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Building the case for PGx testing

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William Check, PhD

January 2013—Mammals have a striking range of gestation periods, from the 12 days and 31 days of the opossum and rabbit to the 266 days and 360 days of the human and whale. Laboratory tests, too, take shorter or longer amounts of time to be delivered into routine clinical practice, with pharmacogenomics beginning to look like the elephant—more than 600 days’ gestation—of laboratory testing. Our first major discussion of this topic was in 2005, and the clinical pathology world had been “expecting” its arrival for some time before that.

Perhaps it’s finally time to hang the stork sign on the laboratory door. In a plenary session at the Association for Molecular Pathology 2012 Annual Meeting on Genomic Medicine, Michael Laposata, MD, PhD, the Edward and Nancy Fody professor of pathology and a professor of medicine at Vanderbilt University School of Medicine, spoke on “Making the Case for Pharmacogenomics Testing: Integration into a Healthcare System.” In his talk, Dr. Laposata, who is also pathologist-in-chief at Vanderbilt University Hospital, described Vanderbilt’s pharmacogenomics program, called PREDICT—Pharmacogenomic Resource for Enhanced Decisions in Care and Treatment.

As Dr. Laposata presented it, the case for pharmacogenomics is self-evident and seemingly incontrovertible. “Would it not be great,” he asked attendees, “if we could select the right antihypertensive or the right antidepressant or the right antiplatelet agent immediately—rather than using the trial and error method and having a poor patient outcome until the drug that works is identified?” PREDICT seeks to achieve this goal for four analytes: warfarin, clopidogrel, simvastatin, and azathioprine. Tamoxifen, abacavir, and tacrolimus are in the works for 2013.

While prior attempts to initiate pharmacogenomics testing centered on warfarin, PREDICT focuses on clopidogrel (Plavix). “It was unfortunate that pharmacogenomics started with warfarin,” Dr. Laposata said in an interview with CAP TODAY. “That experience put a cloud over the whole pharmacogenomics story.” With clopidogrel, on the other hand, “This is where it really matters,” he says. “The case for [PGx for] Plavix is far more compelling.”

Even so, Vanderbilt administrators are not yet seeking payment or reimbursement for pharmacogenomics testing. “We at Vanderbilt do more [pharmacogenomics] because we’re willing to do it without being paid for it,” Dr. Laposata told CAP TODAY. “The key to marketing pharmacogenomics, like any test, is to show how you would use it for taking care of patients. If you try to move government to pay for something that sounds good but they can’t see any concrete benefit, it’s never going to happen. We need to show benefit first.” To this end, Dr. Laposata and his colleagues are collecting clinical experience and conducting a single-center trial.

Dr. Allan

A similar approach and attitude are prevalent at the University of North Carolina, where genotyping of CYP 2C19 alleles, which determine clopidogrel metabolism, is part of routine care. “Our cardiology group is very proactive doing genotyping in their percutaneous coronary intervention patients receiving stents since the FDA’s black-box warning about poor metabolism [of Plavix] increasing the risk of death due to thrombotic events,” says Karen Weck, MD, professor of pathology and laboratory medicine and genetics at UNC and director of molecular genetics. “That test has had the biggest clinical uptake of any pharmacogenomics test here at UNC.” Dr. Weck is associate director of the UNC Institute for Pharmacogenomics and Individualized Therapy.

Like the Vanderbilt group, Dr. Weck and her colleagues have been taking an evidence-based approach. “We have been involved in several clinical trials of pharmacogenomics,” she says. “We have finished a trial for warfarin and are now evaluating the data.” They also did a trial of PGx testing for tamoxifen metabolism and a dose-escalation trial with clopidogrel.

Also like Vanderbilt, UNC is not yet heavily emphasizing reimbursement. “We are charging insurance, since it is a clinical test,” Dr. Weck says. “But I don’t have the data
for how often we are being reimbursed.” 

At the University of Florida College of Medicine, the pathology, pharmacy, and information technology departments collaborated to set up pharmacogenomics testing for clopidogrel. “We believe it will become a big part of future medicine,” says Michael Clare-Salzler, MD, chair and Stetson professor in experimental pathology and director of the Center for Immunology and Transplantation. “We incorporated it as part of our development of molecular medicine. It is not accepted by everyone yet, but it has pretty strong acceptance in the pharmacogenomics community.”

“We see pharmacogenomics for CYP 2C19 as a pilot project,” says Robert Allan, MD, associate professor of pathology and medical director of UF PathLabs. “It is a good prototype to set up the lab protocol and get the chip validated.”

They are also doing a study, in this case to collect data on several other pharmacogenomic applications. “The cost to do genotyping on 256 SNPs [on one chip] is no more than just doing CYP 2C19,” Julie Johnson, PharmD, distinguished professor of pharmacy and medicine, says. “We will generate lots of data, then figure out which genotypes are clinically actionable and make them available.”

Dr. Johnson

Despite all this activity, it is still possible that pharmacogenomics will be an example of “The elephant labored and brought forth a mouse.” For one thing, Dr. Weck notes, “I hear a lot of controversy about whether CYP 2C19 testing should be done. There is some conflicting literature about whether poor metabolizers [of clopidogrel] have an increase in adverse events.” And, of course, we are still awaiting direct evidence that testing for CYP 2C19 will prevent the adverse events.

But a larger issue looms over pharmacogenomics. It may simply disappear as a distinct individual field of testing, subsumed under the 500-pound gorilla in the room—next-generation sequencing. During his AMP talk, Dr. Laposata showed the number of adverse events expected at his hospital from six drugs that are or will be in the PREDICT program. “With next-generation sequencing we get all of these at once,” he said.

Dr. Weck and her colleagues have been awarded a grant to do whole exome sequencing on patients with five medical conditions likely to have a genetic etiology (“Whole exome sequencing and pharmacogenomics,” page 30.) As a side benefit, she says, “We will be getting pharmacogenomic information on all these patients.” She’s particularly interested in the pharmacogenomic component because she thinks it could have the most usefulness in terms of medical treatment.

In his talk, Dr. Laposata reviewed the “unenthusiastic” reception given to pharmacogenomics for warfarin. As a valuable anticlotting agent, warfarin is used in millions of patients each year. “If I have a clot, someone’s going to give me a shot of Lovenox and a pill of Coumadin,” Dr. Laposata said. However, because warfarin has a narrow therapeutic window, it must be dosed accurately, with an INR between 2.0 and 3.0 or 2.5 and 3.5, depending on the indication. Risk of intracranial hemorrhage increases 11-fold for an INR greater than 4.9 and 18-fold for an INR greater than 6.6. Genotyping for CYP C29 and vitamin K epoxide reductase (VKORC1) can help bring the INR into the therapeutic range more often.

However, he noted, physicians who use warfarin said, “I don’t think I need to do this.” He admits: The INR is “a pretty simple way to monitor these patients.”

“We’ve had 20-plus years of experience adjusting people’s Coumadin dose based on INR,” he tells CAP TODAY. “Many doctors know how to do it, including primary care doctors.” When the pharmacogenomic result came back in three to seven days, the INR was often already adjusted into the therapeutic range. “When we told the doctor a patient was hypersensitive to warfarin, the doctor said, ‘I know. I’m down to 2.5 mg per day of warfarin by following the INR.’”

“Clinical studies so far have not showed clinical benefit [of PGx for warfarin],” he adds.

Clopidogrel is another matter. “The Plavix story is much more convincing because there is no INR-type test,” he told his AMP audience. It has been known since 2005 that some patients don’t respond to clopidogrel (Serebruany VL, et al. J Am Coll Cardiol. 2005;45:246–251; Hochholzer W, et al. Circulation. 2005; 111:2560–2564). Among the lowest quartile of Plavix responders, there is a 40 percent risk of recurrent cardiovascular events at six months, compared with zero risk in the lowest two quartiles (Matetzky S, et al. Circulation. 2004;109:3171–3175). Clopidogrel is metabolized by CYP 2C19; by measuring this enzyme one can identify patients who do not have an adequate response and switch them to an alternative antiplatelet agent (Simon T, et al. N Engl J Med. 2009;360:363–375).

At Vanderbilt, testing for CYP 2C19 is done in all patients who are receiving a coronary artery stent by interventional cardiology, as well as patients seen in primary care who are expected to require a coronary artery stent. “Patients chosen for this testing qualify by a complex formula based on clinical and laboratory findings,” Dr. Laposata said. A switch to prasugrel or ticagrelor is recommended in patients homozygous or heterozygous for loss-of-function (LOF) alleles, the most common of which is *2. However, at least 10 alleles of CYP 2C19 are now known, several of which are rare but cause loss of function.“This is more complicated than it started out,” Dr. Laposata said.

To help the physician implement the pharmacogenomic result for CYP 2C19 into patient management, the Vanderbilt program provides support in the form of a pharmacy resident with a fact sheet, supplemented by a “content expert” whom the pharmacy resident can consult. Decision support is provided in the laboratory report, but it quickly became clear this was not adequate. Some physicians were confused by the “*” nomenclature. When Dr. Laposata said, “That’s an allele,” some said, “What’s an allele?” Faced with heterozygous results, some physicians interpreted them like sickle cell, in which only those who are homozygous for the mutant allele have the disease. They didn’t see the need to switch patients from clopidogrel.

Dr. Laposata doesn’t view this lack of familiarity with genetics in a negative way.

“If you’re a proceduralist, you should be spending your time getting better at your procedure,” he says. “I see my role as helping them understand. For a decision this big, most practitioners want to talk to an expert in the field rather than depend on a decision support printout. They want to talk to a colleague who does this for a living and ask, ‘What would you do if you were me?’”

Dr. Laposata shared an incident that demonstrated the potential value of pharmacogenomic testing. A patient received a stent during a two-week period when pharmacogenomic testing for Plavix was unavailable for technical reasons. During that time, the patient had an in-stent thrombosis. Subsequent testing showed that this patient was homozygous for LOF alleles. “This convinced many interventional cardiologists at Vanderbilt of the value of pharmacogenomic testing [for clopidogrel],” he said.

While anecdotes are emotionally powerful, only rigorous data are ultimately convincing, particularly for reimbursement purposes. Dr. Laposata and his colleagues are conducting a clinical study with two outcome measures. First, to determine the number of prescription changes away from Plavix when loss of function alleles are detected. Second, to determine the number of in-stent thromboses or major adverse coronary events in patients originally treated with Plavix and then switched to a different antiplatelet agent.

From March 2011 to February 2012, pharmacogenomic testing for clopidogrel was done in 3,312 patients; 149 had an actionable genotype and a drug-eluting stent. Of these, 131 received a recommendation for a medication change. Only 49 changes were actually made. “We don’t yet have a complete understanding why not everybody is changing medication,” Dr. Laposata says. “I think more changes would have been made if there had been more interaction between cardiologist and coagulation expert.” This interaction is now taking place. “As good as decision support on computer pages is, it really is doctor-to-doctor talk that makes a difference,” he says.

Dr. Laposata calls the second outcome measure, reduction in coronary events, “the big enchilada.”

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