Patients with atrial fibrillation, pulmonary embolism and peripheral vascular disease for several years and have new anticoagulant drugs that are the cornerstone in the treatment of these diseases especially when it comes to prevent stroke in patients with cardiac arrhythmias.
PRADAXAR arrival of dabigatran, rivaroxaban Xarelto as pioneers in giving us wonderful medicines that simplified anticoagulation therapy but is observed everyday a media war to prove who is the best in this race of anticoagulation.
Yet it is not altogether new. the war between the new anticoagulants has been severely increased.
Relying on new evidence along with previously disclosed data, an investigation in the BMJ casts doubt on the reliability of data supporting the anticoagulant dabigatran Pradaxar.
The most important new accusation is that Boehringer Ingelheim 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.
Serius questions about dabigatran potentially higher than reported bleeding risk; the possibility of undertreating or overtreating with fixed doses, especially in older patients and patients with changing renal function; the unknown value of monitoring dabigatran levels and adjusting the dose; and the lack of a specific reversal agent.
The editorialists suggest a shared decision that balances patients’ tolerance of unknown risks, their tolerance of routine laboratory monitoring and dose adjustment, and their risk of stroke.
Boehringer Ingelheim strongly disputes the accusations
Blood level monitoring and dose adjustment for dabigatran Pradaxar could reduce major bleeding risk by 40% compared with well-controlled warfarin, according to company documents allegedly hidden from physicians and regulators.
An investigation by The BMJ released online in the journal concluded that recommendations for use of new generation oral anticoagulants may be flawed because regulators did not see evidence showing that monitoring drug plasma levels could improve safety.
The company 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.
Boehringer-Ingelheim remains insistent that there is no need for monitoring with the drug.
In a press release issued in response to the BMJ investigation, the company said it has provided regulators with the full data set and cited regulators’ conclusion that there is an important health benefit when used as directed.
Employee communications indicated that the company recognized regular monitoring could result in a more complex message and a weaker value proposition.
Guidelines in the U.S., Europe, and Canada have similarly recommended these drugs, in part because they don’t require monitoring of plasma.
The BMJ feature laid out evidence that the company knew that plasma levels of its drug varied dramatically among patients — from 40 to 200 ng/mL — but did not share that information when it came up in European regulatory deliberations in 2012.
That agency’s advisory committee then voted against measuring drug levels or dose titration, citing an unknown therapeutic window and variability of widely available tests, such as activated partial thromboplastin time.
Whereas European regulators did eventually end up including the blood level range in product information without recommending monitoring it, the FDA approach was much less centered on safety.
When the FDA advisory panel considered dabigatran in 2010, one member did bring up the issue of the five-fold variability in plasma levels of the drug, questioning whether plasma level monitoring might be necessary.
The response from an FDA pharmacologist was, We didn’t see a need for monitoring the concentration because we saw in a study a favorable result in all subgroups. Boehringer-Ingelheim said it continues to believe the drug needs no monitoring or dose adjustment.
The truth is the totality of scientific evidence does not support dosing decisions for Pradaxar based on blood levels, it said in the press release. “The research shows that individual patient characteristics, such as kidney function and certain medications, are critical factors in contributing to the risk of bleeding.
Internist Jordan Grumet, MD, of Lake Forest Hospital in Northbrook, Ill., was disturbed that the company left the scientific evidence at that.
Neither agency insisted on the most effective step to reduce bleeding risk optimizing the drug’s anticoagulant effect in each patient.
The FDA pursued a policy making the new drug easier to use with just one primary dose, even though it would increase the risk of hemorrhage in older patients. But the FDA also believed its actions might slightly improve the efficacy of dabigatran in preventing stroke.
A detailed subanalysis of the single pivotal trial for dabigatran for stroke prevention in atrial fibrillation RE-LY was done to see the impact dose optimization could have, but that unpublished simulation model only emerged during litigation proceedings. Under a simulation of dose titration to keep plasma levels at 90 to 140 ng/mL, only 45% of the patients would be on the 150-mg twice-daily dose (the only one in the trial that was approved by the FDA.
Another 26% would need to drop down to the 75-mg dose the FDA came up with as a solution to reduce bleeding risk for renal-impaired patients; 30% would need the 110-mg dose tested in the trial but not approved by the FDA.
If that strategy were followed, major bleeding would be reduced by 20% compared with the 150-mg dose. But there would have been no statistically significant effect on rates of ischemic stroke and serious embolism, albeit with a slightly higher absolute number of events with dose adjustment.
When compared with warfarin, dose-adjusted dabigatran would cut major bleeding risk by 40% without a significant difference in risk of stroke or serious embolism in the projection. Most patients could benefit from a lower dose and reduced bleeding risk with no loss of efficacy.
Drug monitoring for that kind of optimization would also turn up 8% to 17% of patients not getting enough anticoagulant effect from dabigatran who would need to be switched to another anticoagulant to optimally prevent strokes.
The FDA’s focus on boosting stroke prevention efficacy led to rejection of the 110-mg dose Boehringer Ingelheim had proposed it for patients ages 80 and older to reduce bleeding risk that would be needed for dose adjustment.
Not being able to monitor the drug has really been a disadvantage.
Renal excretion is a crucial factor in determining what the blood level of the drug
The population who might find it burdensome to go for regular blood tests are exactly those who have impaired renal function and have an unpredictable response to the medication or may have situations where their renal function drastically changes.
The suggest a shared decision that balances patients’ tolerance of unknown risks, their tolerance of routine laboratory monitoring and dose adjustment, and their risk of stroke,” the two wrote. It would be helpful to quantify the risk of stroke without treatment by using the CHADSVasc score and the risk of bleeding with warfarin using the HASBLED score.
No tool has been validated to quantify risk of bleeding with dabigatran, they noted.
Boehringer Ingelheim agreed: As with any anticoagulant, there needs to be a balanced consideration of stroke risk reduction and bleeding risk but not to stop taking dabigatran.
Discontinuing anticoagulation therapy puts a patient at increased risk of stroke.
While there’s no extensive data published to prove it, variability in blood concentrations is likely for the other newer oral anticoagulants such as apixaban Eliquis, rivaroxaban Xarelto, and edoxaban Savaysa too, according to a letter from Boehringer.
Rivaroxaban and apixaban were also marketed on the theme that plasma level dose adjustment was not needed, as it is with warfarin; more systematic and independent study is needed to establish what price, in terms of preventable hemorrhage and death, is being paid for each of the new drugs in the name of ease of use.
Instead of leaving safety on par with warfarin in favor of ease of use, the safety of all the new anticoagulants could potentially be improved through documenting a therapeutic range for each and individualizing doses.
However, they pointed out that dabigatran does have a pharmacology that would suggest more variability in plasma levels than the rest.
It combines low bioavailability (3% to 7%), two metabolic steps to convert the prodrug into the active drug, and a single primary route of elimination the kidneys),” they explained. As a result, a small difference in metabolic activation or kidney function could have a large effect on plasma level and bleeding risk.
These properties were not shared by two new indirect thrombin inhibitors, apixaban and rivaroxaban, which have much higher bioavailability (50% to 80%) and multiple routes of elimination.
For clinicians, though, such feedback even in the presence of less dramatic blood level variability would be useful.
This concept of needing a way to objectively monitor these new drugs where there is significant clinical risk on both ends of the spectrum is relevant to all of them.
The newer oral anticoagulant NOAC monitoring is a strategy worth investigating.