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29: Idarucizumab for dabigatran reversal, rivaroxaban for PE with active cancer, and an evidence based guideline resource

In this episode I will:

1. Review an article about idarucizumab for dabigatran reversal
2. Answer a drug information question: “Can I use rivaroxaban to treat a pulmonary embolism (PE) in a patient with active cancer?”
3. Share a resource I use that is a collection of evidence based critical care guidelines

Lead author:  Charles V. Pollack

Published in New England Journal of Medicine (NEJM) August 6, 2015

Background

Idarucizumab for dabigatran reversal is in the news again since the FDA approved the drug on October 16, 2015.  This article is interim analysis of an ongoing study of idarucizumab (RE-VERSE AD). It was this study that the FDA based its approval of idarucizumab for dabigatran reversal.

Purpose

To determine the effects of idarucizumab, an antibody fragment, that was developed to reverse the anticoagulant effects of dabigatran.

Methods

The study is a prospective cohort study using 5 g of intravenous idarucizumab to reverse the anticoagulant effects of dabigatran in patients who had serious bleeding (group A) or required an urgent procedure (group B). The primary end point is the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab. A secondary end point is the restoration of hemostasis.

Results

This interim analysis included 90 patients who received idarucizumab (51 patients in group A and 39 in group B). Among 68 patients with an elevated dilute thrombin time and 81 with an elevated ecarin clotting time at baseline, the median maximum percentage reversal was 100%. Idarucizumab normalized the test results in 88 to 98% of the patients, an effect that was evident within minutes. Among 35 patients in group A who could be assessed, hemostasis, as determined by local investigators, was restored at a median of 11.4 hours. Among 36 patients in group B who underwent a procedure, normal intraoperative hemostasis was reported in 33, and mildly or moderately abnormal hemostasis was reported in 2 patients and 1 patient, respectively. One thrombotic event occurred within 72 hours after idarucizumab administration in a patient in whom anticoagulants had not been reinitiated.

Conclusion

The authors concluded that idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes.

I checked with my purchasing pharmacist (thanks Mark!) – idarucizumab is now available via drop ship at a cost of $3500. It requires refrigeration, is good for 48 hours at room temperature, and is good for 6 hours if exposed to light. The dose of idarucizumab is two 2.5 g vials given by IV bolus or infusion over no more than 5 or 10 minutes each. This article will be the subject of journal club at my institution. I imagine it will be added to formulary at our next Pharmacy and Therapeutics meeting.

Drug information question

Q: Can I use rivaroxaban to treat a pulmonary embolism (PE) in a patient with active cancer?

A: Probably.

I took two approaches to answering this question; reviewing the original study that the approval of rivaroxaban was based on (the EINSTEIN-PE study) and reviewing CHEST guidelines.

The New England Journal of Medicine (NEJM) published the EINSTEIN-PE investigators work titled Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism in April 2012. This was a randomized, open-label trial of the efficacy and safety of rivaroxaban as compared with standard therapy consisting of enoxaparin and a vitamin K antagonist in patients who had acute symptomatic pulmonary embolism with or without deep-vein thrombosis. The trial was sponsored by Bayer HealthCare and Janssen Pharmaceuticals.

I wanted to review the study to find out how many patients with active cancer had been enrolled. I opened up a pdf of the study and used the search function (Control+F keys) for the word “cancer”. There is only one instance of the word in the article, and it was in reference to adjusting the statistical analysis based on the presence of cancer. I knew that the information had to be recorded somewhere, so I went back to the NEJM website to find the supplementary material that was published alongside the article.  The supplementary material often has key information needed to determine the external validity of a study.

I used the same search function (Control+F) in the supplementary document. I found that about 5% of the patients in the EINSTEIN-PE study had active cancer. Subgroup analysis for efficacy and safety did not find a difference in patients with active cancer.

Next, I went to the CHEST guidelines to see what their recommendation is for anticoagulating patients with a PE and active cancer:

In patients with PE and cancer, we suggest LMWH over VKA therapy (Grade 2B). In patients with PE and cancer who are not treated with LMWH, we suggest VKA over dabigatran or rivaroxaban for long-term therapy (Grade 2C).

Treatment of VTE with dabigatran or rivaroxaban, in addition to being less burdensome to patients, may prove to be associated with better clinical outcomes than VKA and LMWH therapy. When these guidelines were being prepared (October 2011), postmarketing studies of safety were not available. Given the paucity of currently available data and that new data are rapidly emerging, we give a weak recommendation in favor of VKA and LMWH therapy over dabigatran and rivaroxaban, and we have not made any recommendation in favor of one of the new agents over the other.

Reading this prompted me to do a pubmed search to see if any additional data had been published since October 2011 to help answer whether rivaroxaban can be used to treat PE in a patient with active cancer. In February 2015 in the CHEST journal, a meta-analysis titled Direct Oral Anticoagulants (DOAs) in Patients With VTE and Cancer was published. This meta-analysis found 10 studies comparing DOAs with conventional anticoagulation for treatment of VTE including patients with cancer. Six studies were included in the meta-analysis (two with dabigatran, two with rivaroxaban, one with edoxaban, and one with apixaban), accounting for a total of 1,132 patients. VTE recurred in 23 of 595 (3.9%) and in 32 of 537 (6.0%) patients with cancer treated with DOAs and conventional treatment, respectively. Major bleeding occurred in 3.2% and 4.2% of patients receiving DOAs and conventional treatment, respectively. The authors of the meta-analysis concluded that DOAs seem to be as effective and safe as conventional treatment for the prevention of VTE in patients with cancer. Further clinical trials in patients with cancer-associated VTE should be performed to confirm these results.

For me, this is enough information to say that a patient could be treated with rivaroxaban for PE if they have cancer. Although it certainly is not enough data to recommend rivaroxaban over warfarin or enoxaparin. What is your take on the data? Are you comfortable using a 2015 meta-analysis to go against a 2C recommendation from CHEST based on 2011 data? Let me know at joe@pharmacyjoe.com.

Resource

The resource I’d like to share in this episode is a collection of evidence based guidelines written by the Surgical Critical Care and Acute Care Surgery teams at Orlando Regional Medical Center (ORMC). These guidelines are freely available on the web at http://surgicalcriticalcare.net/guidelines. Some key guidelines I have used from this site are Post-Splenectomy Vaccine Prophylaxis, Electrolyte Replacement, and Seizure Prophylaxis in Traumatic Brain Injury.  The electrolyte replacement guidelines in particular were a tremendous resource when it came time to develop critical care electrolyte replacement guidelines at my institution.   There are over 70 guidelines available at this website! Thank you to Orlando Regional Medical Center for developing and freely sharing these guidelines!

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