CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
Dr. Gage
Although the primary endpoint was statistically significant, the significance was driven largely by the differences in INR greater than four. “The 27 percent relative risk reduction in adverse events was very similar to what we hypothesized,” Dr. Gage says. He adds: “The surprise was how well these elderly patients did after elective hip and knee replacement. Only 1.6 percent of 1,597 patients had a symptomatic deep venous thrombosis or PE. No one died during surgery or during his or her 90-day follow-up. Of course, most of the credit goes to the excellent teams caring for these patients” at Hospital for Special Surgery, Washington
University, Intermountain Healthcare, University of Utah, Rush University Medical Center, and University of Texas Southwestern. “The only intracranial hemorrhage occurred in a patient who fell a couple months after he stopped his warfarin therapy,” Dr. Gage says.
The small number of adverse events made the statistical data challenging for the investigators and clinicians to interpret. Moreover, the results are indicative of the challenge of relying on historical data to make statistical power calculations, particularly in a medical setting where constant improvement in outcomes is the aim.
Are the results applicable to other clinical settings and patient populations? Says Dr. Gage: “I think the results of GIFT are generalizable to other populations who have access to accurate, timely genotyping at the time of warfarin initiation. However, the absolute benefits of genotype dosing will depend on that population’s baseline rate of adverse events.” This speaks to the fact that GIFT took place in major medical centers and used a relatively homogeneous and well-defined patient population that underwent regular INR testing.
The trial also used a 2 × 2 randomization to help orthopedic surgeons answer the question of whether there are safety differences between an INR goal of 1.8 or 2.5. The data comparing potential differences in safety have not yet been published and are still under review, but the fact that half the patients had a lower INR target may have reduced bleeding complications.
GIFT compared pharmacogenetic-guided dosing to a refined clinical algorithm that is not yet the standard of care. “It’s one thing to estimate what the therapeutic dose would be,” Dr. McMillin says, “but it’s another to tell you how to get there using a refined electronic algorithm. It’s like the difference between using a GPS rather than just a map or an address. You could redirect based on how a patient was responding. When you have well-managed coagulation clinics, particularly in major medical centers, the performance of the clinical algorithm is very good and it’s hard to demonstrate an improvement. It was actually rather astounding that GIFT was able to show a difference.” Better results might be seen if pharmacogenetic dosing were tested in a more real-world situation, she adds.
Although the use of an electronic algorithm (for example, Gage, et al., warfarindosing.org) has never been compared with trial-and-error dosing, Dr. Eby believes it would be an improvement. Both are used at Washington University and the goal is to integrate the clinical algorithm into the new electronic health record system slated to come online this year. “The integration of the algorithm would be a short-term goal,” Dr. Eby says, “and I don’t think it comes at an additional cost. It’s one of the attractions of using the clinical algorithm. The information is already available and we can be optimistic it would improve INR control and precision even if we have not compared it to the trial-and-error standard of care.”
Using clinical algorithms rather than pharmacogenetic-guided dosing might be a more practical way to improve warfarin dosing, wrote Jon D. Emery, MBBCh, DPhil, professor of primary care cancer research at the University of Melbourne, in an editorial accompanying the GIFT results. Genotype-guided warfarin dosing probably has clinical utility, he wrote, “but it might be simpler and less expensive to implement wider use of clinical dosing algorithms to reduce the harms of anticoagulation.”
At the University of Utah, Dr. McMillin says, GIFT has reignited a discussion of the best way to administer warfarin, and the university is reconsidering whether to recommend genotyping. Before GIFT, physicians were reluctant to order the additional laboratory test or to integrate an electronic algorithm into their warfarin dose decision-making. The trial has changed that.
Two other changes have come out of GIFT. First is a recognition that it’s important to combine genes, Dr. McMillin says. “We in our community have been focused on single gene-drug pairs, and it’s very shortsighted, a little monovision. I love the warfarin example—a study where we’ve used three different genes because they all play a different role and they’re all important. So one outcome that’s already impacting the pharmacogenomics community is there are more people thinking about multi-gene impact.” Second, GIFT demonstrates success with an electronic algorithm—which is not standard of care now—whereby physicians consult an electronic resource to select drugs and doses. “This demonstrates it actually can work,” Dr. McMillin says.
Clinical benefits aside, a central question remains: reimbursement. The CMS funded GIFT and is reviewing the data, but a decision is not expected soon. Dr. Gage was a coauthor of a cost-effectiveness analysis of using pharmacogenetic information in warfarin dosing for patients with nonvalvular atrial fibrillation (Eckman MH, et al. Ann Intern Med. 2009;150[2]:73–83). He and his coauthors concluded: “For genetic testing to cost less than $50,000 per QALY, it would have to be restricted to patients at high risk for hemorrhage or meet the following optimistic criteria: prevent greater than 32% of major bleeding events, be available within 24 hours, and cost less than $200.” Although these three criteria were met in GIFT, he says, the cost-effectiveness studied in 2009 was for a different population.
Even as newer anticoagulants displace some warfarin use, warfarin is still likely to have an important place in the care of patients, Dr. Eby says, such as those with severe renal failure and mitral valve prosthetics and where financial resources are limited. But so far, the early promise of major pharmacogenomic benefit on patient care, including on warfarin dosing, has not been realized and cost-benefit questions loom large. Preemptive genotyping is one way to lower the cost and increase the benefit. As the cost of gene sequencing declines, it makes more sense clinically and economically to have pharmacogenetic data on a broad range of drugs as part of a patient’s record, which would remove time to result, among other benefits. Dr. McMillin cites the Ubiquitous Pharmacogenomics program in the European Union as the wave of the future. An 8,000-patient clinical trial is underway in the Netherlands, Spain, United Kingdom, Italy, Austria, Greece, and Slovenia to preemptively genotype 4,000 patients across 13 genes that affect the metabolism of 40 commonly prescribed drugs. Outcomes will be compared in the three-year study with those of 4,000 control patients. If the trial is successful, the goal would be to extend the U-PGx program to all EU residents.
Dr. McMillin
“The EU made a major commitment to pharmacogenomics because they think it’s worth it,” Dr. McMillin says. “There are a number of institutions in the U.S. that are doing work on preemptive genotyping and implementing smaller pieces, but it would be a problem for our health care system to implement a Ubiquitous approach because we’re not socialized enough.”
Absent a European-style centralized health authority, preemptive genotyping is a chicken-and-egg situation: Clinical demand is needed to drive positive reimbursement, and positive reimbursement is needed to drive clinical demand. Another necessity would be electronic decision support. “Such a system would do what the warfarindosing.org website does but automatically,” Dr. McMillin says. “It would take the genetic information that is preexisting, combine it with the clinical information that’s extracted, and provide that information directly to the clinician with some additional prediction of risk. The costs in that case have already been expended, so it comes down to the medical evidence that it is going to benefit the patient.” Clinicians will adopt preemptive genotyping, in her view, when it is incorporated into the clinical decision support components of electronic health records. “That’s really what it’s going to take.”
Before this can happen, Dr. McMillin says, there are a few nontechnical obstacles to overcome, and chief among them are the proprietary commercial algorithms. “One of the more unfortunate things in the marketplace right now is the development of proprietary algorithms. There are some companies that are charging huge amounts of money to guide drug and dose selection with their algorithms, and they are proprietary so it prevents access. To use psychiatry as an example, there are now over 20 algorithms that are out there, they’re all proprietary, and none have been compared head to head. The algorithms and the data behind them should be shared for everyone.”
A broader question concerns the future of clinical research like GIFT in a cost-constrained environment dominated by reluctant third-party payers. Why spend the money for the research if there is no way to pay for the benefit? The future may be some combination of using real-world data and sophisticated informatics and artificial intelligence tools, perhaps in partnership with third-party payers with incentives to save money and improve care.
The challenge, Dr. Eby says, is that randomized clinical trials can’t be conducted to answer every clinical question. “Although I am optimistic that clinical research will still drive and provide compelling evidence to change both the funding and practice of medicine, I think the dependence on randomized, controlled trials is what has to change.” Other reliable ways based on clinical experience have to be found to guide medical decisions and reimbursable practice. “This gets into a discussion of how clinical informatics and computational expertise can use real-world data to guide decision-making. And could this same way of analyzing existing data provide convincing data that the outcomes would be better or cheaper if certain practices were adopted?”
The combination of data from trials such as GIFT, the declining cost of genotyping, and advances in clinical informatics may finally allow the field of pharmacogenomics to fulfill its early promise. Though genotyping of warfarin might be hard to justify today given the cost and logistics, warfarin would most certainly merit priority placement on any pharmacogenomic panel of the future.
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Elizabeth Silverman, of New York, NY, is a writer who covers genomics.