Medical Journal Article Says FDA Might Make This Change For Patients Using Eliquis, Pradaxa, Savaysa, Or Xarelto
UPDATE: Xarelto trial results reaffirmed despite faulty device (Reuters, 2/5/16)
Europe's drug regulator said on Friday the defective blood clotting test device used in a key trial for the approval of Bayer's top-selling anti-clotting drug Xarelto did not distort the study's main findings.
"Xarelto can continue to be used as before, in line with the current prescribing information," the European Medicines Agency (EMA) said on its website.
According to this BMJ medical journal article, "Rivaroxaban: can we trust the evidence?", published on February 3, 2016, a faulty medical device used in the clinical trial leading to the FDA's approval of Xarelto (rivaroxaban) has called those results into question.
But in this letter to the New England Journal of Medicine (NEJM), "Point-of-Care Warfarin Monitoring in the ROCKET AF Trial", also published on February 3, 2016, the medical researchers who conducted that Xarelto clinical trial conclude that the use of this device "did not have any significant clinical effect on the primary efficacy and safety outcomes in the trial."
However, going back to the BMJ article, we get this counterpoint:
In a letter submitted to the NEJM (as yet unpublished) and shown to The BMJ, former FDA cardiovascular and renal drug reviewer, Thomas Marcinicak, says: “The care for the warfarin control arm patients [in ROCKET-AF] appears to have been compromised.”
The medical device at issue, which was later recalled by the FDA, allegedly is prone to giving falsely low INR readings. In the context of this Xarelto clinical trial, such readings would have prompted higher doses of warfarin being given to participants — resulting in higher bleeding risks for those given that warfarin — making Xarelto seem comparatively safer.
As background, Xarelto belongs to a class of medicines known as the direct oral anticoagulants (DOAC), which also includes Pradaxa (dabigatran), Eliquis (apixaban), and Savaysa (edoxaban). These still relatively new blood thinners have gained popularity in place of warfarin for the prevention of ischemic stroke in non-valvular atrial fibrillation because, as currently approved by the FDA, routine blood monitoring is not required.
But an earlier investigation by the BMJ medical journal found that the FDA and other drug regulators were not shown some available evidence which indicated that monitoring drug plasma levels for Pradaxa, at least, could improve patient safety.
From this BMJ earlier article, "Dabigatran: how the drug company withheld important analyses", published back in July 2014, we get this not new but still remarkable information:
[Pradaxa (dabigatran)] is one of a new generation of oral anticoagulants.... Guidelines in the US, Europe, and Canada have similarly recommended these drugs, in part because they don’t require monitoring of plasma levels or anticoagulant activity and subsequent dose adjustment, unlike older treatments such as warfarin....
In fact, Boehringer Ingelheim, the maker of dabigatran, has failed to share with regulators information about the potential benefits of monitoring anticoagulant activity and adjusting the dose to make sure the drug is working as safely and effectively as possible. The company also withheld analyses that calculated how many major bleeds dose adjustment could prevent. The company says that this information was not shared because the analysis did not provide a reliable prediction of patient outcomes. [footnotes omitted]
This information leads us back to what may be the most interesting part of the February 2016 BMJ article about the possible Xarelto clinical trial errors which we started with, "Rivaroxaban: can we trust the evidence?".
Here is an extended passage from that article that presents a possible unexpected result flowing from this current Xarelto controversy:
Good outcome for patients?
But in the end might this series of errors lead to a favourable outcome for the regulators—and perhaps patients?
At the end of 2015, both the EMA and the FDA held meetings to discuss the need to measure blood levels of direct oral anticoagulants and adjust the dose accordingly to maximise benefit and minimise harm—despite all the manufacturers claiming that this is not necessary. The meetings were held after The BMJ revealed that Boerhinger Ingelheim, manufacturers of dabigatran, withheld analyses from the regulators that showed how many major bleeds could be prevented by monitoring anticoagulant activity and adjusting the dose.
A presentation to EMA last year by Robert Temple, deputy director for clinical science at the FDA’s Center for Drug Evaluation and Research, suggests that the FDA believes there is a scientific argument for measuring the blood levels of these drugs and adjusting the dose.
“Being too low leads to a stroke, a very bad outcome, and being too high leads to major bleeds, also bad, so that early optimization [of the dose] seems worthwhile,” he said adding that direct oral anticoagulants are “very good, but could probably be better.”
But once a drug is on the market, regulators lack a mandate to act unless there are safety concerns. However, according to Powell, depending on the outcomes of any reanalysis of the ROCKET-AF trial, this might allow them to take action.
“After a drug is approved, it usually takes a safety signal to prompt significant action on the part of the FDA. It is this lack of safety signal that appears to be hindering the FDA in their desire to pursue tailored dosing for [direct oral anticoagulants (DOACs)]. If it turns out that the issue with the [INR] device changes the safety profile of rivaroxaban, this may constitute the safety signal necessary for the FDA to act in this regard,” he said. [footnote omitted]
So we wait to see what this current Xarelto fiasco leads to in terms of possible action by the FDA, EMA, and other drug regulators.
In closing, we draw once again from this July 2014 BMJ article, "Dabigatran: how the drug company withheld important analyses":
Crucially [Pradaxa (dabigatran)] was developed and marketed to be used in fixed dose regimens without the need for dose titration or monitoring of blood levels. This is considered to be a substantial advantage over warfarin.
At every stage in dabigatran’s evaluation, licensing, and marketing, the claim that there was no need to monitor drug levels has been central. It has been a factor in the cost benefit evaluations by bodies like NICE and the successful marketing and widespread uptake of the drug.
It was even highlighted in an FDA press statement in 2010 at the time of its US approval:
“Unlike warfarin, which requires patients to undergo periodic monitoring with blood tests, such monitoring is not necessary for Pradaxa [dabigatran],” said Norman Stockbridge, director of the division of cardiovascular and renal products in the FDA’s Center for Drug Evaluation and Research.
The company’s marketing messages to patients with atrial fibrillation in the US have also included this message prominently: “There are important differences between warfarin and Pradaxa,” says its advertisement, one of which is that there is “No need for regular blood tests to see if your blood-thinning level is in the right range.” [footnote omitted]
Hopefully, as regards this still emerging situation, patient safety will prevail over drug company profit in the end.