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Do NOT ‘Go With the Flow’ for Dabigatran (PRADAXA)!

Worst Pills, Best Pills Newsletter article September, 2016

A TV ad has been airing recently for the new oral anticoagulant (blood thinner) dabigatran (PRADAXA), marketed by the German drugmaker Boehringer Ingelheim (BI). The ad depicts blood cells as animated fish that swim to the brain and cause a stroke; it urges viewers not to “just go with the flow” and to choose dabigatran over other blood thinners such as warfarin (COUMADIN, JANTOVEN).

The Food and Drug Administration (FDA) approved dabigatran to prevent stroke in patients with atrial fibrillation (an irregular heartbeat condition), to prevent blood clots from forming after hip replacement surgery, and to prevent and treat blood clots in the lungs and large veins.[1]

Despite growing evidence to the contrary, BI continues to claim that the drug offers the advantages of not needing dose adjustments and being more effective than warfarin. Warfarin is an affordable and effective drug that has been the standard oral blood thinner since the 1950s. However, it requires frequent monitoring and subsequent dose adjustments, as well as certain dietary restrictions.

The drugmaker’s ad conveniently forgets to mention anything about the $650 million it agreed to pay in 2014 to settle more than 4,000 lawsuits related to major, even fatal, internal bleeding among users of dabigatran.[2]

Initially, Public Citizen’s Health Research Group applied its Seven-Year Rule to dabigatran,[3] discouraging its use until November 2017 — seven years after its initial approval — because the evidence did not show that the drug is a real breakthrough and because of concerns about its risks. Since then, consumer advocates have criticized the FDA for its questionable decision to approve the drug. Therefore, we now are designating dabigatran as Do Not Use.

Untrue claims and withheld information

After marketing dabigatran for several years as a “novel” blood thinner that does not require routine monitoring,[4] BI finally published results that contradicted these very claims from a 2014 sub-study[5] of the Randomized Evaluation of Long-Term Anticoagulation Therapy trial, the main trial used to support approval of dabigatran for atrial fibrillation. The sub-study showed that subjects’ blood levels of dabigatran varied more than fivefold. The sub-study further concluded that there is no single level of dabigatran that provides the best balance between anticoagulation benefits and bleeding risks for all patients.

A 2014 investigation by The British Medical Journal (BMJ) revealed that measuring dabigatran’s blood levels and adjusting the drug’s dose accordingly can substantially reduce the risk of major bleeding, according to internal BI documents.[6]

The BMJ investigation found that as early as 2008, BI officials had decided not to develop a bedside blood testing device for dabigatran, because doing so would undermine the company’s no-monitoring marketing strategy. According to the BMJ, BI officials intentionally withheld this key information from regulators.

Criticism of FDA stance

A 2015 report summarizing findings from an in-depth investigation by the Project on Government Oversight suggests that the FDA took a “lax or permissive” approach toward dabigatran, easing its passage to market and deflecting questions about the drug’s safety after its approval.[7] (See box, below, for examples.)

Dubious Decisions by the FDA
The Food and Drug Administration (FDA) reviewed dabigatran under an accelerated approval program, permitting the drug’s approval based on a single trial (Randomized Evaluation of Long-Term Anticoagulation Therapy [RE-LY]), without a second trial to confirm its findings. Although it initially challenged the quality of the RE-LY trial’s data and decided not to approve dabigatran, the FDA ignored major shortcomings of this trial the second time it considered the drug. For example, the trial was “unblinded,” so researchers knew which subjects were taking dabigatran and which were taking warfarin (COUMADIN, JANTOVEN). According to an FDA advisory committee member, this practice could have biased the results in favor of dabigatran. For example, one FDA reviewer noted that dabigatran subjects were more likely to have their treatment discontinued when they showed signs of trouble, compared with warfarin subjects. The agency permitted scientists with prominent ties to the pharmaceutical industry to serve on the advisory committee that reviewed dabigatran, including some who later received large payments from the drug’s maker. The agency ignored concerns raised by an advisory committee member about the lack of a standard test for monitoring dabigatran. The committee member wondered “how anybody could take a drug that thins the blood and not check it.” Despite dabigatran’s bleeding risks, the FDA did not require a black-box warning for the drug’s label describing the wide range of bleeding complications that can occur; the current black-box bleeding warning is limited to the context of certain spinal procedures. Additionally, before approving the drug, the agency did not require dabigatran’s maker to develop an antidote to reverse bleeding. The agency allows the drug’s manufacturer to publicly claim that dabigatran is superior to warfarin, although the evidence does not back up this claim. The FDA publicly defended dabigatran, despite the mounting adverse event reports it has received related to this drug.

Dubious Decisions by the FDA

The Food and Drug Administration (FDA) reviewed dabigatran under an accelerated approval program, permitting the drug’s approval based on a single trial (Randomized Evaluation of Long-Term Anticoagulation Therapy [RE-LY]), without a second trial to confirm its findings.
Although it initially challenged the quality of the RE-LY trial’s data and decided not to approve dabigatran, the FDA ignored major shortcomings of this trial the second time it considered the drug. For example, the trial was “unblinded,” so researchers knew which subjects were taking dabigatran and which were taking warfarin (COUMADIN, JANTOVEN). According to an FDA advisory committee member, this practice could have biased the results in favor of dabigatran. For example, one FDA reviewer noted that dabigatran subjects were more likely to have their treatment discontinued when they showed signs of trouble, compared with warfarin subjects.
The agency permitted scientists with prominent ties to the pharmaceutical industry to serve on the advisory committee that reviewed dabigatran, including some who later received large payments from the drug’s maker.
The agency ignored concerns raised by an advisory committee member about the lack of a standard test for monitoring dabigatran. The committee member wondered “how anybody could take a drug that thins the blood and not check it.”
Despite dabigatran’s bleeding risks, the FDA did not require a black-box warning for the drug’s label describing the wide range of bleeding complications that can occur; the current black-box bleeding warning is limited to the context of certain spinal procedures. Additionally, before approving the drug, the agency did not require dabigatran’s maker to develop an antidote to reverse bleeding.
The agency allows the drug’s manufacturer to publicly claim that dabigatran is superior to warfarin, although the evidence does not back up this claim.
The FDA publicly defended dabigatran, despite the mounting adverse event reports it has received related to this drug.

Belated, under-researched antidote to dabigatran

Five years after dabigatran hit the market, BI finally made available an antidote to reverse the drug’s bleeding side effects.[8] The main trial supporting approval of the antidote, idarucizumab (PRAXBIND), included 123 patients who were given the antidote because they required emergency surgery or had uncontrolled bleeding.[9] The interim results of this trial, which is currently ongoing, showed that idarucizumab can rapidly reverse dabigatran’s blood-thinning effect, according to lab tests[10] that are not routinely available to health care providers at this time. The trial does not include a comparison group and uses only lab outcomes.[11]

Given the trial’s less than ideal design, some emergency medicine physicians say that the current evidence does not support the use of idarucizumab in every case of bleeding associated with dabigatran.[12] Others predict that this antidote will have little to no effect on patient care,[13] because it likely will be prescribed only rarely.

What You Can Do

You should not start using dabigatran. If you are currently taking this drug, do not stop it suddenly, because doing so will increase your risk for stroke. Instead, talk with your health care provider about switching to warfarin.

We also recommend against using any of the more recently approved blood thinners (rivaroxaban [XARELTO], apixaban [ELIQUIS] or edoxaban [SAVAYSA]) until seven years after the initial approval of each of these respective drugs, because their effectiveness and safety has not been well established relative to warfarin and additional safety concerns have been documented since their original approvals. Although warfarin has some limitations, its anticoagulant effects can be assessed easily using a widely available blood test and reversed quickly with an injection of vitamin K.

References

[1] Boehringer Ingelheim. Drug Label: PRADAXA- Dabigatran Etexilate Mesylate Capsule. November 2015. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ba74e3cd-b06f-4145-b284-5fd6b84ff3c9. Accessed June 14, 2016.

[2] Drugwatch.com. Boehringer Ingelheim to pay $650M to settle 4,000 Pradaxa lawsuits. Modified October 1, 2015. https://www.drugwatch.com/2014/05/28/boehringer-ingelheim-settles-pradaxa-lawsuits/. Accessed June 14, 2016.

[3] Applying the life-saving seven-year rule: An antiarrhythmic and 3 anticoagulants. Worst Pills, Best Pills News. April 2012. /newsletters/view/788. Accessed June 14, 2016.

[4] Cohen D. Dabigatran: How the drug company withheld important analyses. BMJ. 2014;349(g4670).

[5] 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 of Long-Term Anticoagulation Therapy). J Am Coll Cardiol. 2014;63(4):321-328.

[6] Cohen D. Dabigatran: How the drug company withheld important analyses. BMJ. 2014;349(g4670).

[7] Project on Government Oversight. Drug Problems: Dangerous Decision-Making at the FDA. Washington, DC; October 2015.

[8] Food and Drug Administration. FDA approves Praxbind, the first reversal agent for the anticoagulant Pradaxa. October 16, 2015. http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm467300.htm. Accessed June 14, 2016.

[9] Center for Drug Evaluation and Research. Application number 761025Orig1s000. Medical Review(s) for Idarucizumab. August 2015. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/761025Orig1s000MedR.pdf. Accessed June 14, 2016.

[10] Pollack CV, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. New Engl J Med. 2015;373(6):511-520.

[11] Levesque A, Schauer SG, Sessions D. Praxbind in practice. Emergency Physicians Monthly. November 30, 2015. http://epmonthly.com/article/praxbind-in-practice/. Accessed June 14, 2016.

[12] Ibid.

[13] Wells, J. Blood thinner reversal agent gets green light, but how often will it be prescribed? Hamilton Spectator. May 15, 2016. http://www.thespec.com/news-story/6555798-blood-thinner-reversal-agent-gets-green-light-but-how-often-will-it-be-prescribed-/. Accessed June 14, 2016.

Do NOT ‘Go With the Flow’ for Dabigatran (PRADAXA)!

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