Pharmacology Watch

Statin Use in Patients with Abnormal Liver Function

In this issue: Statins and liver function; dosing timing for thyroxine; rivaroxaban for VTE, DVT, and stroke; echinacea and the common cold; and FDA actions.

Statins and liver function

Most physicians are hesitant to use statins in patients with abnormal liver function tests (ALT or AST less than three times the upper limit of normal). A new study suggests that not only are statins safe and effective, they may improve liver abnormalities in patients with fatty liver. In a study recently published in the Lancet, 437 patients enrolled in the Greek Atorvastatin and Coronary Heart Disease Evaluation study population were noted to have moderately abnormal liver tests at baseline, which were possibly associated with non-alcoholic fatty liver disease. Of that group, 227 were treated with a statin (atorvastatin) and 210 were not. Patients treated with a statin had substantial improvement in liver tests (P < 0.0001), whereas the group not treated with a statin had further increases in liver enzyme concentrations. Cardiovascular events occurred in 10% of atorvastatin-treated patients vs 30% of the non-statin group (60% relative risk reduction; P > 0.0001). This was a greater improvement in benefit than seen in patients with normal liver function tests. Fewer than 1% of the participants who received a statin had to discontinue statin treatment because of transaminase concentrations more than three times the upper limit of normal. The authors concluded that "statin treatment is safe and can improve liver tests and reduce cardiovascular morbidity in patients with mild to moderately abnormal liver tests that are potentially attributable to nonalcoholic fatty liver disease" (Lancet 2010;376:1916-1922).

Dosing timing for thyroxine

When is the best time to take thyroxine? Patients are generally told to take it on an empty stomach in the morning and wait at least 30 minutes before eating. A new study suggests that taking thyroxine at bedtime might be a better option. Over 6 months, 105 patients were randomized to take 1 capsule in the morning and 1 capsule at bedtime (one containing levothyroxine and the other a placebo), with a switch after 3 months. Taking levothyroxine at bedtime lowered thyrotropin levels and increased free thyroxine and total triiodothyronine levels (the primary outcome). Treatment did not change secondary outcomes including quality of life. The authors concluded that taking levothyroxine at bedtime is a good alternative to morning intake (Arch Intern Med 2010;170:1996-2003). This would likely benefit patients who find it difficult to wait 30 minutes to eat after taking their thyroxine each morning.

Rivaroxaban: an oral, factor Xa inhibitor

Rivaroxaban is an oral, direct factor Xa inhibitor that is approved in several countries for the prevention of venous thromboembolism (VTE) after orthopedic surgery. It is currently being evaluated by the FDA for this indication. Based on the findings of the EINSTEIN study, it appears the drug is also effective for the treatment of acute deep vein thrombosis (DVT). EINSTEIN consists of three randomized trials of rivaroxaban, one for the treatment of acute DVT, one for treatment of acute pulmonary embolism, and one for continued, long-term treatment in patients who have received treatment for acute DVT or pulmonary emboli. The results of the first and third wings of the study were recently reported in the New England Journal of Medicine.

In the DVT treatment arm, 3449 patients with acute DVT were randomized to rivaroxaban (50 mg twice daily for 3 weeks, followed by 20 mg once daily) or subcutaneous enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol) for 3, 6, or 12 months. In the continued treatment wing of the study, patients were randomized in a double-blind fashion to rivaroxaban 20 mg once daily or placebo for additional 6 or 12 months after completion of 6-12 months of treatment for VTE. The primary outcome for both studies was recurrent DVT. For the treatment of acute DVT, rivaroxaban was non-inferior to enoxaparin-vitamin K antagonist (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.44-1.04; P < 0.001). In the continued treatment study, rivaroxaban had superior efficacy compared to placebo (8 events [1.3%] vs 42 events [7.1%] with placebo; HR 0.18; 95% CI, 0.09-0.39; P < 0.001). There were four patients in the rivaroxaban group with non-fatal major bleeding vs none in the placebo group. The EINSTEIN authors concluded that "Rivaroxaban offers a simple, single-drug approach to the short-term and continued treatment of venous thrombosis that may improve the benefit-to-risk profile of anticoagulation" (N Engl J Med 2010;363:2499-2510).

Rivaroxaban is also being evaluated for the prevention of stroke in patients with nonvalvular atrial fibrillation based on the ROCKET AF study, which was presented at the American Heart Association meetings in November 2010. If approved, it will join the recently approved direct thrombin inhibitor dabigatran (Pradaxa®) for this indication. Both drugs have the advantage over warfarin of not requiring ongoing lab monitoring.

Echinacea and the common cold

The National Center for Complementary and Alternative Medicine (NCCAM), a division of NIH, has been in existence for nearly 20 years, much of the time under the intense scrutiny of the mainstream medical community. Despite NCCAM's attempts to verify the effectiveness of alternative healing practices, most if not all rigorously studied modalities have been shown to be ineffective. The benefit of another alternative staple, echinacea, is questioned with the publication of a NCCAM-sponsored study testing the benefit of the herbal remedy for treating the common cold. More than 700 patients in Wisconsin with new-onset common cold were assigned to one of four groups: no pills, placebo pills (blinded), echinacea pills (blinded), or echinacea pills (unblinded). The primary outcome was severity of the cold by self reporting with secondary outcomes of interleukin-8 levels and neutrophil counts from nasal washes. The comparison of the two blinded groups showed a trend toward benefit for the echinacea group (an average decrease in duration of cold of 7-10 hours out of 1 week; P = 0.089), but no difference in mean illness duration. There were no differences in the secondary outcomes. The authors concluded that the differences in illness duration and severity were not statistically significant with echinacea compared to placebo (Ann Intern Med 2010;153:769-777).

FDA Actions

The FDA is removing the breast cancer indication for bevacizumab (Avastin-Genentech). The somewhat unusual move was made after an FDA advisory panel suggested last summer that the drug did not provide a survival benefit for patients with breast cancer and at the same time caused serious side effects. The drug is still approved for treating cancer of the brain, colon, kidney, and lung.

The FDA advisory panel is recommending approval for the first new diet pill in a decade. Orexigen Therapeutics' Contrave® is a combination of the antidepressant bupropion and the opioid antagonist naltrexone. The drug was recommended for approval by a vote of 13-7, with some committee members voicing concern about potential side effects of the drug and recommending close post-marketing follow-up and studies to assess the risk of major cardiac events. The recommendation to approve the drug was based on studies that show an average weight loss 4.2% greater than placebo.

The FDA has approved denosumab for the prevention of skeletal related events (fracture and bone pain) in patients with bone metastases from solid tumors. The drug, which is given as a once monthly injection, was approved after a 6-month priority review. Denosumab is a monoclonal antibody to RANKL, a protein essential for the formation, function, and survival of osteoclasts. Denosumab in a lower-dose formulation was recently approved for the treatment of osteoporosis under the trade name Prolia™. Amgen Inc. will market the drug for this new indication under the trade name Xgeva™. It is expected to compete strongly with Novartis Pharmaceutical's zoledronic acid (Zometa®), which is approved for the same indication.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, Northern California; Assistant Clinical Professor of Medicine, University of California-San Francisco. Dr. Elliott reports no financial relationships to this field of study. Questions and comments, call: (404) 262-5468. E-mail: