Pharmacology Watch

Dabigatran Leading Race to Replace Warfarin

In this issue: FDA Advisory Committee recommends approval of dabigatran, safety of proton pump inhibitors, effectiveness of glucosamine and chondroitin, FDA Actions.

Advisory Committee recommends approval of dabigatran

In the race to find a drug to replace warfarin, Boehringer Ingelheim may have a leg up with the impending approval of dabigatran. The Cardiovascular and Renal Drugs Advisory Committee of the FDA unanimously recommended approval of the drug in September for the prevention of stroke and systemic clots in patients with atrial fibrillation. Dabigatran is a direct thrombin inhibitor that is given in a fixed dose twice a day and does not require monitoring. It is speculated that dabigatran will replace warfarin as the preferred anticoagulant in many settings, including many patients with atrial fibrillation. The approval was based on the Randomized Evaluation of Long-Term Anticoagulation Therapy trial, which was published last December. The study of more than 18,000 patients with atrial fibrillation showed that dabigatran given at a dose of 110 mg was similar in effectiveness to warfarin in prevention of strokes and systemic embolism, but had a significantly lower rate of major hemorrhage. A higher dose of 150 mg was associated with lower rates of stroke and systemic embolism compared to warfarin and similar rates of hemorrhage (N Engl J Med 2009;361:1139-1151). The FDA panel recommended approval of the higher dose, but was split on recommending the 110 mg dose. There was a slightly higher rate of heart attacks with dabigatran compared to warfarin, although the reviewers did not think this was serious enough to warrant holding the drug back. Dabigatran, once approved, will be marketed as Pradaxa®. Several companies are working on their own products to fill the same niche in what has been estimated to be a $10-20 billion market. Drugs in development include Bristol-Myers Squibb's apixaban and rivaroxaban, which is being jointly developed by Bayer Healthcare and Johnson & Johnson. Both drugs are direct inhibitors of Factor Xa.

Safety of proton pump inhibitors

Recent studies have suggested that proton pump inhibitors (PPIs) may negate some of the benefit of clopidogrel (Plavix®) in patients with cardiovascular (CV) disease. A new study refutes these findings, and at the same time raises more questions about the safety of PPIs. In a nationwide cohort study from Denmark, all patients discharged after first-time myocardial infarction (MI) were reviewed during 2000-2006. Of the more than 56,000 patients, 16% were rehospitalized for MI or stroke or experienced CV death. Nearly 25,000 patients were discharged on clopidogrel, of which nearly 30% received a concomitant PPI. Patients who were discharged on the combination of a PPI with clopidogrel or on a PPI alone had elevated but similar rates of death or rehospitalization for MI at 30 days (hazard ratio [HR], 1.29 for the combination [95% CI, 1.17-1.42]; HR, 1.29 for PPI alone [CI, 1.21-1.37]), indicating that the risk of a PPI with clopidogrel was no higher than a PPI alone. The authors conclude that there seems to be no significant interaction between PPIs and clopidogrel; however, PPIs may be associated with an increased risk for adverse CV outcomes after discharge. The authors postulate that the increased CV risk from PPIs is likely caused by unmeasured confounders (Ann Intern Med 2010;153:378-386). As pointed out in an accompanying editorial, this study may be very confusing for clinicians who have recently received warnings regarding the combination of clopidogrel with a PPI. It further highlights the potential risks of PPIs in patients with questionable or inappropriate indications for the drugs and the need for further studies into their risks and benefits (Ann Intern Med 2010;153:413-415).

Glucosamine and chondroitin

Millions of patients take glucosamine and chondroitin on a daily basis, hoping it is a safe alternative treatment for osteoarthritis. A new study suggests that the combination is ineffective but harmless. In a meta-analysis of 10 trials and more than 3800 patients, glucosamine, chondroitin, or the combination was compared to placebo with regard to pain scores and X-ray appearance of the hip and knee joint. None of the endpoints crossed the boundary of the minimal clinical important difference (95% credible intervals). The authors conclude that compared with placebo, glucosamine, chondroitin, and the combination do not reduce joint pain or have an impact on narrowing of joint space of the hip or knee. They further state that insurers should not cover the cost of these preparations, but since there is little harm, patients may wish to continue buying and taking it (BMJ 2010;341:c4675).

FDA Actions

The FDA has announced that it will significantly restrict the use of rosiglitazone (Avandia®) to patients with type 2 diabetes who cannot control the disease on other medications. The FDA had the option of removing the drug from the market, a move that was recently taken by the European Medicines Agency; however, the agency decided to limit access at least for now. Rosiglitazone has been associated with an elevated risk of cardiovascular events.

The FDA has approved fingolimod (Gilenya®), the first oral drug to reduce relapses and delay disability progression in patients with relapsing-remitting multiple sclerosis. The drug is the first of a new class called sphingosine 1 phosphate receptor modulators. Patients need to be closely monitored for symptomatic bradycardia. Fingolimod will be marketed by Novartis Pharmaceuticals.

The Endocrinologic and Metabolic Drugs Advisory Committee of the FDA has voted against recommending approval of lorcaserin hydrochloride for the treatment of obesity (see September Pharmacology Watch). Although the drug was shown to be effective, resulting in at least a 5% body weight loss for half of patients taking the drug over 1 year, there were concerns over valvular heart disease. Arena Pharmaceuticals argued that valvulopathy was not a significant issue and that they met the FDA's predefined goals for safety. The FDA is not required to follow subcommittee recommendations, however it usually does.

The same subcommittee also recently reviewed the weight-loss drug sibutramine (Meridia-Abbott Laboratories) and delivered a split vote on whether sibutramine should stay on the market. Sibutramine has been the subject of controversy since last November when initial data from the Sibutramine Cardiovascular Outcomes trial revealed a higher rate of cardiovascular disease associated with the drug. The full study was published in September and showed that cardiovascular events were observed significantly more frequently in the sibutramine group than in the placebo group (11.4% vs 10.0%; P = 0.02). The rate of cardiovascular death or death from any cause, however, was no different in the two groups (N Engl J Med 2010;363:905-917). The FDA subcommittee voted 8-8, with 8 members voting to remove the drug from the market and the other 8 voting to allow the drug to remain on the market with tougher warnings and a restricted distribution pattern. The FDA vote is expected later this fall.

The FDA has approved pegloticase for the treatment of refractory gout in patients who have not responded to or can't tolerate conventional therapy. The drug is administered intravenously every 2 weeks. It appears to work by metabolizing uric acid to allantoin, which is then cleared through the kidneys. The approval was based on two 6-month trials in more than 200 patients that showed the drug reduces uric acid levels and reduces uric acid deposits in joints and soft tissue. About one in four patients will experience severe allergic reactions to the infusion, so patients should be given an antihistamine and a corticosteroid prior to administration. The drug was not studied in patients with congestive heart failure and should not be used in this population. Savient Pharmaceuticals will market pegloticase as Krystexxa™.

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. 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: