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.”
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.
Drug Monitoring
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 — 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.”
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.” "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.
Dose Adjustment
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."
What Now?
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 “shocking … 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."
We believe that obtaining legal satisfaction from those who
harmed you shouldn’t require more hardship. That’s why we do everything we can
to streamline the process, and we will file a lawsuit on your behalf if
necessary. If you or a loved one has been affected by Pradaxa, and you believe
it caused harm, contact Chhabra & Gibbs today by going to www.cglawms.com
or by calling this number: 601-948-8005.
