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Apixaban and Rivaroxaban Near Approval for Nonvalvular AF
In this issue: Apixaban and rivaroxaban near approval for nonvalvular atrial fibrillation; fidaxomicin for C. difficile infections; guideline for intensive insulin therapy; and FDA Actions.
Dabigatran for stroke in patients with nonvalvular atrial fibrillation
Dabigatran, a direct thrombin inhibitor, recently was approved for prevention of stroke in patients with nonvalvular atrial fibrillation. The evidence for its benefit is strong enough that the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society recently upgraded their atrial fibrillation guidelines to include dabigatran (Circulation published online February 14, 2011). Meanwhile, the direct factor Xa inhibitor rivaroxaban is working its way through the FDA approval process for the same indication, with approval expected later this year. The latest player in the field is apixaban, also a direct factor Xa inhibitor. Apixaban was studied in a double-blind Phase 3 study of 5599 patients with atrial fibrillation who were at increased risk for stroke and for whom vitamin K antagonist therapy was unsuitable. Patients were randomized to receive apixaban 5 mg twice daily or aspirin 81-324 mg per day with a mean follow-up of 1.1 years. The primary outcome was occurrence of stroke or systemic embolism. The study was terminated early because of a clear benefit in favor of apixaban. There were 51 events (1.6 % per year) in the apixaban group vs 113 events (3.7% per year) in the aspirin group (hazard ratio with apixaban 0.45, 95% confidence interval 0.32-0.62; P < 0.001). The death rate was 3.5% in the apixaban group vs 4.4% in the aspirin group (P = 0.07). The rates of major bleeding or intracranial hemorrhage were similar; however, the risk of first hospitalization for cardiovascular causes was significantly lower with apixaban. The authors suggest that apixaban is more effective than aspirin. In indirect comparisons, apixaban is more effective than aspirin plus clopidogrel and at least as effective as warfarin in preventing stroke or systemic embolism in patients with atrial fibrillation (N Engl J Med published online February 10, 2011). Apixaban is currently being studied head-to-head with warfarin in the ARISTOTLE trial. If the data from that trial looks favorable, it is likely that both apixaban and rivaroxaban also will be approved for this indication in the not-too-distant future. Dabigatran and apixaban are both dosed bid while rivaroxaban is a once-a-day drug. The extent to which these drugs gain general usage at the expense of warfarin in large part will be due to patient preference and cost.
Fidaxomicin for C. difficile infections
A new option may soon be availiable for treating Clostridia difficile infections. Fidaxomicin (not yet approved in this country) is a non-systemic (poorly absorbed) narrow spectrum macrolide antibiotic that is bacteriocidal against C. difficile infections. It recently was compared to vancomycin in a head-to-head Phase 3 noninferiority study of 629 adults. Patients with a positive stool toxin test to C. difficile were randomized to fidaxomicin 200 mg twice a day or vancomycin 125 mg four times a day. The primary endpoint was clinical cure and the secondary endpoint was recurrence within 4 weeks and global cure (no recurrence). Fidaxomicin was noninferior to vancomycin in both the intention-to-treat (88.2% cure rate with fidaxomicin vs 85.8% with vancomycin) and per-protocol analysis (92.1% and 89.8%, respectively). Significantly fewer patients had recurrence with fidaxomicin in both groups (15.4% vs 25.3%, P = 0.005 intention-to-treat, and 13.3% vs 24.0%, P = 0.004 per protocol) although the lower rate of recurrence was in the less virulent strains. For the more virulent strains, the recurrence rate was about 25% for both drugs. Fidaxomicin was associated with a higher rate of hyperuricemia and elevated transaminases (N Engl J Med 2011;364:422-431). An accompanying editorial points out that the incidence and virulence of C. difficile infections is increasing at an alarming rate in this country. Fidaxomicin inhibits vegetative forms of C. difficile while preseving intestinal flora, a combination that holds promise, and if borne out "this new agent could become a recommended therapy for C. difficile infection" (N Engl J Med 2011;364:473-475).
Guideline for intensive insulin therapy
A guideline from the American College of Physicians (ACP) recommends against aggressively controlling blood glucose in hospitalized patients. Intensive insulin therapy (IIT) is no longer recommended for patients in intensive care units, regardless of whether they have diabetes. Specifically, the ACP recommends not using IIT to strictly control blood glucose or even normalized blood sugar in surgical ICU or medical ICU patients, and recommends a target blood glucose level of 140-200 mg/dL if insulin therapy is used. The recommendation is based on multiple studies that show no reduction in mortality with a blood glucose target of 80-180 mg/dL compared with higher targets using a variety of intensive insulin regimens. This includes treatment of patients with myocardial infarction, stroke, acute brain injury, or those under perioperative care. The guideline further recommends that avoiding targets less than 140 mg/dL should be a priority because harm is likely with lower blood glucose targets (Ann Intern Med 2011;154:260-267).
The FDA is warning against the use of terbutaline for prevention or prolonged treatment of preterm labor in pregnant women. The drug, which is approved for treatment of asthma, has been used off label for treatment of preterm labor and uterine hyperstimulation; however, the agency has received postmarketing reports of serious adverse reactions, including heart problems, and even maternal deaths, associated with the drug. The FDA has added a Boxed Warning and Contraindication to the labeling of the drug warning against these uses. This extends to both the IV and oral forms of terbutaline.
The FDA has approved hydroxyprogesterone caporate injection to reduce the risk of preterm delivery before 37 weeks of pregnancy in a pregnant woman with a history of at least one spontaneous preterm birth. The drug is not intended for use in women with a multiple pregnancy, such as a twin pregnancy, or other risk factors for preterm birth. The drug was approved under the FDA's accelerated approval regulations, and, as such, additional studies will be required after approval to show that the drug does indeed have clinical benefit. Hydroxyprogesterone caproate is given once a week by injection into the hip beginning at week 16 and no later than week 21. The drug is marketed by Hologic Inc. as Makena.
The FDA has issued a drug safety alert regarding the risk of serious liver injury with dronedarone (Multaq). The drug which is approved for prevention of atrial fibrillation/flutter has been associated with multiple cases of severe liver injury, including two cases that required liver transplantation. Dronedarone previously was found to double the risk of death in patients with severe heart failure and was approved with a REMS designed to prevent its use in that patient population. Physicians are reminded to advise patients to contact a health care professional immediately with any signs of hepatic injury or toxicity. All patients on dronedarone should get periodic hepatic serum enzymes especially during the first 6 months of therapy.
The FDA has approved a new treatment for head lice. Spinosad is an insecticide originally derived from a naturally occurring soil bacterium. The 0.9% topical suspension was shown to be effective in two Phase 3 active-control, randomized studies in which 86% of patients treated with the active drug were lice free after 14 days compared to 44% of controls. The product should not be used in children under 6 months of age because it contains benzyl alcohol. Spinosad is applied as a single 10-minute application which may be repeated in one week if lice are seen. It will be marketed by ParaPro LLC as Natroba.
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) 262-5404. E-mail: firstname.lastname@example.org.