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Warfarin May Be First to Apply Pharmacogenetics
In this issue: Individualization of therapy with pharmacogenetics; the rate vs rhythm debate; the FDA's Risk Evaluation and Mitigation Strategy; FDA actions.
Individualization with pharmacogenetics
Get used to the word "pharmacogenetics" — the discipline of studying genetic variation and its effect on responses to drugs. Warfarin dosing may be one of the first clinical applications of pharmacogenetics as it now appears that genetic testing may help predict an individual patient's response to the oral anticoagulant. Warfarin dosing can vary as much as 10 times from individual to individual, and currently, slow titration with frequent testing is the only way to safely initiate therapy. A new study, however, uses pharmacogenetic testing to estimate the appropriate warfarin dose. Reviewing data from more than 4000 patients, algorithms were developed based on clinical variables only or clinical variables plus genetic information (CYP2C9 and VKORC1). Compared to algorithms employing clinical data alone, algorithms employing genetic information more accurately identified a larger proportion of patients who would require low-dose (49.4% vs 33.3%; P < 0.001) or high-dose warfarin (24.8% vs 7.2%; P < 0.001). The authors conclude that pharmacogenetic algorithms for estimating the appropriate initial dose of warfarin produces recommendations that are significantly closer to the required stable therapeutic dose than algorithms derived from clinical data alone or a fixed-dose approach, particularly for those that require 49 mg or more per week or 21 mg or less per week. (N Engl J Med 2009;360:753-764). Although pharmacogenetic testing is not yet widely available and may be difficult to obtain prior to initiating warfarin therapy, an accompanying editorial states "pharmacogenetics has the potential to increase benefit and reduce harm in people whose drug responses are not 'average.'" (N Engl J Med 2009;360:811-813).
The rate vs rhythm debate
Rate control vs rhythm control for atrial fibrillation continues to be debated with most of the evidence falling on the side of rate control in recent years, primarily because of adverse effects from anti-arrhythmics. A new drug may change that however. Dronedarone, a derivative of amiodarone, lowers the hospitalization rate and death rate in atrial fibrillation according to a new phase 3 study. More than 4600 patients with atrial fibrillation and one additional risk factor for death (diabetes, stroke, CHF) were randomized to dronedarone 4 mg twice a day or placebo. The primary outcome was first hospitalization due to cardiovascular event or death. After follow-up of 21 months, 30% of patients in the treatment group and 31% patients in the placebo group stopped the drug prematurely due to adverse events. The primary outcome occurred in 31.9% of patients in the dronedarone group vs 39.4% in the placebo group (hazard ratio, 0.76; 95% confidence interval, 0.69-0.84; P < 0.001). Five percent (5%) of people died in the treatment group vs 6% in the placebo group (P = 0.18). Deaths from cardiovascular causes were 2.7% in the dronedarone group vs 3.9% in the placebo group (P = 0.03). The treatment group had higher rates of bradycardia, QT interval prolongation, nausea, diarrhea, rash, and increased creatinine levels. Dronedarone was not associated with higher rates of thyroid or pulmonary-related adverse events. The authors conclude that dronedarone reduced the risk of hospitalization due to cardiovascular events or death in patients with atrial fibrillation (N Engl J Med 2009;360:668-678). Dronedarone is not yet approved in this country, and is being evaluated for other cardiac arrhythmias as well as atrial fibrillation. A trial in heart failure (ANDROMEDA) was terminated early because of increased mortality associated with dronedarone (N Engl J Med 2008;358:2678-2687).
New rules for opioid prescribing
The FDA is considering new tightened restrictions on use of opioid drugs. Manufacturers of these drugs will be required to have a Risk Evaluation and Mitigation Strategy to ensure that "the benefits of the drugs continue to outweigh the risks." The affected opioids include fentanyl, hydromorphone, methadone, morphine, oxycodone, and oxymorphone. This is in response to raising rates of misuse and abuse of these drugs as well as accidental overdoses, which have increased in the last 10 years. The agency plans to have a number of meetings later this year that will include patient groups, federal agencies, and other non-government institutions. Part of the strategy is to make sure that physicians prescribing these products are properly trained in their safe use.
In February, the American Pain Society-American Academy of Pain Medicine Opioids Guidelines Panel published clinical guidelines for the use of chronic opioid therapy and chronic noncancer pain. The guideline was commissioned because of the increased use of chronic opioid therapy for noncancer pain and the high risk for potentially serious harm associated with these drugs including opioid-related adverse effects. The guideline's recommendations include: Before initiating chronic opioid therapy (COT), clinicians should conduct a history, physical, and appropriate testing including assessment of risk for substance abuse, misuse, or addiction. A benefit-to-harm evaluation should be performed and documented before starting COT and on an ongoing basis for all patients on COT. Informed consent should be obtained when initiating therapy, and a continuing discussion with the patient regarding therapy should include goals, expectations, risks, and alternatives. Clinicians may consider a written COT management plan. Patients should be reassessed periodically including monitoring of pain intensity and levels of functioning.
For high-risk patients or those who have engaged in aberrant drug-related behaviors, clinicians should periodically obtain urine drug screens or other information to confirm adherence to the plan of care. For patients at risk of addiction, mental health or addiction specialists should be consulted, and if aberrant drug-related behaviors continue, referral for assistance in management or discontinuation of COT should be considered. The guideline also deals with dose escalations, use of methadone, treatment of opioid-associated adverse effects, cognitive impairment associated with COT that may affect driving and workplace safety, use in pregnancy, and state and federal laws that govern the medical use of COT (J Pain 2009;10:113-130).
The FDA has issued a public health advisory regarding the risk of progressive multifocal leukoencephalopathy (PML) associated with use of efalizumab (Raptiva®) for the treatment of psoriasis. Four cases have been reported (3 have been confirmed). The FDA is recommending that health care professionals monitor patients on efalizumab, as well as those who have discontinued the drug, for signs and symptoms of neurologic disease.
The FDA has reaffirmed its position regarding cholesterol-lowering drugs stating that "elevated amounts of low-density lipoprotein … are a risk factor for cardiovascular diseases … and that lowering LDL cholesterol reduces the risk of these diseases." The statement is in response to results from the ENHANCE trial, which indicated that there was no significant difference between simvastatin plus ezetimibe (Vytorin®) vs simvastatin alone (Zocor®) in reducing carotid atherosclerosis. There was, however, a greater reduction in LDL in the Vytorin group vs the Zocor group (56% reduction vs 39% reduction, respectively). The statement from the FDA suggests that the results of ENHANCE do not change the FDA's position that greater LDL lowering is beneficial, and recommends that patients currently on Vytorin or other cholesterol-lowering medications should not change their therapy. The update is available on the FDA's web site at www.FDA.gov.
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: firstname.lastname@example.org.