PRADAXA IS NOT AS SAFE AS IT SEEMED

February 29, 2012 (Palmerston, New Zealand) — Further details of bleeding events associated with the introduction of dabigatran in New Zealand have highlighted the problems of embracing a new drug too quickly [1].

"We are concerned that the potential risks of this medication are not generally appreciated," a group led hematologist Dr Paul Harper (Palmerston North Hospital, New Zealand), writes in a letter to the March 1, 2012, issue of the New England Journal of Medicine. They compile a list of 78 episodes of bleeding with dabigatran, one of which may have contributed to the death of the patient, and conclude that four major factors contributed to these events: prescriber error, impaired renal function, patient age, and lack of a reversal agent.

Of the 44 bleeding events that occurred in their patients, they note that two-thirds of the patients were over the age of 80 years, 58% had moderate or severe renal impairment, and half weighed less than 60 kg. They add that the bleeding risk is not completely mitigated by a dose reduction, as 22 of their patients had a bleeding episode while receiving a reduced dose.

Harper told heartwire that he thinks the bleeding problems with dabigatran have been a particular problem in New Zealand as a result of the country embracing the drug too enthusiastically when it was first introduced for AF last year.

He explained that dabigatran was unusual in that it was introduced with no restrictions and was made freely available with full reimbursement. He commented: "Usually a new drug is introduced here on special authority, which means that doctors have to fill out forms and tick boxes to justify its use. That is a good safety mechanism, as you have to think about all the relevant issues before prescribing. But dabigatran did not have that caveat; I think the government wanted it be used. They saw it as a good replacement for warfarin and wanted as many people as possible to switch. The uptake was very quick--too quick. Doctors were very keen to prescribe it, and everyone got carried away."

Prescriber error

Harper believes GPs were so enthusiastic to get their patients onto the drug that many did not fully consider issues like age and renal function. "There wasn’t enough education on these issues. And some patients were started on dabigatran before their warfarin had cleared. As a result, we saw a lot of bleeding. We had patients admitted to our hospital with major bleeds having taken dabigatran just for a few days, and because there is no reversal agent, we didn't know how to manage them. If patients have poor renal function, it can take days for the drug to clear. One patient with a hip fracture who needed urgent surgery had to wait eight days for their coagulation to go back to normal before surgery could be performed."

Harper says the lack of a reversal agent for dabigatran is a major concern. "All the normal clotting factors don't work very well with dabigatran, and this wasn't highlighted enough when the drug was first introduced."

The situation in New Zealand has calmed down now, but use of the drug has fallen dramatically, because of the bleeding experience. "All the initial enthusiasm has completely disappeared. The bleeding issue got a lot of press attention here, with newspapers reporting deaths possibly related to the bleeding, and now there is a strong public feeling against the drug," Harper notes.

He estimates that around 7000 patients started taking dabigatran in the first few weeks it was available in New Zealand. "For a country with a population of just four million, that is a high rate." But he says new patients have now slowed to about 150 a week, and there are still only a total of about 8000 patients on the drug, with many people having stopped taking it after the press coverage, and others stopping because of GI side effects.

Lessons about enthusiasm

Harper believes the drug is a good option for younger patients who are fit and healthy apart from their AF, but it should be used with extreme caution in older frail patients, especially those with reduced renal function. "I would say it could be used in older patients if they have good renal function and no history of bleeding or GI issues."

He says the dabigatran experience has been a lesson in not getting too enthusiastic about a drug before it has been used in the real world. "The clinical-trial experience is very different from the real world. In RE-LY, one-third of patents were over 80 and only 20% had impaired renal function, whereas in the real world, half of AF patients over 80 have impaired renal function."

The authors of the letter conclude: "Our audit illustrates the difficulty in extrapolating trial data into clinical practice and emphasizes the need for postmarketing surveillance and adverse-event reporting to detect groups whose risk factors may not be apparent in a clinical-trial setting. Our review of unselected cases has limitations but highlights the need for appropriate prescriber education."

Harper has developed an iPhone app to help clinicians use dabigatran. It provides dosing information, advice about how to manage bleeding, and when to stop treatment before surgery. Called "Managing Dabigatran," it is available free from the iPhone App Store. The present version is based on New Zealand guidelines, but a new international version should be available within a few days.