Blood level monitoring and dose adjustment for dabigatran (Pradaxa) could reduce major bleeding risk by as much as 20% compared with unadjusted use, according to company analyses 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.”
Internal documents obtained through freedom of information requests and litigation implied that drug maker Boehringer-Ingelheim determined optimal plasma levels to minimize bleeding risk that would have little or no impact on effectiveness in cutting risk of ischemic stroke, but didn’t share that data in a bid to boost dabigatran’s commercial success.
“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.â€
Boehringer-Ingelheim remains insistent that there is no need for monitoring with the drug.
In a press release issued in response to the 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.”
However, the point is not whether there’s a net benefit when used unmonitored and untitrated — it’s that the net benefit wasn’t maximized, which could have saved lives, an accompanying analysis by Thomas Moore, of the Institute for Safe Medication Practices in Horsham, Pa., and colleagues suggested.
Employee communications indicated that the company recognized that suggesting that regular monitoring was needed could result in “a more complex message and a weaker value proposition.”
Indeed, “Guidelines in the U.S., 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,” Cohen wrote.
The BMJ feature laid out evidence that the company knew by 2011 that plasma levels of its drug varied more than five-fold for the same dose among patients but should be kept in the 40-to-200 ng/mL range to maximize benefit and minimize harm â€” but did not share that information when it came up in European regulatory deliberations in 2012.
A “review of the EMA meeting materials shows that the company slide presentation did not include all their relevant data on plasma level variability of dabigatran.â€
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.
The company had already settled on the Hemoclot thrombin inhibitor assay, which is available only for research use in the U.S. The same month as the EMA vote, its employees published a paper highlighting the accuracy of that test for assessing both the anticoagulant activity and plasma concentrations of dabigatran.
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, Moore’s group said.
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.
“That seems awfully big to me in a drug that we’re proposing to use without therapeutic monitoring,” said Darren McGuire, MD, a cardiologist at the University of Texas Southwestern Medical Center in Dallas, during the meeting.
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 routine dose adjustment.
“The truth is the totality of scientific evidence does not support dosing decisions for Pradaxa 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.
“The right thing to do for society is to pursue this further, but they would have had to do large-scale double-blind randomized controlled trials and that would have been expensive.â€ Â “The crux is the moral issue. What they did is probably morally repugnant, but not necessarily illegal.”
And regulators share the blame in that, Moore’s group argued.
In the end, “neither agency insisted on the most effective step to reduce bleeding risk — optimizing the drug’s anticoagulant effect in each patient,” Moore’s group concluded.
“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.”
The agency also slacked off in allowing company oversight of the review of cardiovascular events it required after concerns arose around bleeding, Cohen argued.
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,” Moore’s group concluded.
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.
“Because the simulations did not offer reliable predictions of actual patient outcomes, they were not provided to regulators,” the Boehringer Ingelheim statement said. “However, all of the data that was used for the simulations had already been provided.”
It continued, “It is inappropriate to provide regulators simulations that are unreliable and have limitations. Post-hoc exploratory analyses are commonly performed to generate or test hypotheses and are not structured to direct patient management. Thus, they generally are not shared with regulators and first need to be tested in a clinical trial, as many hypotheses, such as the one discussed here, prove to be incorrect.”
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.
Senior managers at the agency cited the danger of too many people taking that lower dose, saying in the official approval decision document, “One could attempt to discourage this behavior through education, but that strategy might not prove very effective.”
Moore’s group urged the manufacturer and regulators to agree on a therapeutic range and recommend initial dose adjustment based on plasma measurements in order to substantially improve the safety of the drug.
The FDA needs to approve the Hemoclot plasma level test so that physicians can monitor levels and make the 110-mg strength available as other Western nations have done, Moore’s group added.
Not being able to monitor the drug has really been a disadvantage, commented vascular neurologist Cathy Sila, MD, director of the University Hospitals Case Medical Center Comprehensive Stroke Center in Cleveland.
“Renal excretion is a crucial factor in determining what the blood level of the drug is.”
“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. If they become dehydrated or have acute or chronic kidney injury, they may have precipitous swings of their drug levels.”
Electrophysiologist David Haines, MD, of the Beaumont Hospital in Royal Oak, Mich., called the investigation findings â€œshocking â€¦ but not entirely surprising.”
He speculated that the investigation would prompt a closer look and approval of the Hemoclot test.
“I think when that test becomes available it will become fairly routine to test trough levels of this drug after new initiation of the drug in patients and then down-adjust the dose if necessary.”
Meanwhile, clinicians are left to hash out the options with the patient, noted an editorial by Blake Charlton, MD, and Rita Redberg, MD, both of the University of California San Francisco.
“We 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.
“Patients and doctors tolerant of unknown risk and close monitoring will have to choose which drives them more strongly, with the more conservative option being warfarin,” Charlton and Redberg noted. “Patients intolerant of frequent monitoring and unknown risk will find themselves with no appealing options.”
Boehringer Ingelheim agreed: “As with any anticoagulant, there needs to be a balanced consideration of stroke risk reduction and bleeding risk.”
But it urged patients not to stop taking dabigatran based on the BMJ investigation without talking with their physicians. “Discontinuing anticoagulation therapy puts a patient at increased risk of stroke.”
Other Newer Oral Anticoagulants
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 employee Paul Reilly, PhD, and RE-LY study authors in the Journal of the American College of Cardiology last month responding to criticism that data on dabigatran and plasma levels had been suppressed.
That is a point worth pursuing, Cohen argued.
“Rivaroxaban and apixaban were also marketed on the theme that plasma level dose adjustment was not needed, as it is with warfarin,” she wrote. “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, Moore agreed.
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, Sila argued.
“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.”
Patrick D. Lyden, MD, chair of neurology at Cedars-Sinai Medical Center in Los Angeles, dismissed the BMJ investigation as neither scientific nor clinically relevant.
However, he agreed that newer oral anticoagulant [NOAC] monitoring is a strategy worth investigating.
“Further research should be funded by industry or government to test the hypothesis that monitoring blood levels could improve the safety and efficacy of NOAC use in patients with atrial fibrillation.”
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