American Stroke Association Meeting Report — Abstract 213 (Room 152)
LOS ANGELES, Feb. 19, 2016 – A new medication reverses the blood-thinning effects of the anticoagulant dabigatran in patients suffering a brain bleed, potentially limiting the extent of bleeding, according to research presented at the American Stroke Association’s International Stroke Conference 2016.
Dabigitran is prescribed to people with atrial fibrillation to prevent blood clots from forming in the heart and traveling to the brain causing a stroke. Patients on blood-thinning drugs, such as dabigatran (Pradaxa), who suffer a type of bleeding that occurs inside the skull (intracranial hemorrhage) are at high risk of complications or disability. Idarucizumab (Praxbind) is an antibody that chemically binds and neutralizes the blood-thinning effects of dabigatran.
An interim analysis of the first 90 patients in a study called RE-VERSE AD (REVERSal Effects of idarucizumab in patients on Active Dabigatran) showed that idarucizumab effectively reversed dabigatran’s anticoagulant effects, said Richard A. Bernstein, M.D., Ph.D., lead study author and director of the stroke program at Northwestern Memorial Hospital in Chicago, Illinois.
Bernstein presented the results of 90 brain hemorrhage patients enrolled in the REVERSE-AD study. This included 11 men and seven women (average age 79).
In patients who received two 2.5-gram of idarucizumab infusions in a 15-minute period, blood tests revealed that dabigatran’s blood-thinning effect was 100 percent reversed in all 18 patients with brain bleed.
“This is definitely good news,” Bernstein said. “Idarucizumab rapidly and completely reverses the effect of dabigatran in patients with brain hemorrhage. Once the dabigatran is reversed, we can focus on taking care of the patient without worrying about the blood thinner.”
The new results are part of a large on-going phase III study testing idarucizumab in a range of patients who take dabigatran and have dangerous bleeding or need urgent surgery or other procedures that carry serious bleeding risks.
Idarucizumab was approved by the U.S. Food and Drug Administration in October 2015 as the first medicine designed to reverse dabigatran.
Researchers say before idarucizumab was available, patients on dabigatran who needed emergency surgery were given purified clotting factors, which carry the risk of patients’ clotting systems forming dangerous blood clots.
“Idarucizumab gets rid of the dabigatran, but doesn’t seem to carry with it any tendency to increase clotting. This should make perioperative management easier and safer,” Bernstein said.
Idarucizumab’s success so far might persuade more people to take a blood thinner when their doctors recommend it. “The biggest problem we face in preventing stroke in patients with atrial fibrillation is that almost half of patients don’t take any blood thinner at all,” Bernstein said. “I see the biggest impact of idarucizumab as providing reassurance to patients that if bleeding while taking dabigatran does occur, we can quickly reverse the dabigatran. This reassurance could lead to more strokes prevented by increasing the use of an effective blood thinner.”
Co-authors are Charles V. Pollack Jr., M.D.; Jeffrey I. Weitz, M.D.; Paul A. Reilly, Ph.D.; John Eikelboom, M.B.B.S., M.Sc.; Menno V. Huisman, M.D., Ph.D.; Pieter W. Kamphuisen, M.D., Ph.D.; Jörg Kreuzer, M.D.; Jerrold H. Levy, M.D. and Thorsten Steiner, M.D., Ph.D. Author disclosures are on the abstract.
The study was funded by Boehringer Ingelheim. Praxbind and Pradaxa are both marketed by Boehringer Ingelheim of Ridgefield, Connecticut.
Any available downloadable video/audio interviews, B-roll, animation, graphic, and images related to this news release are on the right column of the release link http://newsroom.heart.org/news/new-drug-reverses-the-effects-of-blood-thinner-in-patients-with-brain-hemorrhage?preview=3526b77201c750c0e1160b975f68484c
Video clips with researchers/authors of the studies will be added to the release link as available.
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Statements and conclusions of study authors that are presented at American Heart Association scientific meetings are solely those of the study authors and do not necessarily reflect association policy or position. The association makes no representation or warranty as to their accuracy or reliability. The association receives funding primarily from individuals; foundations and corporations (including pharmaceutical, device manufacturers and other companies) also make donations and fund specific association programs and events. The association has strict policies to prevent these relationships from influencing the science content. Revenues from pharmaceutical and device corporations are available at http://www.heart.org/corporatefunding.
The news release focuses on research that found that the drug idarucizumab (marketed as Praxbind) can stop the anticoagulant effects of the popular blood-thinner dabigatran (marketed as Pradaxa) for patients who have intracranial hemorrhage, or bleeding in the brain. The findings are based on an interim analysis of an ongoing study, and the release offers a fuzzy description of the evidence — did only 18 patients receive idarucizumab while bleeding in the brain? Or was it 90? We’re not at all certain. There is also no discussion of cost or potential harms. The findings may be of interest to medical researchers and clinicians, which were presumably the audience for the conference where this research was presented. However, given the limitations of the study data, we are left to wonder why these findings were selected for a news release designed to reach a much larger audience.
We don’t have firm numbers on how many people take dabigatran, but we know it’s a large number — a 2014 article in The BMJ reported that dabigatran “had achieved blockbuster status (where annual global turnover for a medicine exceeds $1bn)” by April 2012. We also know that dabigitran is widely prescribed for patients with atrial fibrillation, and that the drug can cause significant adverse side effects. The 2014 BMJ article notes that the FDA received reports of 542 patient deaths and 2367 reports of haemorrhage among patients taking dabigatran in 2011. If idarucizumab can help limit potential harms associated with a widely used drug, that’s interesting — and worth reporting. In fact, the FDA has already approved idarucizumab “for use in patients who are taking the anticoagulant Pradaxa (dabigatran) during emergency situations when there is a need to reverse Pradaxa’s blood-thinning effects.” (The release also makes note of the FDA approval.) So, presumably, the news value here is specifically focused on idarucizumab’s utility in reversing the effects of dabigatran in patients with intracranial hemorrhage. Given the small number of patients involved, and the fact that the relevant clinical trial is expected to continue until mid-2017, this finding carries limited news value. We think it would have been wiser to wait for a more robust data set and analysis before presenting the findings to reporters.
The release doesn’t mention cost at all. According to NEJM Journal Watch, the cost is reported to be in the ballpark of $3,500 per use, which we consider to be a very conservative amount.
The benefit as described in the release is stopping dabigatran’s blood-thinning effects, and the release states that: “In patients who received two 2.5-gram of idarucizumab infusions in a 15-minute period, blood tests revealed that dabigatran’s blood-thinning effect was 100 percent reversed in all 18 patients with brain bleed.” Because the findings were presented at a conference, there is no paper for us to read (and we looked for — but could not find — the study abstract), so it’s impossible for us to compare the language in the release to any material written by the researchers conducting the study.
We do have some concerns about the presentation of the benefits. How the reversal of dabigatron anticoagulant effect was measured is not described. The patients included in the study had all previously suffered an intracranial bleed. Their long term outcomes are unknown and we do not know if those treated with idarucizumab have better outcomes. We discuss some of these problems in more detail below under the “Evidence” criterion.
The release notes that idarucizumab “doesn’t seem to carry with it any tendency to increase clotting,” but does not tell readers anything else about potential harms. Could idarucizumab contribute to other problems? Readers don’t know. Even if there are no health risks associated with idarucizumab, it’s important to tell readers that. And, according to the Praxbind website, there are potential adverse effects.
This is very difficult to evaluate. The release, to its credit, notes that the findings stem from an “interim” analysis in an ongoing study. However, the release then gets confusing. On first reference to study size, the release states that: “An interim analysis of the first 90 patients in a study called RE-VERSE AD…showed that idarucizumab effectively reversed dabigatran’s anticoagulant effects.” Given that the release has already focused on intracranial hemorrhage, this might lead the reader to think that idarucizumab reversed dabigatran’s effects in 90 patients with “brain bleed.” In the following paragraph, the release refers to “the results of 90 brain hemorrhage patients enrolled in the REVERSE-AD study. This included 11 men and seven women.” That math doesn’t add up. And when we get to the next paragraph we read that “In patients who received two 2.5-gram of idarucizumab infusions in a 15-minute period, blood tests revealed that dabigatran’s blood-thinning effect was 100 percent reversed in all 18 patients with brain bleed.” And here’s the thing — what about the other 72 patients? According to the language in the release, they were also brain hemorrhage patients. Were they not taking dabigatran in the first place? Were they not given idarucizumab? Or did they receive idarucizumab, but in different doses? Or at different times? What were other important outcomes such as walking and talking? It’s impossible to tell what’s going on here, which makes it impossible to assess the quality of evidence.
There’s no disease mongering here. However, we think the lack of clarity in one sentence could lead to confusion about the risks associated with brain hemorrhage: “Researchers say before idarucizumab was available, patients on dabigatran who needed emergency surgery were given purified clotting factors, which carry the risk of patients’ clotting systems forming dangerous blood clots.” What level of risk were they talking about?
The release does tell readers that the study was funded by Boehringer Ingelheim, which markets both Praxbind and Pradaxa. However, it tells readers that study author disclosures (i.e., conflicts of interest) “are on the abstract.” Given that there is no link to the abstract, and we couldn’t find it when we looked (and we did look), that’s not very useful. We did look up Richard Bernstein, who is the lead study author, and his faculty page lists Boehringer Ingelheim under “Industry Relationships.” Readers shouldn’t have to hunt down an abstract (or look an author up online) to learn that.
The release doesn’t name the three oral anticoagulants that are available including warfarin, which is the power player in this area. Warfarin (brand name Coumadin) is the main alternative and many prefer it to other anticoagulants in spite of the need to check international normalised ratio (INR) levels, which give an indication of clotting risk. That is why this new drug might be important and why the cost comparison we mentioned above is also important.
Instead of talking about those other important alternatives the release notes that “Researchers say before idarucizumab was available, patients on dabigatran who needed emergency surgery were given purified clotting factors, which carry the risk of patients’ clotting systems forming dangerous blood clots.”
The release notes that idarucizumab was approved by the FDA in October 2015, so readers can assume that it’s available (and it is).
The release’s claim to novelty is that idarucizumab works to counteract the blood-thinning effects of dabigatran in patients with cranial hemorrhage. We agree it’s borderline novel since we would expect the drug to reverse the effects regardless of the underlying condition. It’s reasonably clear that we already knew idarucizumab countered the effects of dabigatran in other populations (given that the FDA has already approved it to do just that).
The release doesn’t over-reach in this regard.