Pharmacology Watch

Zolpidem and Risk of Falls in Hospitalized Patients

In this issue: Zolpidem and risk of falls; AVR and anticoagulation; statins in cancer patients; and FDA actions.

Zolpidem and risk of falls

Zolpidem (Ambien) increases the risk of falls in inpatients, according to a new study from the Mayo Clinic. The records of hospitalized patients who were not in the intensive care unit were reviewed in this retrospective cohort study. The rate of falls was compared in those who were administered zolpidem vs those for whom it was prescribed but not administered. After controlling for age, gender, insomnia, delirium, dose of zolpidem, Charlson comorbidity index, Hendrich's fall risk score, length of stay, visual impairment, gait abnormality, dementia/cognitive impairment, and concomitantly administered meds, the rate of falls was four times higher in those administered zolpidem (n = 4962) vs those who were prescribed but did not receive zolpidem (adjusted odds ratio 4.37, 95% confidence interval [CI], 3.34-5.76; P < 0.001). The authors conclude that zolpidem was a strong, independent, and potentially modifiable risk factor for inpatient falls. The authors suggest that changing order sets so that zolpidem use is not encouraged could potentially reduce fall rates in hospitalized patients. They also suggest that there is limited evidence to recommend other hypnotic agents as safer alternatives (J Hosp Med published online Nov. 19, 2012. doi: 10.1002/jhm.1985).

Anticoagulation and AVR

Bioprosthetic valves are preferred to mechanical valves for aortic valve replacement (AVR) in the elderly because of lack of need for anticoagulation in the long-term, but short-term anticoagulation is required. The duration of anticoagulation after valve replacement has been unclear. Now, a new study from Denmark suggests 6 months is optimal. Using the Danish National Patient Registry, more than 4000 patients who had a bioprosthetic AVR between 1997 and 2009 were identified. Rates of stroke, thromboembolic events, cardiovascular death, and bleeding were assessed along with warfarin treatment duration. Rates of events per 100 person-years in patients not treated vs those treated with warfarin for 3 months were 7 vs 2.7 for stroke, 13 vs 4 for thromboembolic events, 11.7 vs 5.4 for bleeding, and 32 vs 3.8 for cardiovascular death. The rate of cardiovascular death was 6.5 vs 2.0, favoring warfarin from 90 days to 179 days. The authors conclude that stopping warfarin within 6 months of bioprosthetic AVR surgery was associated with increased cardiovascular death. These findings challenge the current guidelines that recommend 3 months of antithrombotic treatment after AVR surgery suggesting that "patients will gain from an additional 3 months of warfarin treatment in terms of reduced cardiovascular death without risking significant increase in bleeding events" (JAMA 2012;308:2118-2125). An accompanying editorial states that this study provides important information to help clinicians understand the benefits and risks of warfarin use after bioprosthetic aortic valve implantation, but it does not address the issue of adjunctive aspirin or the role of new novel oral anticoagulants (JAMA 2012;308:2147-2148).

Statins in patients with cancer

Patients taking a statin when diagnosed with cancer have a better prognosis than patients who are not taking statins, according to a new study. This study also used the Danish Registry in which all patients with a cancer diagnosis between 1995 and 2007 were evaluated. Roughly 19,000 patients were on a statin prior to diagnosis and 277,000 were not. Those taking statins were 15% less likely to die of any cause and 15% less likely to die of cancer (hazard ratio 0.85, 95% CI, 0.82-0.87 for cancer). The benefit was present regardless of statin dose or cancer type. The authors suggest that this is biologically plausible since cholesterol is needed for cell proliferation. They suggest "a need for trials of statins in patients with cancer" (N Engl J Med 2012;367:1792-1802). Previous studies have suggested reduced cancer mortality with statins in patients with prostate cancer and reduced recurrence rates in breast cancer patients.

FDA actions

The FDA has concluded a safety review of dabigatran (Pradaxa) and found that the drug is not associated with more serious bleeding events than warfarin. The review was done using insurance claims and data from the FDA's Sentinel Initiative. According to the FDA, the bleeding rates are consistent with the observations from large clinical trials, including RE-LY, which showed that bleeding rates in patients newly started on dabigatran were similar to rates associated with new use of warfarin. Therefore, the FDA has not changed its recommendation regarding dabigatran (FDA Drug Safety Communication, Nov. 2, 2012). The next day, The New York Times published an article reporting that dabigatran has been associated with more than 500 deaths in the United States since it was introduced. It also detailed several tragic cases of bleeding deaths associated with the drug. The article indicts the FDA stating "... the approval process was not sufficiently rigorous because it allowed a potentially dangerous drug to be sold without an option for reversing its effects." The article also mentions more than 100 lawsuits that have been filed in federal courts "...and thousands more are expected" (The New York Times Nov. 3, 2012:B1).

The FDA has expanded the approval of rivaroxaban (Xarelto) to include treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), both for acute treatment and prevention of recurrence. The drug is already approved for prevention of DVT and PE after knee and hip replacement surgery and for prevention of stroke in patients with non-valvular atrial fibrillation. It is the first oral drug approved to treat DVT and PE since warfarin was approved 60 years ago; but unlike warfarin, rivaroxaban can be used as monotherapy from diagnosis until treatment is discontinued. Approval was based on three studies of nearly 9500 patients with DVT or PE randomized to rivaroxaban, enoxaparin/vitamin K antagonist, or placebo. Rivaroxaban was equivalent to enoxaparin/vitamin K antagonist and superior to placebo for preventing recurrent DVT or PE.

The FDA has approved a new egg-free flu vaccine for adults. The vaccine is manufactured using cultured mammalian cells instead of fertilized chicken eggs. The manufacturer claims that the cell culture technology enables a rapid response to public health needs, such as a pandemic, since cell culture technology allows vaccines to be manufactured within weeks as opposed to traditional flu vaccines that depend on a large number of fertilized chicken eggs to grow the virus. Cell culture technology is used for several other vaccines including polio, rubella, and hepatitis A vaccines. Approval was based on a randomized, controlled clinical study of 7700 adults ages 18-49. The new vaccine was 83.8% effective in preventing influenza when compared to placebo. Injection site reactions are the most common side effects. The new vaccine is marketed as Flucelvax by Novartis.

The FDA has approved the first Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). Tofacitinib, dosed orally twice a day, is approved for RA patients who have failed methotrexate. The drug will compete with the parenteral RA drugs adalimumab (Humira), etanercept (Enbrel), and infliximab (Remicade). Tofacitinib carries a boxed warning regarding the increased risk of opportunistic infections, tuberculosis, cancers, and lymphoma; increases in cholesterol and liver enzymes; and decreases in blood counts. Approval was based on seven clinical trials in which the drug showed improvements in clinical response and physical function compared to placebo in patients with moderate-to-severe RA. Tofacitinib will be marketed by Pfizer as Xeljanz. The cost is projected to be just over $2000 per month, similar to other non-methotrexate biologic treatment options.

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: