Surgery News - April 2008 - (Page 4)

NEWS SURGERY NEWS • A P R I L 2 0 0 8 Advances in Genotyping Help Fine-Tune Warfarin Dosing BY MITCHEL L. ZOLER Else vier Global Medical Ne ws esearchers extended their understanding of how genetic-variant analysis can help target the correct warfarin dose when starting and maintaining patients on anticoagulant therapy, results from 297 patients show. Their goal is a reliable and cost-effective genetic test that can guide physicians to administering the ideal warfarin dose to each patient. Warfarin is tricky to use and requires frequent monitoring to make sure that each patient is maintained in their target anticoagulant range. “I have little doubt that in the future genotyping will become part of standard care for patients receiving warfarin,” said Dr. C. Michael Stein, lead investigator of the new study and professor of medicine and pharmacology at Vanderbilt University in Nashville, Tenn. Warfarin “is difficult to use and the consequences of overor under-anticoagulation are so potentially serious that incorporation of information that helps to predict response into the [dosing] algorithms used to treat patients is likely,” he said in an interview. Last August, the Food and Drug Administration approved adding to warfarin’s labeling information about the impact of genetic variations on dosing, and in Sep- R tember the agency approved marketing of a genetic test for the two genes that have the biggest impact on warfarin activity, VKORC1 and CYP2C9. In November, a team at LDS Hospital in Salt Lake City reported results from the first controlled study to compare genotype-guided warfarin dosing with a standard treatment algorithm that determined warfarin doses based only on age, gender, and weight. The results failed to show a significant effect of genotype guidance using VKORC1 and CYP2C9 for the study’s primary end point, a reduction in anticoagulant levels that were out of the target range for patients’ international normalized ratios (INRs) (Circulation, 2007;116:2563-70). The new study results, based on a median of 43 days of warfarin treatment, showed that genetic variants of VKORC1 are a major determinant of variability in sensitivity to warfarin both immediately after treatment starts and throughout treatment. In contrast, variants of the CYP2C9 genotype had a significant impact on INR levels only after the first 2 weeks of treatment (N. Engl. J. Med. 2008;358: 999-1008). “Our findings suggest that early on in therapy VKORC1 is a bigger determinant of dose requirement. But that does not mean one can ignore CYP2C9; it kicks in later,” said Dr. Stein. “Genotyping should still be done before the first dose [of warfarin], and it might as well be done for both variants at the same time,” commented Dr. Jeffrey L. Anderson, associate chief of cardiology at LDS Hospital in Salt Lake City and head of the Utah group. The new study enrolled adult patients who began a warfarin regimen at a Vanderbilt clinic during July 2002–July 2004. The target INR for each patient was selected by their physician on the basis of their indication for treatment. Patients underwent genotyping using tests that are not commercially available, and the study had no commercial sponsorship or other financial disclosures. (The earlier report from LDS Hospital also did not use commercial tests and had no commercial sponsorship or other financial disclosures.) The study had four primary outcomes: time to the first INR within the therapeutic range, time to first INR greater than 4.0, total time that INR levels were above the therapeutic range relative to total follow-up time, and overall INR response over time. These measures were assessed relative to the genotype profiles of each patient. The study was observational and was not designed to compare different strategies for calculating the optimal warfarin dose. The average age of the 297 patients in- cluded in the analysis was about 61 years. About 41% received warfarin following joint-replacement surgery, and 36% received anticoagulation because of atrial fibrillation or flutter. During the study, patients had a median of nine INR measurements with a range of 2-42 measures. In general, the VKORC1 haplotypes significantly affected INR levels throughout follow-up. This gene codes for vitamin K epoxide reductase, an enzyme involved in activating vitamin K, an essential clotting cofactor. Patients with one or two of the A haplotypes of this gene require lower warfarin doses to achieve their target INR than patients with two non-A alleles. Variants of the CYP2C9 genotype did not produce significant INR effects until after the first 2 weeks of warfarin treatment. This gene codes for a cytochrome P450 enzyme that is primarily responsible for the metabolic clearance of the S-enantiomer of warfarin. Patients with certain common genetic variants of this gene need lower doses of warfarin than do patients with the wild-type allele, and they have an increased risk of over-anticoagulation and serious bleeding. The study reported by the Utah group last November probably failed to show a significant clinical advantage from genotyping because it was too small, said both Dr. Anderson and Dr. Stein. Jury Still Out on Routine Use of Bispectral Index Monitoring B Y S H E R RY B O S C H E R T Else vier Global Medical Ne ws studies underway will help settle the Two debate about whether Bispectral Index monitoring should be used routinely on patients given general anesthesia in order to reduce or prevent awareness during surgery. Funded by two $500,000 grants from the American Society of Anesthesiologists and the Foundation for Anesthesia Education and Research, the randomized, blinded, controlled studies will look separately at a broad group of 30,000 patients undergoing surgery and a more select group of 6,000 surgical patients at higher risk of “anesthesia awareness.” Results should be available in 3-4 years. One or two patients among every 1,000 given general anesthesia can have some level of awareness and memory of events during surgery, ranging from hearing conversations to feeling pain and realizing they haven’t been given adequate anesthesia. Among higher risk patients—those undergoing procedures such as open heart surgery and emergency C-section, those taking medications that interact with anesthetics (such as drugs for pain or epilepsy), and those who cannot tolerate high levels of anesthetics—that number increases to 1 of every 100. “They can go on to have problems afterward like posttraumatic stress disorder,” said Dr. George Mashour, principal investigator of the all-comers trial. In recent years, high-profile cases have focused attention on anesthesia awareness. For example, in 2006, a 73-year-old minis- ter in Virginia was given paralyzing drugs in preparation for surgery but did not receive general anesthesia until 16 minutes after the first cut into his abdomen. His family said in a lawsuit against the hospital that he subsequently couldn’t sleep, suffered nightmares, and believed people were trying to bury him alive. He committed suicide 2 weeks after the surgery. Other patients who do receive general anesthesia at the appropriate time can come back to awareness during surgery. “I think the field may have been in a little bit of denial” about anesthesia awareness until recently, said Dr. Mashour, director of neuroanesthesiology at the University of Michigan, Ann Arbor. Patient advocates and manufacturers have pushed the use of Bispectral Index (BIS) monitors, which monitor brain electrical activity levels correlating with levels of unconsciousness and depth of anesthesia. Use of BIS monitors is not uncommon, especially for patients at higher risk of anesthesia awareness, though there is scant evidence of the superiority of BIS monitors over conventional—and less costly—monitoring methods to ensure adequate delivery of anesthesia. “Just because something is being used or being done doesn’t mean it should be,” said Dr. Michael Avidan, principal investigator of the trial for higher risk patients. “We need to have good justification for it.” The only prospective, randomized, controlled double-blind trial, which compared BIS monitoring with routine care in 2,463 adult surgical patients at high risk of anesthesia awareness, found an 82% reduction in the risk of awareness in the BIS group the anesthesiologist when a patient falls below a desired minimal alveolar concentration (MAC) level, the conventional monitoring method in the control group. An earlier pilot study by Dr. Avidan and associates in 2,000 high-risk patients suggested that an augmented MAC protocol is twice as sensitive as A slightly high Bispectral Index monitoring value indicated BIS monitoring for the need to administer more anesthesia preoperatively. detecting anesthe(reported in 2 patients) versus the control sia awareness. Adding the computer algogroup (reported in 11 patients) (Lancet rithm to MAC monitoring would require “a change in behavior and culture” in 2004;363:1757-63). In that Australian study, patients re- anesthesiology, but without adding cost, ceived IV general anesthesia—a practice Dr. Avidan noted. BIS monitors cost around $5,000 each, common outside the United States, where most anesthesia is administered via in- and the electrodes cost $17.50 per operahaled gases. “When giving an IV anes- tion. For the 21 million general anesthetthetic, you can’t measure the blood level ics administered each year in the United of the anesthetic in real time,” as you can States, the electrodes could add $368 milby measuring the gas that a patient lion in costs. A 2006 “practice advisory” from the breathes out, said Dr. Avidan, of Washington University, St. Louis. “You can American Society of Anesthesiologists imagine that a brain function monitor suggests that physicians consider using may be more useful when using an IV brain-monitoring machines like BIS monitors on a case-by-case basis rather than anesthetic.” The two current studies

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Surgery News - April 2008

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