By Turna Ray
Adoption of pharmacogenomically guided warfarin dosing — a strategy not widely prescribed by doctors and not generally reimbursed by insurers — could potentially face another hurdle with the approval of a new anticoagulant by the US Food and Drug Administration.
Last week, the FDA approved Boehringer Ingelheim's Pradaxa (dabigatran etexilate) for the prevention of stroke and blood clots in patients with atrial fibrillation. Pradaxa is an inhibitor of thrombin, an enzyme that facilitates blood clotting.
In the clinical trial supporting Pradaxa's approval, atrial fibrillation patients taking the drug had fewer strokes than those who took warfarin.
Furthermore, "unlike warfarin, which requires patients to undergo periodic monitoring with blood tests, such monitoring is not necessary for Pradaxa,” Norman Stockbridge, director of the Division of Cardiovascular and Renal Products at the FDA's Center for Drug Evaluation and Research, said in a statement announcing Pradaxa's approval.
Based on the price of Pradaxa in Canada, where the drug was approved in 2008, the new anticoagulant may cost four to five times more than generic formulations of warfarin, even with the additional costs related to therapeutic monitoring. Generic warfarin plus the cost of INR monitoring, costs between $500 and $600 per year. Following the US approval of Pradaxa, analysts estimated that the wholesale acquisition cost of the drug will be around $6.75 per day, and the price at the retail pharmacy will be $7.90 per day, or $237 per month.
At a conference on comparative effectiveness held at the National Institutes of Health's campus in Bethesda, Md., last week, some speakers felt that Pradaxa's entrance onto the market could relegate genetically guided warfarin dosing to the history books as one of the early examples of pharmacogenetics where the markers had clinical validity but lacked clinical utility.
The UK's National Health Service has authorized Pradaxa as a drug for the primary prevention of venous thromboembolic events in adults who have undergone hip replacement surgery or knee replacement surgery. According to a cost-effectiveness review by UK's National Institute of Health and Clinical Excellence, Pradaxa, without the need for monitoring, would reduce administration costs and may support adherence to treatment.
In the meantime, supporters of PGx testing to administer generic warfarin believe that the intervention could also improve outcomes and lower costs by avoiding adverse events in certain subpopulations. With PGx testing costing between $200 and $500, generic warfarin with genetic testing (even if it isn't covered by insurance) might still cost less per year compared to Pradaxa. No head to head study has been yet been reported comparing the cost and utility of PGx-guided warfarin dosing and Pradaxa.
The FDA first updated warfarin's label in 2007 to reflect the influence of the CYP2C9 and VKORC1 genes in metabolizing the drug. Although the agency recommended doctors consider lower initiation doses for patients with variations in these genes, at the time, the FDA held off on making specific dosing recommendations until ongoing outcomes studies were completed. Then, earlier this year, the FDA once again changed warfarin's label to include specific pharmacogenomically guided dosing ranges (PGx Reporter 02/03/10).
Even with FDA's guidance on PGx testing for warfarin and its approval of several tests, insurers and doctors have been reluctant to back the genetic strategy over traditional methods to dose the drug using INR monitoring and clinical factors. Critics say more data on clinical utility is needed and test results need to be available on a point-of-care basis for the intervention to be truly useful for patients with acute conditions.
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Meanwhile, supporters of the PGx strategy have maintained that genetic testing makes dosing more accurate and can reduce hospitalizations for non-acute health conditions. And now, even with the approval of Pradaxa, some believe the new therapy ─ indicated for atrial fibrillation patients and recommended at a lower dose in patients who have impaired kidney function ─ leaves open situations where it may be preferable to use the old drug with genetic testing.
Brian Gage, an internist and health service researcher at Washington University School of Medicine and one of the developers of warfarindosing.org ─ a website that calculates warfarin doses for healthcare providers using genetics and clinical factors ─ believes that genotyping-based warfarin dosing may be a better option for patient populations who can't receive Pradaxa.
Robert Epstein, Medco's chief medical officer, believes that with time the utility of personalized medicine strategies will unfold . "It is great for patients and physicians to have an alternative to warfarin after so many years with no other choice," Epstein told PGx Reporter. "Like any new drug, though, we will learn with actual patient experience more about the specific subpopulations who are better served by each agent."
Some of Medco's customers who have signed up to participate in the pharmacy-benefit manager's personalized medicine program have access to genetic testing for warfarin administration. In June, Medco published results from a PGx warfarin study in the Journal of the American College of Cardiology that found that genotyped patients, including those with atrial fibrillation, had 31 percent fewer all-cause hospitalizations and 28 percent fewer hospitalizations for bleeding or thromboembolism.
However, CVS Caremark's PBM division, which also launched a PGx testing pilot program this summer, has not made warfarin genotyping available to its customers. At the time of the program launch, Rick Schatzberg, CEO of Generation Health, said that by the time the test results come back, they are "no longer actionable." Generation Health is the genetic testing benefits management firm that is administering CVS' personalized medicine program.
In the end, when it comes to choosing the right anticoagulant for a patient, it will not be a black-and-white choice between warfarin and Pradaxa, but a far more nuanced decision factoring in market experience, cost, and genetics. Particularly, as more consumers have access to their pharmacogenetic data before arriving at a hospital or stepping into a doctor's office, the use of genetic information to dose warfarin will start to become more useful in the clinic.
"Pharmacogenetic testing for warfarin response is most impactful when the genotype is known before warfarin is prescribed," Schatzberg told PGx Reporter over e-mail. "This is because the genotype has the greatest potential to inform the initial doses (loading and maintenance doses)."
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The battle for scripts between warfarin with PGx testing and new fixed-dose anticoagulants like Pradaxa will also likely ensue when patients are first initiated on an anticoagulant. "To the extent that Pradaxa captures 'initial anticoagulant prescription choice' there will be less demand for genetic testing to inform initial warfarin doses," Schatzberg added. "However, because of decades of familiarity with warfarin and its low cost, warfarin will continue to be started and for those patients pharmacogenomic testing promises to improve safety while retaining efficacy."
Pradaxa vs. Warfarin PGx
Boehringer Ingelheim touted Pradaxa's approval as the first time in more than five decades that an alternative to warfarin is available to consumers.
Bristol-Myer Squibb's Coumadin was approved by the FDA in 1954; generic versions of the drug are available. Although more than 2 million patients are prescribed warfarin in the US annually, between 1 percent and 5 percent of patients experience a major bleeding event due to incorrect dosing. According to an American Enterprise Institute-Brookings paper, the annual costs associated with warfarin-related adverse reactions are in the order of $1.1 billion.
"The approval makes Pradaxa available to a broad spectrum of patients, with the 150 mg bid dose approved for all patients except for a small subset with severe renal impairment (creatinine clearance 15-30 mL/min) where the approved dose is 75 mg bid," Boehringer Ingelheim said in a statement.
The pivotal study used to support Pradaxa's approval, called the randomized evaluation of long term anticoagulant therapy trial, or RE-LY, investigated whether in more than 18,000 patients with atrial fibrillation two blinded doses of Pradaxa (150 mg twice daily and 110 mg twice daily) were as effective at preventing strokes as controlled warfarin, with target INR of 2.0-3.0. To partake in the study, patients with non-valvular, persistent, paroxysmal, or permanent atrial fibrillation had to have additional risk factors, such as suffer a stroke previously, have symptomatic heart failure, have a left ventricular ejection fraction of less than 40 percent, be 75 years or older, or be 65 years or older with diabetes mellitus, coronary artery disease, or hypertension.
The primary study endpoint was to determine Pradaxa's noninferiority to warfarin in reducing the occurrence of the composite endpoint, including stroke and systemic embolism. The study was designed to see whether Pradaxa preserved more than 50 percent of warfarin’s impact on reducing stroke as seen in previously conducted randomized, placebo-controlled trials of warfarin in atrial fibrillation patients.
In the study, the 150 mg dose of Pradaxa reduced the risk of stroke and systemic embolism by 35 percent beyond the reduction achieved with warfarin. "Besides providing superior efficacy compared to warfarin, dabigatran etexilate does not require monitoring or related dose adjustments, is not affected by food, and no dose adjustment is required for many common co-medications in AF patients," Boehringer Ingelheim stated. The 110 mg dosing arm was not approved by the FDA.
However, in RE-LY, researchers reported that as seen with other anti-clotting drugs, life-threatening and fatal bleeding was among the most common adverse events reported by Pradaxa-treated patients. Pradaxa's label notes that the risk of major bleeds was similar between the Pradaxa 150 mg and warfarin arms for most patients based on baseline characteristics, except for those 75 years or older, where "there was a trend towards a higher incidence of major bleeding" on the new drug.
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Also common among patients receiving Pradaxa were gastrointestinal events, including dyspepsia, nausea, upper abdominal pain, gastrointestinal hemorrhage, and diarrhea. The rates of adverse reactions leading to treatment discontinuation were 21 percent for Pradaxa at the 150 mg dose and 16 percent for warfarin.
In approving the drug, the FDA stated that Pradaxa will be available with a Medication Guide that informs patients taking the drug of the risk of serious bleeding. Patients will receive this guide each time they fill a prescription for the drug.
In addition to the atrial fibrillation population, Boehringer Ingelheim is also studying Pradaxa in other settings, but in all cases it seems the company is highlighting the fact that Pradaxa does not require therapeutic monitoring as the main advantage over warfarin. Generation Health's Schatzberg observed that if the new drug is to capture the significant portion of the anticoagulant market held by warfarin, then Pradaxa will have to "continue to demonstrate the ability to thin blood without the need for serial invasive blood testing."
Yet, studies suggest that Pradaxa administration could be further improved therapeutic drug monitoring.
In the Dec. 10, 2009, issue of the New England Journal of Medicine, researchers from Boehringer Ingelheim, McMaster University in Ontario, Canada, and others reported results from the RE-COVER study, which found that among patients with acute venous thromboembolism, a fixed dose of Pradaxa was non-inferior to warfarin, had a similar safety profile, and "does not require laboratory monitoring."
In a letter to the editor regarding the RE-COVER trial, however, Dirk Peetz and Karl Lackner of the Johannes Gutenberg University in Mainz, Germany, pointed out that "there are many indications [for which] the fixed dose may not be ideal in all situations," citing as an example the fact that the RE-COVER trial suggested that Pradaxa might have increased effectiveness in patients weighing less than 50 kg or who have a creatinine clearance of less than 50 mL/min.
Although the superiority of Pradaxa in this subpopulation was not a statistically significant finding, "it suggests that anticoagulation was (not unexpectedly) more intense in these subgroups and that treatment with dabigatran could be optimized by therapeutic drug monitoring," Peetz and Lackner wrote in their letter. "It is surprising that in the era of personalized medicine, this is apparently not nearly as appealing to physicians as the prospect of anticoagulation without laboratory monitoring."
State of Warfarin PGx
At the comparative effectiveness conference in Bethesda, Robert Temple, director of the Office of Medical Policy at FDA's Center for Drug Evaluation and Research, wondered aloud why PGx testing to dose warfarin hasn't taken off despite FDA's support and several studies suggesting that genotyping patients can yield better outcomes than when the drug is dosed by trial and error via INR monitoring.
The barriers, according to payors, are mainly the lack of data from large, randomized clinical trials proving that routine genetic testing to dose warfarin improves outcomes and lowers costs.
For example, one study, published in Circulation in November 2007, called Couma-Gen, was a much anticipated randomized-controlled trial conducted by researchers at the University of Utah and LDS Hospital of Intermountain Healthcare. It compared outcomes when patients were initiated on warfarin by genetic risk factors versus clinical factors only. The study did not reach its primary endpoint of a reduction in bleeding outcomes, but researchers concluded that "an algorithm guided by pharmacogenetic and clinical factors improved the accuracy and efficiency of warfarin dose initiation."
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Medco's observational study, in which hospitalizations were reduced by 30 percent when patients were given warfarin with the help of PGx data, has also been challenged by naysayers of PGx testing in this setting. In the study, physicians were not blinded to which cardiac patients were receiving genetic testing, leading some to charge that the study results may have been inflated due to the Hawthorne effect ─ a type of bias in which study subjects improve behavior simply in response to being studied and not as a result of the intervention. Additionally, the median turnaround time for genetic testing results in the study was 32 days, which Medco acknowledged would be a drawback of implementing genetic testing in clinical practice.
Additionally, a study published in the Annals of Internal Medicine in 2009 found that while genetic testing to dose warfarin may not be cost-effective in the "typical" atrial fibrillation patient, such testing could incur savings in patients at high risk of hemorrhage, if it is available within 24 hours, costs less than $200, and prevents 32 percent of bleeding events (PGx Reporter 01/21/09).
Labs and diagnostic firms selling genetic tests for warfarin dosing advertise turnaround times ranging from 24 hours to up to a week or more, which payors and doctors don't feel is fast enough to be useful in acute settings, where a point-of-care genetic test is needed.
Many doctors and payors have held off on adopting genetic testing for warfarin, waiting for new anticoagulants to come to market, like Pradaxa, which aren't hampered by warfarin's dosing variability. But since Pradaxa has its own set of adverse events and limitations, this gives some hope that the story isn't over for PGx testing and warfarin.
Medco's Epstein noted that based on the data available today, atrial fibrillation patients with renal impairment or who are 75 or older, or those who experience gastrointentinal adverse reactions with Pradaxa, may still be considered warfarin candidates. Additionally, PGx testing may still be applicable to dose warfarin when used in a variety of disease settings, whereas Pradaxa's indication is currently only limited to atrial fibrillation patients.
"What will be interesting over time is to develop the personalized scientific basis, prior to prescribing either drug, to determine which patient is a better candidate for which drug," Epstein said. "It’s a personalized medicine story that has yet to unfold."
Similarly, Gage also felt that there is still an open window among atrial fibrillation patients where warfarin administration with PGx testing may be preferable to Pradaxa. "In RE-LY, [Pradaxa] was more effective than warfarin at preventing strokes (including hemorrhagic strokes), but it did cause more dyspepsia and myocardial infarctions," Gage pointed out to PGx Reporter in an e-mail.
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Meanwhile, test makers and researchers are conducting studies to make the clinical utility and cost-effectiveness case for genetic testing for warfarin.
Last year, the Centers for Medicare & Medicaid Services found insufficient evidence demonstrating that PGx-guided warfarin dosing improves health outcomes for Medicare beneficiaries. Although the government payor decided not to cover such testing for Medicare recipients, CMS said that it would reimburse for PGx testing when performed as part of a prospective, randomized controlled trial (PGx Reporter 05/06/09). Two warfarin PGx studies have so far received funding from CMS under this model.
Gage's five-year Genetics Informatics Trial of Warfarin, looking at the utility of genetic testing to personalize warfarin dosing in orthopedic patients, received $3.7 million from the National Heart, Lung, and Blood Institute and the genotyping for patients in this trial is being reimbursed by CMS. Gage has previously suggested that PGx-guided dosing for warfarin may be useful and cost-effective in non-acute medical settings, like orthopedic patients, where the turnaround time of the test results is not a factor.
Iverson Genetics is also being reimbursed by CMS to genotype more than 7,000 patients in a two-year trial investigating whether adverse events are reduced when PGx testing is used to dose first-time warfarin users (PGx Reporter 07/28/10).
Despite the entrance of a new anticoagulant, these studies will continue and the results might point hone in on subpopulations of patients in whom genetic testing improves outcomes and saves money when given warfarin more accurately.
In response to Boehringer Ingelheim's RE-COVER study published in NEJM, David Teachey of the Children's Hospital of Philadelphia wrote to the journal editors that "the anticipated cost of [Pradaxa] in the US, as calculated on the basis of its cost in Canada, would be approximately $7,000 to $9,000 per patient-year (four to five times the cost of warfarin, despite the increased physician and laboratory costs required to monitor the INR)."
The one-time cost of between $200 and $500 for PGx tests plus the yearly cost of warfarin its seems would be cheaper than Pradaxa. For those who already have certain genotypic data on various drug responses through direct-to-consumer genetic testing services like 23andMe, could potentially avoid this additional testing cost at the point of care altogether.
Genetic testing providers contacted for this story did not respond to questions. Boehringer Ingelheim did not respond to questions for this article.