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FDA Looks into Pradaxa Bleeding Risk; What Does it Mean for PGx-Guided Warfarin Dosing?


Originally published Dec. 12.

By Turna Ray

The US Food and Drug Administration
is concerned about the number of patients experiencing serious bleeding events after treatment with Boehringer Ingelheim's blood thinner Pradaxa — a move that may have implications for the uptake of genetic testing for the competing generic anticoagulant warfarin.

The agency communicated last week through its MedWatch drug safety reporting system that it has received post-marketing reports that some patients taking Pradaxa (dabigatran etexilate mesylate) are experiencing serious bleeding events. The FDA said it "is working to determine whether the reports of bleeding in patients taking Pradaxa are occurring more commonly than would be expected, based on observations in [a] large clinical trial that supported the approval of Pradaxa."

Last month, Boehringer Ingelheim said that between March 2008 and Oct. 31, 2011, there were 260 fatal bleeding events associated with Pradaxa worldwide.

Despite the post-marketing reports of higher-than-expected bleeding incidences, the agency last week advised that patients do not discontinue Pradaxa without talking to their doctors since sudden stoppage of blood thinning medications can increase the risk of stroke.

"Bleeding that may lead to serious or even fatal outcomes is a well-recognized complication of all anticoagulant therapies," the FDA said in its drug safety notice. "At this time, FDA continues to believe that Pradaxa provides an important health benefit when used as directed and recommends that healthcare professionals who prescribe Pradaxa follow the recommendations in the approved drug label."

The FDA approved Pradaxa last year for the prevention of stroke and blood clots in patients with atrial fibrillation based on results from an 18,000-patient study that compared the efficacy and safety of Pradaxa to the older anticoagulant warfarin.

In that study, called RE-LY, researchers found that patients treated with the newer drug, given at 150 mg twice a day, experienced a similar bleeding risk, but a lower incidence of stroke and blood clots compared to those receiving warfarin. In the warfarin-treated population, the rate of major bleeding was 3.36 percent per year compared to 3.11 percent per year in the group receiving 150 mg of Pradaxa. The rate of hemorrhagic stroke was 0.38 percent per year in the warfarin-treated arm, compared to 0.10 percent per year with 150 mg of Pradaxa.

Once Pradaxa was approved, many industry observers believed that it would replace warfarin, a drug that has been on the market since 1954. One of the drawbacks with warfarin treatment is that the drug's dose must be adjusted and monitored for each patient, since too much or too little can lead to fatal bleeding or blood clots. Pradaxa doesn't have the dosing variability associated with warfarin, and so patients on the drug don't require periodic testing to gauge how their blood is clotting.

However, some in the healthcare industry believe doctors can use genetic testing to gain more certainty about the specific warfarin dosing ranges for a patient and avoid serious adverse reactions. The FDA first changed warfarin's label in 2007 to reflect the influence of the CYP2C9 and VKORC1 genes in metabolizing the drug. Then, in 2010, the FDA once again updated warfarin's label to include specific pharmacogenomically guided dosing ranges (PGx Reporter 2/3/2010).

Despite these labeling changes, pharmacogenetic testing to dose warfarin has not been adopted by the majority of healthcare providers in the US. One reason for the slow uptake is that physicians are comfortable adjusting the dose of warfarin with standard INR monitoring to assess how patients' blood is clotting. In addition, the lengthy turnaround time for genetic test results has made that approach impractical in certain settings.

Given this background, when Pradaxa was approved, many in the drug industry felt that it would be a new alternative for individuals who are newly prescribed an anticoagulant and who wish to avoid the dose monitoring and variability with warfarin. The availability of next-generation anticoagulants such as Pradaxa indicated that genetic testing to dose warfarin would ultimately be unnecessary.

However, as pharmacy-benefit manager Medco has observed, some patients who switched from warfarin to Pradaxa have not stayed on the drug. Medco examined prescription claims between Nov. 1, 2010, and Dec. 31, 2010, for 1,143 patients prescribed Pradaxa and found that 17 percent of the time patients did not stay on the drug after the first four months of treatment.

“We are seeing a sizable proportion of patients drop off treatment in a fairly short time. This is a twice-daily drug and stroke prevention outcomes may be particularly sensitive to how consistently patients take it, pointing to a need and opportunity to provide dedicated and proactive patient support," Eric Stanek, senior director of personalized medicine research at Medco, said in a statement when Medco presented this data at the American Health Association's Scientific Sessions last month.

Based on this data, Medco advocated the need for more patient education. "No matter how effective [Pradaxa] can be at preventing a stroke, it won't work if patients don't take it, which means doctors and pharmacists need to regularly monitor persistence and discuss adherence to therapy," Donald Pittman, national practice leader of the Medco Cardiovascular Therapeutic Resource Center, said in a statement.

Pradaxa is included in Medco's Part D formulary as a Tier 2 drug. However, Medco is also enthusiastic about using genetic testing to dose warfarin, since a significant portion of the PBM's revenues come from dispensing generic drugs.

Genetic testing for warfarin is featured in Medco's personalized medicine program and the PBM's payor and employer customers can choose to provide enrollees the option of receiving genetic testing for the drug.

To prove the clinical utility of genetic testing in this setting, Medco conducted a study, published last year in the Journal of the American College of Cardiology, that found that genotyped patients receiving warfarin, including those with atrial fibrillation, had 31 percent fewer all-cause hospitalizations and 28 percent fewer hospitalizations for bleeding or thromboembolism than patients receiving warfarin who did not get genotyped (PGx Reporter 3/17/2010).

At a recent conference in Cambridge, Mass. on companion diagnostics, Bryan Dechairo, senior director of Medco Personalized Medicine, discussed the need for more real-world studies to establish the clinical utility and cost-effectiveness of genetic testing to personalize medications. "For a health plan … that's the biggest cost, hospitalization," Dechairo said.

As a result, he noted that the PGx study on warfarin "is something that's going to resonate with them when they're making a coverage decision."

Separately, a cost-effectiveness study published last year in the Annals of Internal Medicine, found that that total costs associated with preventing stroke in atrial fibrillation patients were $143,193 for adjusted-dose warfarin, $164,576 for low-dose Pradaxa, and $168,398 for high-dose Pradaxa. For low-dose Pradaxa, the incremental cost-effectiveness ratio compared with warfarin was $51,229 per quality-adjusted life year and $45,372 per QALY for high-dose Pradaxa.

"The cost effectiveness of high-dose [Pradaxa] improved with increasing risk for stroke and intracranial hemorrhage," researchers led by James Freeman of Stanford University concluded in the AIM article. "[Pradaxa] may be a cost-effective alternative to warfarin depending on pricing in the US."

This retrospective analysis, however, does not factor in cost savings when genetic testing is used to dose warfarin and reduce adverse reactions or hospitalizations. Another study published in AIM 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 1/21/2009).

Some personalized medicine experts feel that for patients starting warfarin for the first time, the cost savings will be particularly meaningful when patients are genotyped for CYP2C9 and VKORC1 status prior to seeing their doctors.

Medco has said it is monitoring outcomes of patients treated with Pradaxa versus those who receive warfarin with the aid of genetic testing. Such a study may answer the key clinical utility and cost-effectiveness questions that payors and physicians will need to decide whether to prescribe Pradaxa and when to administer warfarin with the aid of genetic testing.

Besides Pradaxa, the FDA this year also approved J&J/Bayer's Xarelto, another anticoagulant option for knee or hip replacement surgery patients for the reduction of the risk of blood clots, deep vein thrombosis, and pulmonary embolism; and for non-valvular atrial fibrillation patients for the reduction of stroke. In the pivotal ROCKET AF trial, researchers found Xarelto was non-inferior to warfarin, and patients had a similar risk of major bleeding events, but intracranial and fatal bleeding occurred less frequently in the Xarelto arm.

Have topics you'd like to see covered in Pharmacogenomics Reporter? Contact the editor at tray [at] genomeweb [.] com.