Don't use dabigatran off-label with mechanical valves, Canadian docs warn

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Lynlw

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http://www.theheart.org/article/145...20120927_EN_Heartwire&utm_campaign=newsletter

Don't use dabigatran off-label with mechanical valves, Canadian docs warn

Primary-care practitioners may be putting the lives of patients with prosthetic heart valves at risk by switching their anticoagulation from warfarin to newer agents such as dabigatran (Pradaxa, Boehringer Ingelheim), say Canadian researchers [1]. Dr Joel Price (University of Ottawa Heart Institute, ON) and colleagues report the cases of two women who had undergone valve replacement some years before and had been faring well on warfarin; they were switched to dabigatran and subsequently suffered valve thromboses.

"The message is that dabigatran has really been approved only for patients who have non-valvular AF, but people are starting off-label use because of the perceived convenience of the medication," senior author Dr Munir Boodhwani (University of Ottawa Heart Institute, ON ) told heartwire. "To go and use it off-label is potentially harmful. There is a need to educate a variety of people who are involved in the management of anticoagulation—for example, hematologists, family physicians, and internal-medicine specialists, as well as cardiologists

"I do think these drugs carry a lot of promise to potentially be applicable in these contexts," he adds. "However, there is a need for dose-finding studies and clinical trials to demonstrate safety and efficacy in this setting. Until then, use of such agents off-label should be avoided. It's very premature and potentially dangerous. People might have thrombosis of their valve and may die from it without ever realizing that this was the problem," he stresses........


In a letter to the editor, published online September 26, 2012 in the Journal of the American College of Cardiology, Price and colleagues outline the cases of the two patients they encountered. The first was a 51-year-old woman who had had a mechanical aortic valve fitted eight years previously and who had been compliant with warfarin therapy with no adverse events. Two months prior to presenting with a four-week history of progressive exertional dyspnea, her general practitioner had switched her from warfarin to dabigatran (150 mg twice daily) for mechanical-valve anticoagulation.

An echo revealed severe prosthetic aortic-valve stenosis and severe left ventricular dysfunction with a probable mass on the prosthesis. The patient was transferred to the Ottawa Heart Institute in cardiogenic shock and taken as an emergency to the operating room—with a partial thromboplastin time (aPTT) of 27 seconds—where she experienced a cardiac arrest. A transesophageal echo (TEE) followed by surgical exploration confirmed multiple masses on the prosthetic aortic valve, which was replaced without complication. Dialysis was performed while she was on bypass to reduce circulating levels of dabigatran; despite this, she experienced extensive coagulopathy. Fortunately, her postoperative course was uneventful, with complete end-organ recovery.

The second patient was a 59-year-old woman who had had a mechanical mitral-valve replacement in 2007 for rheumatic disease and who had presented for routine follow-up. She had been treated with warfarin for the past five years without complication. Three months earlier, her family physician had switched her to dabigatran (150 mg twice daily) and she reported progressive dyspnea over the past two months.

TEE showed a large thrombus on the atrial aspect of the valve, and the patient's aPTT was 54 seconds. Dabigatran was stopped, and three days later the patient was taken to the OR, where large amounts of thrombus were found on the mitral valve. A mitral-valve replacement and a tricuspid-valve repair were performed, and the patient had an uneventful recovery.....
.........

Price and colleagues note that both patients had been anticoagulated for years with warfarin and never experienced thrombotic or bleeding events. Within one month of being switched from warfarin to dabigatran, both became symptomatic and were subsequently diagnosed with thrombosis. "While a causal link is not certain, the temporal association is highly suggestive," they observe.

The failure of one patient to achieve adequate anticoagulation and the fact that a second experienced valve thrombosis despite therapeutic aPTT levels "highlights the importance of medication testing for a specific indication. AF may represent a lesser thrombotic risk than
mechanical prosthesis, particularly mitral," they state.



"While there are a wealth of data and clinical experience on dosing and therapeutic response to warfarin in this context, data are unavailable for dabigatran. Off-label use of novel drugs should be avoided until data from well-designed clinical studies are available."

To this end they note that RE-ALIGN—a phase 2 dose-finding trial with dabigatran in patients with mechanical valves—is now under way, employing doses ranging from 150 to 330 mg twice daily, adjusted based on renal function and the results of the Hemoclot (Aniara, West Chester, OH) assay.


full article at link
 
http://www.theheart.org/article/145...20120927_EN_Heartwire&utm_campaign=newsletter
"While there are a wealth of data and clinical experience on dosing and therapeutic response to warfarin in this context, data are unavailable for dabigatran. Off-label use of novel drugs should be avoided until data from well-designed clinical studies are available."

To this end they note that RE-ALIGN—a phase 2 dose-finding trial with dabigatran in patients with mechanical valves—is now under way, employing doses ranging from 150 to 330 mg twice daily, adjusted based on renal function and the results of the Hemoclot (Aniara, West Chester, OH) assay.

Thanks for sharing Lyn. Remarkably, off-label use seems to happen a lot, many FDA approvals here in the US discuss this potential in great detail and measures that need to be taken to avoid it. Still, from a patient's perspective, it's hard to imagine the mindset of doctors doing so with absolutely no evidence yet. While the dose finding trial is underway, it is just the very beginning of a long and deliberate process to evaluate safety. And if a similar path to the Pradaxa A-Fib trials occurs, then it will be at least a 7 year process, perhaps longer. I posted a bit of this a few months ago, but for those not aware, here's why:

Boehringer Ingelheim launched the "RE-ALIGN" trial to begin evaluation of Pradaxa in approximately 400 patients with mechanical heart valves (mitral and aortic). The scheduled start was October 2011 and completion was targeted for August 2012. As the article states, it is a only a preliminary (Phase II) study, so not yet at the effectiveness stage, targeted primarily for evaluating dosage algorithms. Then, there will need to be a follow-up study of the same patient group scheduled to complete in December 2018 to evaluate long term safety. The natural assumption would be that if all goes well (and only if all goes well), a full scale trial (randomized, much larger patient group, etc) to directly compare safety and effectiveness with Warfarin would begin to happen somewhere in between.

Pradaxa did go through this type of process for AFib patients. In late 2003, a fairly limited Phase II study began to evaluate dosages. Then, in late 2005, a full scale trial (RE-LY) began with a patient group of 18,000 that were followed for 3 years (through end of 2008) to compare safety and effectiveness with Warfarin. Then, in late 2010, Pradaxa was approved in the US as a "substitute" (non-inferior - although even that was questionable for a variety of reasons) for Warfarin in A-Fib patients.

Most interesting to me, and perhaps a potential "deal-breaker", the "RE-ALIGN" valve dosing study includes not only the "standard" 150 mg dose of Pradaxa, but also a 300 mg dose. The 300 mg dose had been evaluated for A-Fib as well, but was eliminated due to higher frequency of major bleeding. In the A-Fib trial, major bleeding was comparable overall between Pradaxa 150 and Warfarin, so if the valve study should determine that a 300 mg dose is necessary due to heightened stroke risk (compared to A-Fib), the logical assumption would be that major bleeding increases, which potentially could render the use of Pradaxa as unsafe in comparison to Warfarin.

Now, this is all only my own speculation of course, but hey, at least I've put some thought into it...unlike some of the negligent doctors out there prescribing Pradaxa off-label!
 
Although in the US and Canada and many other countries physicians are free to prescribe drugs for unapproved uses (off-label), I'm still more than a bit surprised any doctor would do what was done in this report, especially if the patients were doing well enough on warfarin, as these appeared to be doing. The marketing of these newer agents for AF-related thrombosis prevention has been among the heaviest hitting I have ever seen, and I worked for Big Pharma for 30 years and saw it all. I dealt with numerous $Billion drugs and their promotion programs. I saw and was involved in a huge amount of off-label use of drugs, but it was always done carefully, and, at least in my case, for uses that had a good amount of supportive data and were beneficial to the patient, just not approved for a variety of reasons. I don't think the company making these new agents encouraged these physicians to use them in this manner, BUT the HUGE amount of promotion around these agents arguing their advantages over warfarin for AF, is being swallowed hook, line and sinker by the cardiology community, including my own cardiologist. I've encouraged him to take a very careful look at the data and be more vigilant watching for problems. The history of drug development is littered with promising agents that gain approval only to be scuttled a few years down the road when widespread use exposes serious problems that in retrospect were present pre-approval but did not get exposed until the case numbers were much larger. So, I'm rather leery of these agents and will be for a couple of years. I guess what happened in this report was bound to take place at some point, and I hope it squashes any further thoughts of trying this again until the research is complete.
 
Thanks for all the information. This is important stuff and patients need to educate themselves. Many thanks.
 
Although in the US and Canada and many other countries physicians are free to prescribe drugs for unapproved uses (off-label), I'm still more than a bit surprised any doctor would do what was done in this report, especially if the patients were doing well enough on warfarin, as these appeared to be doing. The marketing of these newer agents for AF-related thrombosis prevention has been among the heaviest hitting I have ever seen, and I worked for Big Pharma for 30 years and saw it all. I dealt with numerous $Billion drugs and their promotion programs. I saw and was involved in a huge amount of off-label use of drugs, but it was always done carefully, and, at least in my case, for uses that had a good amount of supportive data and were beneficial to the patient, just not approved for a variety of reasons. I don't think the company making these new agents encouraged these physicians to use them in this manner, BUT the HUGE amount of promotion around these agents arguing their advantages over warfarin for AF, is being swallowed hook, line and sinker by the cardiology community, including my own cardiologist. I've encouraged him to take a very careful look at the data and be more vigilant watching for problems. The history of drug development is littered with promising agents that gain approval only to be scuttled a few years down the road when widespread use exposes serious problems that in retrospect were present pre-approval but did not get exposed until the case numbers were much larger. So, I'm rather leery of these agents and will be for a couple of years. I guess what happened in this report was bound to take place at some point, and I hope it squashes any further thoughts of trying this again until the research is complete.

Bill:

Thank you for your take on this. I always appreciate your posts regarding pharmacology.
Do doctors ever role-play and put themselves in the place of their patient? After all, we’re not just a file, a chart, a name. We’re the ones who would stroke out – NOT the prescribing doctor.
 
Thanks so much for this post. This is what puzzles me as someone on Warfarin/Coumadin. If I had no events or issues for 5 years on this drug, I would not allow a doctor to put me on anything else unless there was ample research showing that it is safe, and equally effective, etc. These people just blindly trusted their doctors and that put them in danger, one good lesson here is "trust but verify".
 
.......... people just blindly trusted their doctors and that put them in danger, one good lesson here is "trust but verify".

AMEN...to this post. I was one of the people who "just blindly trusted their doctors" for years....but the older I get, the more cynical I become. I have learned that docs put their pants on, one leg at a time...just like me, and just like me, they are not infallible. I follow the "trust but verify" statement with any "professional" advisor....whether they be a doctor, a lawyer, or a candle stick maker.
 
Thanks for this Lynn!!
Will definatly, be cautious about this now as there was talk of me going on it after it had got its licence for A-fib, i think i'm happy on my injections lol!!
xxxx
 
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