Getting the dabigatran (Pradaxa) story right… Correcting four common mistakes.

This purpose of this post is to clarify misstatements made in a recent New York Times article about the anticoagulant drug dabigatran (Pradaxa). The piece had three major inaccuracies, plus one thought-error from a cardiology leader. I write these words because the most valuable tool in the treatment of AF is knowledge. Getting it right is critical. (For readers that persist, I offer a bonus at the end.)

The thrust of the Times’ story concerned editorials in the British Medical Journal that questioned the safety of dabigatran. The first non-warfarin anticoagulant has had plenty of controversy, the most recent of which involves the findings of this RE-LY sub-study. Researchers analyzed blood samples from 9,183 patients in the original RE-LY study and found plasma dabigatran levels can vary up to five-fold. Common sense holds that five-fold variations in plasma levels of any drug might be significant. In this case, high levels of dabigatran correlated with bleeding, and low levels might have predisposed to ineffective stroke prevention though no correlation was found between stroke events and blood levels, likely due to the small number of strokes in the study. (I have had two low-risk AF patients suffer major strokes while taking dabigatran. Other colleagues have reported similar anecdotes.)

The FDA knew about these variations in dabigatran levels but felt the outcomes (strokes, bleeds and deaths) from the original 18-000-patient RELY study, which favored dabigatran without monitoring, was enough to approve the drug. The Times’ piece also mentioned the fact that Boehringer Ingelheim paid $650 million to settle thousands of claims brought by patients alleging harm from the drug.

Before addressing the article’s mistakes, it is laudable that mainstream media emphasizes the notion of weighing risks. All medical decisions are a gamble–an exercise in probability. We must get past the idea that any drug, surgery or procedure is free of tradeoffs. You cannot prevent strokes in patients with atrial fibrillation without exposing them to bleeding risks.

Now to four mistakes made in the article. They serve as good teaching points.

Warfarin flail:

“Patients [on warfarin] are supposed to avoid leafy greens and cruciferous vegetables like Brussels sprouts because they contain vitamin K, which facilitates blood clot formation.”

I am so utterly tired of correcting this mistake. It is completely wrong. Patients on warfarin can indeed eat green vegetables; they should just eat them consistently. I have vegetarians who do beautifully on warfarin. The problem comes when people vary the weekly dose of vegetables. Warfarin works by inhibiting vitamin K-dependent clotting factors. If one eats the same amount (dose) of vitamin K, the caregiver can easily adjust warfarin dose. In fact, some have even suggested adding a small dose of vitamin K to patients who have difficulty controlling INRs. This is not a nitpicky criticism; patients on warfarin have disease, and they should not be avoiding healthy plant-based foods. Plus, it’s such a rookie mistake.

Relative risks do not belong in explanatory health journalism:

“You could have had a much safer drug,” said Dr. Deborah Cohen, the investigations editor at The BMJ, who wrote two articles last month critical of Pradaxa’s record. By carefully monitoring drug levels in patients, “you could reduce major bleeds by 30 to 40 percent, compared to well-controlled warfarin,” she said.

This misleading quote should not have been allowed to stand alone. The rate of major bleeding in patients on the 150-mg-dose of dabigatran in the RE-LY trial was 3.11%; it was 3.36% in the warfarin group. If you made dabigatran perfectly safe (0 bleeds), the best it could have been was 3.36% better than warfarin, not 30-40%. Dr. Cohen was talking about relative risk reduction, which is not important to the patient considering taking a drug. Patients facing the gamble of treatment should care about absolute risks. What’s more, the sub-study that showed dabigatran levels vary and correlate with bleeding cannot determine how many bleeds would have been prevented with dabigatran monitoring. It’s possible monitoring could have made outcomes worse.

All anticoagulant drugs get riskier in complicated patients:

“Some who take Pradaxa may be at greater risk of bleeding — particularly older patients, anyone with kidney problems, those with a history of ulcers or gastrointestinal bleeding, and patients who take other drugs that increase bleeding (like aspirin).”

The problem with this statement is that all the new anticoagulants pose greater risks in patients with kidney problems, ulcers, and those taking antiplatelet drugs, such as aspirin. This is not a dabigatran specific issue. Rivaroxaban, apixaban and edoxaban have the same issues with renal clearance, to varying extents. Warfarin, too, is riskier in patients with a history of GI bleeding. It doesn’t mean we don’t recommend anticoagulant drugs in these patients–it just changes the odds of the gamble. Consider that AF patients with risk factors for bleeding are almost always at higher risk of stroke as well.

Yes. People with AF can and should control their diet:

“The person who is 50, who has a busy professional life with a lot of travel, can’t necessarily control their diet, and actually likes to eat things like broccoli and kale — they feel liberated,” said Dr. Patrick O’Gara, the director of clinical cardiology at Brigham and Women’s Hospital in Boston.

This thought-error is on the current president of the American College of Cardiology. With respect, here is what I mean: The busy 50-year-old professional person probably has AF precisely because he hasn’t controlled his diet or travel schedule. The inference (I take) from Dr. O’Gara’s statement is that the new anticoagulants are good for professionals because they are more convenient and require less of a commitment than warfarin. This, my friends, is the core problem in the way many doctors approach the care of patients with AF. Too much convenience is why patients, especially professionals, get AF. And, let’s be honest, if a person has a heart rhythm disorder as serious as AF, he or she should damn well control their diet and travel schedule. AF patients should make a commitment to their health. The enabling of patients with pills, and other “easy” solutions to lifestyle-related diseases is one of the reasons we have so much AF, and hypertension and diabetes and degenerative joint disease. AF is a disease, yes, but it is also a window onto the overall health of the person.

The next paragraph is a bonus for readers who have persisted.

 Genetics play a significant role in dabigatran levels:

Finally, if you want to worry about dabigatran, I would be most worried about this sobering study. Researchers did genome-wide association analyses on 2944 patients from the RE-LY database and found nearly one in three patients carried a minor allele that associated with lower exposure to the active dabigatran metabolite. The Achilles heel of dabigatran looks to be its diversity of metabolism from pro-drug to active drug. Did you know that dabigatran is given as pro-drug and requires enzymatic conversion to active drug? The bioavailability of dabigatran turns on genetic determinants, and in the best case is only 6% bioavailable.

A former Indiana mentor used to holler at us: “no data was better than bad data.”

JMM