New Evidence of Flaws in Approach to PRADAXA Dosing

When dabigatran (PRADAXA) was first approved by the Food and Drug Administration (FDA) in 2011 for preventing stroke-causing clots in patients with atrial fibrillation (the most common abnormal heart rhythm),[1] Public Citizen’s Health Research Group flagged the new drug as “Do Not Use for Seven Years.” We made this designation because the drug did not represent a clinical breakthrough over the existing treatment for that condition, warfarin (COUMADIN, JANTOVEN), and much was still unknown about its risks.

One of our concerns with dabigatran, an anticoagulant (blood thinner), was that the drug is sold in only two doses, and there is currently no way to monitor levels of the drug in the blood easily to see whether they are too high or too low. Now, new research suggests that the limitations of dabigatran’s two-dose approach may not yield the best results for some patients with atrial fibrillation, particularly elderly patients, most of whom have age-related reduced kidney function.

More studies must be done before doctors can apply a better dosing approach, and this new research reinforces our recommendation that patients avoid using dabigatran until more is known about its benefits and risks.

The two-dose approach

Dabigatran is currently available at 150 milligrams (mg) twice daily for most adults, and 75 mg twice daily for those with impaired kidney function.[2] In the key clinical trial testing dabigatran’s effectiveness, the 150 mg dose was shown to be effective at reducing the risk of stroke and blood clotting in patients with atrial fibrillation.[3]

The previous standard anticoagulant for atrial fibrillation patients, warfarin, is administered at a dose that is tailored to achieve appropriate blood levels in each individual patient. Finding the right dose requires periodic monitoring to ensure that the level of anticoagulation is within the desired range. Too low and the drug is not effective in preventing blood clots; too high and the bleeding risk becomes unacceptably high.

Dabigatran’s simpler approach gave the drug’s manufacturer a major selling point over warfarin. Rather than having to monitor patients periodically to adjust the dose, doctors could now offer patients the convenience of a twice-daily pill at a constant dose.

One size may not fit all

A new analysis of the data from the key dabigatran clinical trial seems to cast doubt on whether the fixed-dose approach is really the safest option for some patients.

The study, published in February 2014 in the Journal of the American College of Cardiology, looked at blood tests from more than 9,000 atrial fibrillation patients who had enrolled in the original major trial comparing dabigatran with warfarin.[4]

The tests showed that blood levels of the drug varied widely even among patients who were all taking the same dose. In fact, blood levels of the drug varied more than fivefold among different patients.[5]

The biggest factor affecting blood levels of dabigatran was kidney function. As kidney function declined, dabigatran levels increased. Patients with moderate kidney impairment on average had blood levels of the drug more than two times higher than those of patients with normal kidney function.[6] However, for any given level of kidney function, blood levels of the drug still varied over a wide range among patients taking the same dose. This means that other factors besides kidney function also affect dabigatran levels.

The study found that age and gender significantly affect the level of dabigatran in the blood. Older patients showed higher levels than younger patients, and women were more likely than men to have higher levels of the drug. The researchers believed much of the difference for older patients was due to decreased kidney function in this group.[7]

Importantly, blood levels had a clear impact on the risks and benefits of the drug. People with higher levels were less likely to develop a blood clot that led to a stroke or other serious injury, but they were also more likely to have major bleeding.[8] The study’s authors analyzed the risk of stroke and major bleeding separately across the wide range of dabigatran levels seen in patients. Their analysis predicted that by targeting a relatively low level of dabigatran in the blood, doctors could dramatically reduce the risk of major bleeding without significantly increasing the risk of stroke.[9] Achieving this ideal balance between the benefits and risks of dabigatran would require that patients undergo some type of monitoring of the drug’s levels in the blood.

The authors also suggested that even if blood levels could not be tested easily in nonresearch settings, it may be safer for older patients, those with multiple other illnesses, or those with mild or moderate kidney impairment to take a reduced dose. (Patients with severe kidney impairment should not take the drug at all.)[10]

Will the dosing change?

Before doctors can start adjusting the dosing of dabigatran based on levels of the drug in the blood, the safety and effectiveness of doing so must be tested in another controlled clinical trial. Also, doctors would need to be able to routinely order dabigatran blood level tests for patients, but currently no such test is widely available.[11]

Unfortunately, dabigatran’s manufacturer, Boehringer Ingelheim, has little incentive to invest in developing a blood test for the drug or running a large clinical trial to assess dosing strategies. This is because a tailored dosing approach would reduce the convenience of the drug, which has been a big selling point as the company tries to attract patients currently taking warfarin.

What You Can Do

Never stop taking a medication without consulting with your doctor. This is particularly important with anticoagulants, because suddenly stopping increases the risk of stroke from blood clots in certain patients.

Much remains unknown about the safety of dabigatran, and this drug has not demonstrated a clear clinical benefit over warfarin for patients with atrial fibrillation. We therefore recommend that if you have atrial fibrillation and need to start a blood thinner, warfarin is the best choice.

Also, if you are already taking warfarin, we recommend that you remain on it and not switch to dabigatran until more is known about the drug’s risks and benefits.

If you are already taking dabigatran, our advice is different. Discontinuing dabigatran (or any anticoagulant) for atrial fibrillation increases your risk of blood clots. Transitioning onto another anticoagulant when you stop taking dabigatran may help reduce, but not necessarily eliminate, these risks. We advise that if you are already on dabigatran, you continue treatment unless your doctor advises you to stop for another reason.

References

[1] Food and Drug Administration. Drugs@FDA. https://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails.

[2] Pradaxa label. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ba74e3cd-b06f-4145-b284-5fd6b84ff3c9. Accessed October 30, 2014.

[3] Ibid.

[4] Reilly PA, Lehr T, Haertter S, et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY trial (randomized evaluation and major bleeding in atrial fibrillation patients). J Am Coll Cardiol. 2014;63:321-328.

[5] Ibid.

[6] Ibid.

[7] Ibid.

[8] Ibid.

[9] Ibid.

[10] Pradaxa label. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ba74e3cd-b06f-4145-b284-5fd6b84ff3c9. Accessed October 30, 2014.

[11] Reilly PA, Lehr T, Haertter S, et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY trial (randomized evaluation and major bleeding in atrial fibrillation patients). J Am Coll Cardiol. 2014;63:321-328.