Overview of the Unproven Blood-Thinner–Reversal Drug Idarucizumab (PRAXBIND)

In 2015, the Food and Drug Administration (FDA) granted accelerated approval for the intravenous drug idarucizumab (PRAXBIND)[1] to reverse the effect of the new oral anticoagulant (blood thinner) dabigatran (PRADAXA)[2] when needed before emergency surgery or urgent procedures or in life-threating or uncontrolled bleeding.

Public Citizen’s Health Research Group has designated idarucizumab as a Do Not Use medication because its approval was based on limited evidence that remains inconclusive about the clinical benefits of the drug.

We previously designated dabigatran itself as a Do Not Use medication because it does not have a clear clinical advantage over warfarin (COUMADIN, JANTOVEN), the standard, affordable oral anticoagulant whose blood-thinning effects have been well-established and can be monitored easily using a widely available blood test and successfully reversed quickly, if necessary, with an inexpensive vitamin K injection.[3]

In contrast, dabigatran was approved by the FDA in 2010 with neither a reversal agent at that time nor a routinely available laboratory test to monitor its anticoagulant effect.

Uncertain evidence of effectiveness

Idarucizumab, a monoclonal antibody that binds to dabigatran, was granted a ‘‘breakthrough therapy’’ designation by the FDA to expedite its approval to meet the unmet need for dabigatran reversal.[4]

The evidence supporting idarucizumab’s effectiveness was limited to data from two early-phase placebo-controlled studies in healthy volunteers and interim results from a then-ongoing uncontrolled clinical trial called “RE-VERSE AD” in patients treated with dabigatran.

The healthy-volunteer studies enrolled “non-bleeding” subjects who were given dabigatran for four days, and then idarucizumab on the fourth day. Notably, the subjects in these studies were not representative of most patients receiving anticoagulants, who tend to be older and sicker.[5]

The interim results from the RE-VERSE AD trial involved only 123 adults already being treated with dabigatran to prevent blood clots who needed to undergo emergency surgery or urgent procedures or had life-threatening or uncontrolled bleeding — all of whom were given idarucizumab.

All three studies showed that idarucizumab in most subjects reduced blood levels of dabigatran and normalized research tests that measure blood clotting.

However, the most clinically meaningful outcome, cessation or control of bleeding, was studied in the RE-VERSE AD trial only, and only as a secondary outcome. Full results from this trial (which had a total enrollment of 503 subjects) were published in 2017.[6] Importantly, bleeding cessation could not be assessed in the 98 subjects who had intracranial (within or around the brain) bleeding.

Although bleeding cessation was confirmed in 66% of 203 subjects with life-threatening or uncontrolled bleeding (mostly gastrointestinal) within 24 hours of idarucizumab administration in the RE-VERSE AD trial, it could not be determined in 33% of the subjects. In two (1%) of these 203 subjects, bleeding ceased before idarucizumab was administered.

Among 197 subjects in the RE-VERSE AD trial who received idarucizumab prior to emergency surgery or urgent procedures, 93% had good reversal of dabigatran’s blood-thinning effect. However, for many subjects, this reversal may have been due to transfusions and other blood products that were administered to these subjects, rather than idarucizumab.

Another important issue observed in the RE-VERSE AD trial was a “rebound” in dabigatran levels in the blood after idarucizumab administration. This occurred within 12 hours of idarucizumab administration in 23% of RE-VERSE AD subjects, with 14% of subjects having elevated levels 24 hours after idarucizumab administration, resulting in continued or recurring bleeding in some of them.

Overall, 20% of RE-VERSE AD subjects died after idarucizumab treatment and 7% developed a thrombotic event (such as a stroke or blood clot).[7] Although the drugmaker (Boehringer Ingelheim) argued that these outcomes could be a complication of the bleeding or other existing conditions among subjects, it is impossible to exclude the role of idarucizumab itself in these deaths because the trial did not include a control group.

In fact, some FDA scientists recommended that Boehringer Ingelheim conduct a safety study to compare death rates among subjects in the RE-VERSE AD trial with those for subjects in earlier dabigatran trials who did not receive idarucizumab.[8] Yet, senior agency officials rejected this recommendation and no such comparative studies were required.

Notably, the aforementioned studies were funded by Boehringer Ingelheim, the same company that manufactures dabigatran. This represents a conflict of interest and increases the potential for bias because researchers in such trials tend to attribute clinical benefits to the studied medications, especially when the trials are uncontrolled and unblinded,[9] which was the case for the RE-VERSE AD trial.

Troubling real-world studies

Researchers who are independent of Boehringer Ingelheim conducted an observational study using medical claims data from a nationally representative sample of 271 U.S. hospitals to retrospectively compare hospital deaths between patients who received idarucizumab and those who did not receive the drug to treat dabigatran-associated gastrointestinal bleeding or intracranial bleeding.[10] For gastrointestinal bleeding, those researchers found no difference in hospital death rates between 1,124 patients who received idarucizumab and 153 who did not receive the drug. However, for patients with intracranial bleeding, they found a higher hospital death rate among the 112 patients who received idarucizumab compared with the 217 who did not receive it (12% versus 3%, respectively).

In another study, Canadian researchers prospectively evaluated all patients who received idarucizumab for the purpose of reversing extensive dabigatran-induced intracranial hemorrhage in three advanced-care hospitals.[11] They found that all five patients that met their study criteria fared poorly (four died and the fifth was barely conscious and paralyzed on one side of the body) even though their coagulation parameters had normalized after idarucizumab adminitration.

Furthermore, several case studies also have demonstrated that idarucizumab does not cause complete reversal of dabigatran-induced bleeding in some patients.[12],[13],[14]

What You Can Do

If you have a condition that requires you to use an oral anticoagulant, do not take dabigatran or any other new oral anticoagulant that would require the use of idarucizumab or another new reversal agent in case of serious bleeding or prior to surgical procedures. Instead, talk to your doctor about choosing warfarin.

Never stop any anticoagulant suddenly without consulting your doctor first because doing so increases your risk of blood clots and stroke.
 

References

[1] Boehringer Ingelheim Pharmaceuticals, Inc. Label: idarucizumab (PRAXBIND). April 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761025s002lbl.pdf. Accessed February 4, 2021.

[2] Boehringer Ingelheim Pharmaceuticals, Inc. Label: dabigatran (PRADAXA). July 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022512s039lbl.pdf. Accessed February 4, 2021.

[3] Do NOT ‘go with the flow’ for dabigatran (PRADAXA)! Worst Pills, Best Pills News. September 2016. https://www.worstpills.org/member/newsletter.cfm?n_id=1057. Accessed February 4, 2021.

[4] Food and Drug Administration. Medical review(s) for application number 761025Orig1s000. August 27, 2015. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/761025Orig1s000MedR.pdf. Accessed February 4, 2021.

[5] idarucizumab (Praxbind). Prescrire Int. 2016;25(176):260-263.

[6] Pollack CV Jr, Reilly PA, van Ryn J, et al. Idarucizumab for dabigatran reversal - full cohort analysis. N Engl J Med. 2017;377(5):431-441.

[7] Boehringer Ingelheim Pharmaceuticals, Inc. Label: Idarucizumab (PRAXBIND). April 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761025s002lbl.pdf. Accessed February 7, 2021.

[8] Food and Drug Administration. Summary review, application number 761025Orig1s000. October 16, 2015. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/761025Orig1s000SumR.pdf. Accessed February 7, 2021.

[9] Stöllberger C, Pommer P, Schneider B, Finsterer J. Concerns about idarucizumab for dabigatran reversal. Blood Coagul Fibrinolysis. 2016;27(4):473-474.

[10] Singh S, Nautiyal A, Belk KW. Real world outcomes associated with idarucizumab: population-based retrospective cohort study. Am J Cardiovasc Drugs. 2020;20(2):161-168.

[11] Wang JJ, Villeneuve E, Gosselin S. Poor outcomes after dabigatran-associated intracranial hemorrhage despite idarucizumab reversal. Toxicol Commun. 2019;3(1):16-18.

[12] Alhashem HM, Avendano C, Hayes BD, Winters ME. Persistent life-threatening hemorrhage after administration of idarucizumab. Am J Emerg Med. 2017;35(1):193.e3-193.e5.

[13] Stecher A, Vene N, Mavri A, et al. Late rebound of dabigatran levels after idarucizumab reversal in two patients with severe renal failure. Eur J Anaesthesiol. 2017;34(6):400-402.

[14] Steele AP, Lee JA, Dager WE. Incomplete dabigatran reversal with idarucizumab. Clin Toxicol. 2018;56(3):216-218.