular Atrial Fibrillation) looked at more than 14,000 patients with atrial fibrillation. Patients were randomized to warfarin or rivaroxaban (20 mg/day). The time in therapeutic range for warfarin was 57.8%. With a primary endpoint of stroke and non-CNS systemic embolism, rivaroxaban was associated with a rate of 1.71 events per 100 patient-years vs 2.16 for warfarin (P = 0.015 for superiority and P < 0.001 for non-inferiority). On an intention to treat (ITT) basis, event rates were 2.12 for rivaroxaban vs 2.42 for warfarin (P = 0.117). There were 55 intracranial bleeds with rivaroxaban compared with 84 with warfarin (P = 0.019). Rivaroxiban also showed numerically fewer MIs (0.91 vs 1.12 per 100 person-years; P = 0.12). All-cause mortality was 1.87 in the rivaroxaban group vs 2.21 in the warfarin group (P = 0.073). In the ITT analysis, mortality was 4.52 vs 4.91 (P = 0.152), respectively.

This study (presented at the American Heart Association Scientific Sessions; Chicago, IL; Nov. 15, 2010) was the seventh Phase III trial in the development of rivaroxaban, with other studies evaluating the drug for prevention and treatment of venous thromboembolism, indications that Bayer and Johnson & Johnson have already filed with the FDA. It is also expected that a new drug application will be filed soon for the prevention of stroke in patients with nonvalvular atrial fibrillation. Like dabigatran, rivaroxaban requires no monitoring and has few drug interactions. Rivaroxaban has the advantage of being dosed once a day compared to twice-daily dosing for dabigatran.

Non-adherence: A New Way to Measure

A new study examines drug adherence in an interesting way — by looking at the rate of prescriptions abandoned at the pharmacy. Traditional non-adherence studies have looked at refill rates, pill counting, and patient reports of medication use. But prescriptions abandoned at the pharmacy represent a potential opportunity to intervene and improve adherence at the very onset of the prescribing process.

Researchers used the CVS pharmacy database to evaluate more than 10 million prescriptions filled by more than 5 million patients. The overall abandonment rate was 3.27%, although nearly half of those were eventually filled by the same drug or a similar drug within 30 days. Not surprisingly, patients were least likely to abandon opiate prescriptions, and were most likely to abandon expensive prescriptions. Prescriptions with a copayment of $40-$50 and those with a copayment of more than $50 were 3.4 times and 4.68 times more likely to be abandoned, respectively, than prescriptions with no copayment (P < 0.001 for both comparisons). New users of medications were more likely to abandon prescriptions than prevalent users, and prescriptions that were delivered to the pharmacy electronically were 1.64 times more likely to be abandoned than those that were not electronic (P < 0.001); however, they were unable to determine whether written prescriptions were never delivered to the pharmacy by patients.

The authors concluded that prescription abandonment represents an important opportunity to intervene and improve adherence (Ann Intern Med 2010;153:633-640). An accompanying editorial points out that the rate of abandonment in this study was actually quite low. Others studies have suggested that 17%-20% of patients do not pick up new prescriptions, and 8% of patients' prescriptions are denied by health plans. Physicians and pharmacists are urged to remain mindful that costs are an important barrier to adherence and that lower cost alternatives should be prescribed "whenever feasible" (Ann Intern Med 2010;153:680-681).

FDA Actions

The FDA has asked the manufacturers of propoxyphene-containing pain medications (Darvon®, Darvocet®, and generics) to withdraw them from the market. The withdrawal is based on new data showing the drugs are associated with serious and fatal heart arrhythmias. Health care professionals are advised to stop prescribing propoxyphene and patients are asked to contact their health care providers to discuss switching to other pain medications. Propoxyphene has been the target of consumer groups for more than 30 years because of evidence of poor efficacy in treating pain and a high level of side effects including falls.

The FDA has approved duloxetine (Cymbalta®) for the treatment of chronic musculoskeletal pain. Duloxetine, a serotonin-norepinephrine reuptake inhibitor, was previously approved for treating depression, generalized anxiety disorder, diabetic neuropathy, and fibromyalgia. The new indication for musculoskeletal pain includes low back pain and osteoarthritis. The expanded indication was based on the results of four double-blind, placebo-controlled trials, which showed that patients treated with duloxetine had significantly greater pain reduction than those patients treated with placebo. Duloxetine is marketed by Eli Lilly and Company.

The FDA has approved lurasidone for the treatment of schizophrenia in adults. The drug is classified as an atypical antipsychotic, and like other drugs in this class, carries a boxed warning regarding an increased risk of death associated with off-label use to treat behavioral problems in older adults with dementia. Common adverse reactions include drowsiness, feelings of restlessness, nausea, agitation, and Parkinsonian symptoms such as bradykinesia, tremor, and muscle stiffness. Lurasidone will be marketed by Sunovion Pharmaceuticals as Latuda™.

The FDA has approved a new injectable cephalosporin, ceftaroline, to treat community-acquired bacterial pneumonia (CABP) and bacterial skin infections, including those caused by methicillin-resistant Staphylococcus aureus. Ceftaroline was approved based on data from four studies that showed the drug to be as effective as ceftriaxone for the treatment of CABP and as effective as vancomycin plus aztreonam for the treatment of acute bacterial skin and skin structure infections. The recommended dose for patients with normal renal function is 600 mg given as a one-hour IV infusion every 12 hours. Ceftaroline is marketed by Forest Laboratories as Telflaro™.

The FDA's Vaccines and Related Biological Products Advisory Committee has recommended an expanded indication for Gardasil®, Merck's quadravalent human papillomavirus vaccine to prevent anal intraepithelial neoplasia and anal cancer in males and females ages 9-26. The approval was based on a phase III double-blind, placebo-controlled trial in which more than 4000 males were randomized to receive the three-dose vaccine or placebo. There was a significant reduction in the rate of anal intraepithelial neoplasia or anal cancer, especially in men who have sex with men. The vaccine is already approved for prevention of genital warts and cervical, vulvar, and vaginal cancer in females ages 9-26 and prevention of genital warts in males ages 9-26.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5468. E-mail: