Dabigatran: how the drug company withheld important analyses
In an investigation by The BMJ Deborah Cohen finds 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
An investigation by The BMJ shows how the manufacturers of a blockbuster anticoagulant stroke drug withheld from the regulators important analyses regarding how to use the drug as safely and effectively as possible.
Dabigatran is one of a new generation of oral anticoagulants for stroke prevention in patients with non-valvular atrial fibrillation recently recommended in guidelines from the National Institute for Health and Care Excellence for England and Wales.1 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.2 3 4
Yet information about dabigatran disclosed through previously confidential internal company documents released during litigation in the US—which they have settled for $650m (£380m; €480m)—and as a result of an investigation by The BMJ, show that the evidence on which these guidelines were based is incomplete.
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.
Anticoagulation is a risky procedure. In the UK, warfarin is one of the drugs most commonly implicated in emergency hospital admissions as a result of major bleeds5 and the drug’s anticoagulant activity is monitored to reduce those risks.
In the single key trial comparing dabigatran with warfarin in non-valvular atrial fibrillation, major and minor bleeding occurred in 16.4% of patients a year taking the higher dose of dabigatran compared with 18.15% a year for warfarin. However, even after the regulators asked Boehringer to re-examine the trial data for missed events, it is still not clear whether we know how many fatal and life threatening bleeds there were in the trial.6
Nevertheless, internal documents show how the company had produced extensive analyses that show how that bleeding risk may be reduced. The company found that if the plasma levels of the drug were measured and the dose was adjusted accordingly major bleeds could be reduced by 30-40% compared with well controlled warfarin. The adjustment would have little or no effect on the risk of ischaemic stroke. It has also identified the plasma levels at which the dose adjustment should occur to reduce the risk of a major bleed.
The conclusion of the analyses was: “Optimally used (=titrated) dabigatran has the potential to provide patients an even better efficacy and safety profile than fixed dose dabigatran and also a better safety and efficacy profile than a matched warfarin group.”
But the company has told The BMJ that it has not shared this information with either doctors or regulators. The European Medicines Agency confirmed this, adding, “If we discover that the company withheld any relevant information, we will not hesitate to take necessary action” and will make “changes to the current recommendations.”
Internal emails released during litigation perhaps show that some within the company did not want these conclusions to be known. During internal email discussions about the potential merits of drug plasma monitoring one Boehringer employee, whose name has been redacted, said: “This may not be a onetime test and could result in a more complex message (regular monitoring) and a weaker value proposition.” Even as employees expressed concerns that elderly patients were being harmed, the company did not share these analyses with the regulators.
However, the company said that the emails made public had been selected to show it in a bad light and restated its claim that the anticoagulant activity or plasma concentrations of dabigatran do not need to be monitored.
“The analysis did not provide a reliable prediction of patient outcomes, and therefore we did not share the simulation with FDA or EMA,” a spokesperson told The BMJ.
“Our scientists determined, and the FDA concurred, that the research does not support making dosage decisions based on plasma concentrations—a conclusion based solely on science and patient welfare,” he said.
The spokesperson also reiterated the safety of dabigatran. “The FDA has publicly reported its own post-marketing analysis, concluding that dabigatran’s post-marketing bleeding rates do not appear to be higher than [those with] warfarin,” he said.
What is dabigatran?Dabigatran is one of the new oral anticoagulants and is known as a direct thrombin inhibitor. Other new oral anticoagulant drugs are rivaroxaban and apixaban and are direct factor Xa inhibitors. Before this new group of drugs emerged, vitamin K antagonists, such as warfarin, were the mainstay of antithrombotic therapy. When dabigatran was licensed in Europe in 2008, it was the first new oral anticoagulant to be approved in over 50 years.
Market advantage Crucially 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.7
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.”8
The fact that dabigatran was the first new oral anticoagulant for over half a century also allowed the new drug to benefit from regulatory policies in the US promoting innovation; before being licensed for atrial fibrillation it was studied in a single large phase III trial rather than in at least two trials, as is normally required for approval.9
Internal documents show that the trial was designed to “validate a NOAC [new oral anticoagulant] with no monitoring.” The trial, called RE-LY, randomised participants to either warfarin or one of two doses of dabigatran (150 mg or 110 mg twice daily), and was published in the New England Journal of Medicine in September 2009.10
The paper concluded that patients given the 150 mg twice daily dose of dabigatran had lower rates of stroke or systemic embolism than those given warfarin. They also had similar rates of major bleeding.
However, the regulators had concerns about the design and oversight of the trial, which initially delayed the drug’s approval.11 The FDA mandated a review of missed events after concerns about data quality.6
Regulators’ questions before licensingIn the run-up to dabigatran being licensed, discussions about the possible need to monitor dabigatran came up at both the FDA and the EMA. Documents obtained under freedom of information show the EMA was concerned about the need to monitor the plasma levels of the drug to reduce the risk of bleeding; not just at the time of the decision to grant a licence to market the drug for stroke prevention in non-valvular atrial fibrillation in 2011, but also later when widespread use of the drug led to safety concerns.
They also show that the drug’s licence in Europe was conditional on the availability of an accurate test to monitor the drug. This was decided to be the Hemoclot test. However, the agency repeatedly relied on the drug company for answers and to be transparent and open about the interpretation of their data.12
EMA documents from early 2010 also show that Boehringer had “identified dabigatran concentrations not to be exceeded because of the increased risk of bleeding . . . The 200 ng/mL concentration is the value at trough not to be exceeded because of the increased risk of bleeding.”
This value is reiterated in EMA’s published drug assessment report. It also stipulates a lower end of the range of 48 ng/mL.13 During the US drug approval process in September 2010 one FDA adviser also raised the question of monitoring dabigatran because of the large differences in plasma levels among people taking the drug.
“I’m struck by what my eyeball tells me about a five-fold variability [in plasma levels] within the 90% confidence [interval] of the 150-dose. That seems awfully big to me in a drug that we’re proposing to use without therapeutic monitoring,” said Darren McGuire, a cardiologist on the panel in 2010. However, McGuire’s concerns were not pursued by the agency.
So did Boehringer give this information to the FDA, as it had to the EMA? And if the EMA assessment included an upper threshold why isn’t it included in prescribing information to UK doctors? A spokesperson for Boehringer said that the company “never told EMA or any regulatory authority that 200 ng/mL was a level ‘not to be exceeded,’”
The company spokesperson said that EMA had agreed to say in the label that dabigatran concentrations greater than 200 ng/mL “may be associated with an increased risk of bleeding,” adding that as a result The BMJ’s questions about whether this information has also been shared with the FDA and how many lives could have been saved if the upper limit of 200 ng/mL had been shared more widely was “moot.”
However, internal documents show that the scientists the company had used to coordinate the trial show that EMA’s statement might have merit. When discussing how best to publish analyses of data from the RE-LY trial, Stuart Connolly, one of the principal investigators of the RE-LY trial, said in an email in July 2012: “There is very good reason to never go above 200 ng/ml. It is less clear at the low end due to the paucity of events but somewhere around 40-50 seems prudent for a lower boundary.”
In the end, the FDA approved dabigatran in October 2010 for use in stroke prevention in non-valvular atrial fibrillation without the need to adjust the dose in each patient; the EMA followed suit in August 2011.
Although the EMA approved the 110 mg and 150 mg doses, the FDA approved only the 150 mg twice daily dose and asked for a 75 mg twice daily dose to be developed for patients with severe renal impairment.12 The 75 mg dose was not tested in clinical trials and was chosen on the basis of pharmacodynamic and pharmacokinetic data collected by the company.
Early concernsOnce on the market, dabigatran proved a rapid success. By April 2012, it had achieved blockbuster status (where annual global turnover for a medicine exceeds $1bn), prompting Boehringer board member Hubertus von Baumbach to say: “The launch of Pradaxa [dabigatran] is among the most successful market introductions in the pharmaceutical industry in the past few years.”
But even as the sales of dabigatran were rapidly growing, concerns about fatal bleeds were beginning to emerge—particularly in elderly people, who are at much higher risk of bleeding.
Indeed, during discussions about licensing the drug for non-valvular atrial fibrillation, the EMA was concerned that dabigatran would be “largely used in an elderly population which is known to be at a higher risk of bleeding” —a concern that internal company documents show to be justified.
Boehringer Ingelheim marketing data showed that “45% of Pradaxa patients are 76 years or older” and “30% of patients are 80 years or older.” However, only 40% of participants in the RE-LY trial were over 75 and 17% over 80.
By the end of 2011 regulators were concerned as postmarket reports accumulated about cases of severe bleeding and deaths among patients taking dabigatran. A QuarterWatch report analysed all the adverse events submitted to the FDA’s reporting system in 2011.14 It found the most commonly identified drugs reported to the FDA were the anticoagulants dabigatran and warfarin. For dabigatran alone, this included 542 patient deaths and 2367 reports of haemorrhage. Warfarin accounted for 72 deaths in the same period.
“The need to achieve greater safety in anticoagulant treatment should be a drug safety priority. While dabigatran is replacing warfarin in the market as a drug that is easier to use, the priority need is for stroke prevention treatments that are safer,” the report authors wrote.14
What did Boehringer know?Documents released during US litigation have shown that the company worried about how to improve the drug’s safety. Questions were being asked about whether the drug had a therapeutic range within which risks could be minimised and benefits could be maximised and if it would therefore need monitoring and dose adjustment.
Although the RE-LY trial protocol did not require monitoring of blood levels in patients taking dabigatran, the investigators collected drug plasma concentrations during the trial. Internal documents circulated within the company in August 2011 show that employees completed a subgroup analysis of these data.
Some of the conclusions of this analysis were eventually published online in the Journal of the American College of Cardiology in September 2013 under the title “The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients.”15 The lead author was Paul Reilly, a Boehringer employee, and coauthors included other company employees as well as Stuart Connolly and Salim Yusef from McMaster University in Canada and Lars Wallentin from the Uppsala Clinical Research Centre, Sweden.
The paper, which was first drafted in August 2011, examined a critical question: how much did the benefits (reduced risk of ischaemic stroke) and harms (increased risk of bleeding) vary across the drug’s plasma concentration range. This “has important implications for the benefit-risk ratio in individual patients,” both the draft and published papers said. They found that there was a fivefold variation in blood plasma concentration with each dose.
Reilly’s paper reported that renal function was the most important determinant of dabigatran concentration, and age is the most important covariate. “The large majority of patients achieve a favourable balance of benefit and risk with a fixed dose of DE [dabigatran] 110 or DE [dabigatran] 150, guided by a consideration of patient characteristics,” the published paper said.
However, the 2011 draft also suggested there was an optimal plasma concentration range of the drug and went beyond tailoring dose according to patient characteristics.
It found that there was a fivefold variation in blood plasma concentration with each dose. “Monitoring of plasma concentrations or antithrombotic activity . . . would be required to identify these patients. A dose adjustment could improve the benefit-risk ratio,” according to the 2011 draft seen by The BMJ.
But internal emails released during US litigation show how the company grappled with the implications of the paper. In an internal email in 2011, Andreas Clemens, a medical team leader for the drug, stated that he was “phobic” and “not happy with the conclusion”—that an optimal balance between benefit and risk occurs in the range of concentrations between 40 ng/mL and 215 ng/mL.
The company knew what damage the paper might do—and yet emails show that in July 2012 Connolly thought that it was a good paper that “will have an impact on thinking about dabigatran” and points to “optimization of safety and efficacy in the range from 40-200 ng/mL.”
However, the scientists’ concern conflicted with that of some in the company. An email in October 2012 shows a company official saying that “The publication will [do] more harm than be useful for us, neither in the market but especially harmful in the discussions in the regulatory bodies.”
Clemens also wrote that he believed that the findings were important and should be published but with revision. “The world is crying for this information—but the tricky part is that we have to tailor the messages smart.”
Emails from February 2013 show that company employee Jutta Heinrich-Nols wrote to other employees to recommend that the company reconsider whether to publish this study.
“This will make any defense of no monitoring to HA [health authorities] extremely difficult (i.e. Health Canada, TGA) and undermine our efforts to compete with other NOACs [new oral anticoagulants]. As I am not empowered to release or stop any publications I would like to ask you to check once again whether this is really wanted.,” an email said.
Publishing the research results, she warned, could make it “extremely difficult” for the company to defend its long-held position to regulators that dabigatran did not require monitoring.
The BMJ contacted the three independent doctors working with the data and asked them about the apparent conflict around what was contained in the paper.
Wallentin said that while the academics had access to the RE-LY database and freedom to analyse what they wanted, “all scientific projects are submitted to and approved by the RE-LY publications committee. The content of all publications are of course at the end based on discussions followed by modifications to reach a consensus among all coauthors,” he said.
The BMJ has found that the company did defend the notion that the drug did not require monitoring of plasma levels or anticoagulant activity to health authorities.
As the number of fatal bleeds accumulated and company employees deliberated Reilly’s analyses, the EMA started to formally consider the key issue that the manufacturer was trying to avoid: that dabigatran would need to be monitored and the dose adjusted. In early 2012 the agency convened its scientific advisory group of experts to give it advice about these issues. Specifically, it wanted to know if there was a “need for stronger and more specific recommendations for measurement of dabigatran related anticoagulation,” specifically in those groups at increased risk of bleeding.
The European agency also asked the committee to “discuss and suggest appropriate monitoring frequency and laboratory tests.” On 9 March, 2012, Boehringer gave a presentation to the committee, details of which The BMJ has obtained under a freedom of information request, along with the agency’s minutes of the meeting.
The EMA’s minutes show that routine monitoring of anticoagulant activity was discussed “in depth” by the committee. However, most experts voted against it.
The committee thought that this was justified because “the desired plasma drug level and the therapeutic window are not known” and “there is significant variability of more widely available tests such as the aPTT [activated partial thromboplastin time] making interpretation difficult.”
In the end, the final recommendations simply stressed the need to monitor renal function and patient characteristics before and during treatment and “make dose reductions in certain patients”—and not routinely measure plasma concentrations or anticoagulant activity. Dabigatran is predominantly excreted by the kidneys.
Some of the analyses and conclusions outlined in Reilly’s 2011 paper, which was produced over six months before EMA’s safety meeting in March 2012, were absent from the company’s presentation to the committee.
Aspects of Paul Reilly’s 2011 paper that were not in the company’s presentation include a graph showing that beyond a certain plasma concentration of the drug major bleeding events continued to increase as the plasma levels increased with little effect on rates of stroke and systemic embolism.12 This graph was, however, published in 2013 in the Journal of the American College of Cardiology. Also absent from the presentation were data showing that some people taking dabigatran may have a suboptimal dose, putting them at “an appreciably higher” stroke risk.
In the meeting, company officials highlighted the importance of measuring creatinine clearance to assess renal function. The company also chose to present statistics in which the plasma level variability seemed to be about 2.3-fold instead of 5.5-fold as documented in Reilly’s paper. The presentation added that the European label currently includes monitoring for renal function and cut-off values for dabigatran exposures with increased bleeding risk and plasma level data from RE-LY. But stated: “Routine monitoring of the anticoagulant activity is not necessary.”
The unpublished version of the Reilly paper, however, stated that “targeting a specific concentration range may optimize the benefit-risk . . . A dose adjustment could improve benefit-risk ratio,” it said. But the company’s presentation to the EMA’s ad-hoc committee did not include this information.
The BMJ asked Boehringer if it was confident that it had presented all the internal analyses of the RE-LY trial data that were available to them to EMA’s ad-hoc safety meeting for the assembled experts to discuss.
We also asked if it had made the European agency aware during the meeting that company analyses suggested “targeting a specific concentration range may optimize the benefit-risk” and that: “monitoring of plasma concentrations or antithrombotic activity . . . would be required to identify these patients. A dose adjustment could improve the benefit-risk ratio,” as had been described in the draft publication.
A spokesperson for the company said: “At the meeting, BI presented analyses and information that were relevant to these issues and available at the time. All RE-LY trial data, along with extensive analyses of that data, had previously been provided to EMA.”
The spokesperson also said that the company did not tell EMA’s safety committee that monitoring plasma concentrations and targeting a specific concentration range were being discussed internally as they were “hypotheses in drafts of a paper that the authors of that paper rejected as they refined their analysis.”
The company spokesperson also stated that such models “are inherently imprecise and carry a margin of error.” The reasons for this, the spokesperson said, is that the modelling is “not based on data that directly measured the efficacy and safety outcomes for patients subject to monitoring and dose adjustment,” adding that: “the data that the simulation was based on was not sufficiently robust to reliably derive plasma concentration thresholds for dose adjustment and then predict patient outcomes.”
The BMJ asked Boehringer if it could provide any more information to clarify the issue and to support its assertion that the modelling wasn’t reliable. It’s not clear from the information provided when or why these particular models were rejected and considered to be inaccurate given that the data and the models have been used for other purposes, including publications and regulatory decisions.
The company has said that it provided all the trial data—which it is obliged to do—and extensive analyses. However, the question of the extent of sharing of internal company analyses of the data with the regulator is a grey area, as there is no legal obligation on a company to share such data.
However, Steve Nissen, department chair of cardiovascular medicine at the Cleveland Clinic and one of the members of the FDA’s advisory committee considering dabigatran for use in non-valvular atrial fibrillation, told The BMJ: “If there is clinically useful information about the relationship between drug levels and the safety of dabigatran, it is the moral obligation of the company and its investigators to share this information with the medical community. Withholding such information for commercial purposes is unacceptable.”
The Hemoclot testIt wasn’t just the absence of a therapeutic range that persuaded the ad-hoc meeting to stop short of recommending the measurement of the drug’s plasma levels. There was the problem of how to test the dabigatran’s anticoagulant activity or its plasma levels.
Before dabigatran was licensed by EMA, documents obtained under freedom of information show that the European agency insisted on there being a device to monitor the drug levels available on the market. It was decided that this should be the Hemoclot test (diluted thrombin time).
What tests to use was discussed at the 2012 meeting. The company’s presentation showed a graph using clotting time plotted against plasma concentration. But this was dismissed as having “limited sensitivity.”
The Hemoclot test was discussed at the 2012 meeting—and proposed by some experts—but rather than discuss ways of ensuring its uptake, the test was dismissed by the committee as it is “under development” and “may not be available in many laboratories in the EU and some time is required to obtain the results.” (In the US the Hemoclot thrombin inhibitor assay is available only for research use.)
Why the committee came to that conclusion rather than suggest wider use is unclear. That same month (March 2012) company employees published a paper that highlighted the accuracy of the Hemoclot test in patients taking dabigatran.
The paper stated that Hemoclot thrombin inhibitor assay was a “rapid, established, standardized and calibrated” and “should provide accurate and consistent results” when assessing both the anticoagulant activity and calculating plasma concentrations of dabigatran. 16
Commercial interestsFrom an early stage, Boehringer planned to develop and market a drug that did not require plasma level monitoring. Internal documents show that even though there had been deaths associated with major bleeds in the clinical trial and there was no antidote—a decision had been made not to support the development of a bedside monitoring device.
The rationale for this was laid bare in an email on 3 June 2010. An employee from the cardiology division of the company brought up the issue of the utility of such a device. In an email they said: “2 years ago [in 2008] there was an informed decision NOT to develop this. As this would go against the ‘no monitoring’ idea/claim.”
Soon after Boehringer told the EMA’s committee that adjusting dose for plasma levels was not necessary, it was considering relaunching the drug based on adjusting the dose to a specific therapeutic range. The company wanted to know if it could find a “unique selling” point for dabigatran since rivaroxaban and apixaban—two other new oral anticoagulants—had come onto the market. “Could individualised dosing be a unique selling point for Pradaxa in the marketplace,” a June 2012 document entitled “Potential mid to long term strategy for Pradaxa in SPAF [stroke prevention in atrial fibrillation]” said.
The document noted that prescribers often wanted to know the extent of the anticoagulation each patient is receiving with their current anticoagulant. Company employees produced yet more analyses, which they summed up in the strategy document and accompanying slide presentation circulated to Boehringer executives.
It analysed whether “a one-time initial measurement (perhaps repeated annually and in some instances, such as moderate renal impairment, in shorter intervals)” followed by titration of dabigitran to reach an optimal dose would be the safest and most effective way of using the drug.
After an “intense effort” using data simulations and data from RE-LY, it found that by doing this, it “could preserve the effect on ischemic stroke prevention but with a reduction of major bleeding events compared to well controlled warfarin of perhaps up to 30-40%.” The data also suggested that such an approach would even lead to fewer gastrointestinal bleeds with dabigatran “compared to warfarin in such a setting.”
The company were also keen to get the 110 mg twice daily dose on the market in the US, and this would be needed for individualised dosing.12
“[The] FDA has indicated that such modeling data, together with clinical data (eg, a PK/PD [pharmacokinetic/pharmacodynamic] study) on a titration strategy, may be the only way forward to an approval of the 110 mg dose in the US,” the document said. After considering regulatory and other obstacles, the company has thus far not elected to pursue this strategy.
By comparing a 150 mg twice daily dose used under recommendations for use stipulated by the EMA—which advocates patient selection and renal monitoring—to a regimen in which dabigatran that was monitored and titrated accordingly, the company calculated that major bleeds could also be reduced.
(Diagram - click source below)
But neither doctors nor the regulators have ever been made aware of the company calculations circulated in June 2012—including the number of major bleeds that could be prevented and at what plasma levels the drug should be titrated.
A Boehringer spokesperson said: “The analysis did not provide a reliable prediction of patient outcomes, and therefore we did not share the simulation with FDA or EMA,” adding: “All of the data that was used for the analysis had already been provided to the regulatory authorities”
But in their mid to long term strategy document, company officials also wondered if patients who had low levels of dabigatran in their blood despite receiving the higher dose would have to stop treatment. And if so, what percentage of people with atrial fibrillation would this account for?
There were also questions over what the implications would mean for people taking dabigatran for conditions other than atrial fibrillation (such as venous thromboembolism).“Will this negatively impact the product perception?” the document said.
However, detailed information about the optimal therapeutic range would have been useful to doctors. Paul Chin, a clinical pharmacologist, at Christchurch Hospital, University of Otago, in New Zealand, has been trying to identify the optimal range for patients for some time using what information was publicly available. “It would have been useful for doctors to know that patients at the extremes of trough concentrations have much higher risks of stroke (very low concentrations) or bleeding (very high concentrations), and how to detect this,” he said.
Chin says that he asked Boehringer for RE-LY data on plasma concentrations and glomerular filtration rate back in 2011. “But we got what is probably the standard reply that it’s confidential and would have to be taken up with corporate and we’ll get back to you sometime,” he said.
In June 2012, he and a group of other academics published a paper in the British Journal of Clinical Pharmacology that caught the eye of company executives. It stated that testing in clinical practice has been “largely downplayed.”
The paper pointed out that the UK guidelines from Boehringer advocating renal testing in some patients did not go far enough, “leaving some individuals likely to be overdosed and some perhaps underdosed.” It advocated the use of the Hemoclot test.
Internally, the paper triggered discussions. One employee was worried about the adverse effects of dabigatran—particularly in older people. “We should not ignore that in those over 80 years old, even the 110 mg had a unfavourable trend compared to warfarin (major bleeding 80 years: hazard ratio 1.12 (95% confidence interval 0.84, 1.49),” the employee wrote, arguing that Boehringer needed to study this further before another independent group did.
Facing concerns that the company had not put the data contained within the Reilly paper into the public domain earlier, Reilly and colleagues stated in a letter to the Journal of the American College of Cardiology: “Of the new oral anticoagulants, RE-LY is the only trial that has published extensive data on this topic. It is likely that other anticoagulants will also exhibit variability in blood concentrations.”17
Boehringer’s Reilly makes a point worth pursuing. 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 haemorrhage and death, is being paid for each of the new drugs in the name of ease of use.
Indeed, Hugo ten Cate, medical director of the Maastricht thrombosis anticoagulation clinic and coeditor in chief of Thrombosis Journal, has been concerned about the lack of published studies on dose adjustment in the new oral anticoagulants for some time.
This combined with a lack of antidote has been a “major hurdle in the safe introduction of NOACs,” he wrote in March 2012.
“It is critical that pharmaceutical companies take their responsibilities and provide and publish all relevant data on drug levels and coagulation test responses so that it becomes clear what the approximate therapeutic and harmful ranges of laboratory test outcomes are, for each anticoagulant agent. There is no good reason not to be transparent in these matters, even if it would entail the small risk that doctors would want to optimise therapy based on lab test results,” he said.
Source : BMJ (July 2014)
Risk of Bleeding With Dabigatran in Atrial Fibrillation
Inmaculada Hernandez, PharmD1; Seo Hyon Baik, PhD1; Antonio Piñera, MD2; Yuting Zhang, PhD1
Importance It remains unclear whether dabigatran etexilate mesylate is associated with higher risk of bleeding than warfarin sodium in real-world clinical practice.
Objective To compare the risk of bleeding associated with dabigatran and warfarin using Medicare data.
Design, Setting, and Participants In this retrospective cohort study, we used pharmacy and medical claims in 2010 to 2011 from a 5% random sample of Medicare beneficiaries. We identified participants as those newly diagnosed as having atrial fibrillation from October 1, 2010, through October 31, 2011, and who initiated dabigatran or warfarin treatment within 60 days of initial diagnosis. We followed up patients until discontinued use or switch of anticoagulants, death, or December 31, 2011.
Exposures Dabigatran users (n = 1302) and warfarin users (n = 8102).
Main Outcomes and Measures We identified any bleeding events and categorized them as major and minor bleeding by anatomical site. Major bleeding events included intracranial hemorrhage, hemoperitoneum, and inpatient or emergency department stays for hematuria, gastrointestinal, or other hemorrhage. We used a propensity score weighting mechanism to balance patient characteristics between 2 groups and Cox proportional hazards regression models to evaluate the risk of bleeding. We further examined the risk of bleeding for 4 subgroups of high-risk patients: those 75 years or older, African Americans, those with chronic kidney disease, and those with more than 7 concomitant comorbidities.
Results Dabigatran was associated with a higher risk of bleeding relative to warfarin, with hazard ratios of 1.30 (95% CI, 1.20-1.41) for any bleeding event, 1.58 (95% CI, 1.36-1.83) for major bleeding, and 1.85 (95% CI, 1.64-2.07) for gastrointestinal bleeding. The risk of intracranial hemorrhage was higher among warfarin users, with a hazard ratio of 0.32 (95% CI, 0.20-0.50) for dabigatran compared with warfarin. Dabigatran was consistently associated with an increased risk of major bleeding and gastrointestinal hemorrhage for all subgroups analyzed. The risk of major bleeding among dabigatran users was especially high for African Americans and patients with chronic kidney disease.
Conclusions and Relevance Dabigatran was associated with a higher incidence of major bleeding (regardless of the anatomical site), a higher risk of gastrointestinal bleeding, but a lower risk of intracranial hemorrhage. Thus, dabigatran should be prescribed with caution, especially among high-risk patients.
Source : JAMA (Jan 2015)
Monoket (isosorbide mononitrate) Tablets
Used to prevent angina attacks (chest pain). Isosorbide mononitrate will not treat an angina attack that has already begun.
- ...added...Do not use monoket in patients who are taking certain drugs for erectile dysfunction (phosphodiesterase inhibitors), such as sildenafil, tadalafil, or vardenafil. Concomitant use can cause severe hypotension, syncope, or myocardial ischemia.
- Do not use monoket in patients who are taking the soluble guanylate cyclase stimulator riociguat. Concomitant use can cause hypotension.
- ...added...Concomitant use of monoket with phosphodiesterase inhibitors in any form is contraindicated (see CONTRAINDICATIONS). Concomitant use of monoket with riociguat, a soluble guanylate cyclase stimulator, is contraindicated (see CONTRAINDICATIONS).
Source : FDA (October 2014)
Dilatrate SR (isosorbide dinitrate) Sustained Release Tablets
Isosorbide dinitrate is used to prevent angina (chest pain) caused by coronary artery disease. It does not work fast enough to relieve the pain of an angina attack that has already started.
- Do not use dilatrate®-SR in patients who are taking certain drugs for erectile dysfunction (phosphodiesterase inhibitors), such as avanafil, sildenafil, tadalafil, vardenafil. Concomitant use can cause severe hypotension, syncope, or myocardial ischemia. Do not use dilatrate SR in patients who are taking the soluble guanylate cyclase stimulator riociguat. Concomitant use can cause hypotension.
- Concomitant use of dilatrate®-SR with phosphodiesterase inhibitors in any form is contraindicated (see CONTRAINDICATIONS).
- Concomitant use of dilatrate SR with riociguat, a soluble guanylate cyclase stimulator, is contraindicated (see CONTRAINDICATIONS).
Source : FDA (October 2014)
Amiodarone Linked to Cancer Risk in Men
The risk of cancer was increased in men taking the antiarrhythmia drug amiodarone (Nexterone), particularly in those with extensive exposure to the drug, a retrospective study found.
Among men taking amiodarone, the risk for any cancer rose by almost 20% compared with the general population, with a standardized incidence ratio of 1.18 (95% CI 1.02 to 1.36, P=0.022), according to Chia-Jen Liu, MD, of National Yang-Ming University Hospital in Yilan, Taiwan, and colleagues.
And for men whose cumulative defined daily doses in a year exceeded 180, the risk was 46% higher (SIR 1.46, 95% CI 1.11 to 1.89, P=0.008), the researchers reported online in Cancer.
Amiodarone has been associated with a number of potentially serious adverse events, including thyroid dysfunction, pulmonary fibrosis, and skin and thyroid malignancies, and a meta-analysis suggested a possible cancer link.
To examine the potential for an association with cancer, Liu and colleagues analyzed data from the Taiwanese National Health Insurance Research Database, identifying 6,418 patients who received amiodarone between 1997 and 2008.
More than half were men, the median age was 70, and median follow-up was 2.57 years.
Comorbidities were common, including hypertension (76%), heart failure (47%), chronic obstructive pulmonary disease (44%), and diabetes (39%).
During observation of almost 22,000 person-years, 280 cancers were identified.
Patients who had received amiodarone had a borderline increased risk of about 10% for all cancers (SIR 1.12, 95% CI 0.99 to 1.26, P=0.067), with a lag time of about 2 years.
Women did not appear to be at increased risk (SIR 99, 95% CI 0.79 to 1.23).
A possible explanation for the gender difference was that women clear the drug more quickly than men. Amiodarone has a half-life of almost 2 months and can accumulate in tissues, the researchers explained.
Among men, an elevated risk was seen for those ages 20 to 60 (SIR 1.67, 95% CI 1.07 to 2.48, P=0.025) and those over 80 (SIR 1.41, 95% CI 1.07 to 1.83, P=0.016).
Multivariate analysis identified these factors as being associated with increased risk:
- Age: hazard ratio 1.04 (95% CI 1.03 to 1.06, P<0.001)
- Male: HR 1.90 (95% CI 1.38 to 2.62, P<0.001)
- Cirrhosis: HR 3.70 (95% CI 2.10 to 6.52, P<0.001)
- Socioeconomic status: HR 0.63 (95% CI 0.45 to 0.87, P=0.006)
- Cumulative daily doses: HR 1.001 for each additional dose (95% CI 1 to 1.002, P=0.022)
But they didn't find any differences for specific types of cancer, including lung, thyroid, and skin.
That was a surprising finding, according to E. Kevin Heist, MD, PhD, of Massachusetts General Hospital Corrigan Minehan Heart Center in Boston, who was not involved in the study.
"Most carcinogens tend to increase risk of individual cancers," Heist told MedPage Today.
"Even things like radiation that affect all cells of the body tend to increase individual cancer risks. So it does make one wonder why this is different than other known carcinogens, and whether in fact this is a real finding," Heist said.
The researchers also pointed out that the numbers of individual cancers were small and the follow-up of 2.57 years may not have been long enough to detect actual differences.
Other limitations of the study included its cohort design, the unavailability of information on potential risk factors such as smoking, family history, and exposure to environmental toxins.
"Although extensive screenings for occult cancers in patients currently undergoing treatment with amiodarone appears to be impractical, we suggest that cancer events should be routinely reported in future amiodarone trials," the researchers concluded.
For the time being, patients who need amiodarone should still receive it, but clinicians should exercise caution, Heist advised.
"I think the big messages are keep using it when you need to use it, but make sure you need it and make sure a safer alternative antiarrhythmic drug is not an option or has not been tried," he said.
Source Medpage Today via Cancer - Cancer
Su V, et al. "Amiodarone and the risk of cancer: a nationwide population-based study" Cancer 2013; DOI: 10.1002/cncr.27881.
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Too many drug types are compromising heart health: doctors
About 80 million Americans suffer from heart disease, the nation's No. 1 killer, and most are on multiple drugs.
Some cardiologists think prescribing has gotten out of hand.
The criticism was voiced by a number of leading heart doctors who attended the annual scientific sessions of the American College of Cardiology, held on March 9-11 in San Francisco. They said eliminating certain drugs could potentially improve care without compromising treatment. Evidence is growing that some medications are not effective.
Patients who need multiple daily doses of a given drug often fail to take them, said Dr. Steven Nissen, head of cardiology at the Cleveland Clinic and a past president of the ACC. "There is also the question about whether the benefits are additive."
Among the medications cardiologists are giving a second look: AbbVie's Niaspan, or prescription niacin, which aims to raise good cholesterol; so-called fenofibrate such as top-selling branded drug TriCor (also from AbbVie), which lowers blood fats called triglycerides; and beta-blockers, most of which are inexpensive, older generics.
'EAGER TO ADD, RELUCTANT TO TAKE AWAY'
A person who has had a heart attack typically leaves the hospital on a beta-blocker to slow the heart, an ACE inhibitor to reduce blood pressure, clopidogrel and aspirin to thin the blood and prevent clots, and a statin to reduce cholesterol, said Dr. Micah Eimer, a cardiologist with Northwestern Medicine in suburban Chicago.
"That's a minimum of five medications, and each one has a proven mortality benefit. It's practically malpractice if you don't prescribe those," Eimer said. "But we have no data on when it's advantageous to take (patients) off."
Many patients are on many more drugs, according to research by Dr. Harlan Krumholz, a Yale University professor of cardiology and public health. Using Medicare data, he found that heart failure patients, those whose hearts are too weak to pump blood sufficiently, were prescribed an average of 12 drugs; some were on 30.
"We are eager to add medicines and reluctant to take them away," said Krumholz, who heads the Yale-New Haven Hospital Center for Outcomes Research and Evaluation and is a frequent critic of how drugs are sold and used. "So people accrue medications over time."
Many drugs are prescribed widely, even though evidence they actually work is weak, he said.
Unexpected serious side effects arose in a huge study of a Merck & Co long-acting niacin drug aimed at raising good HDL cholesterol, according to data released at the conference on Saturday. [ID:nL1N0C11ZL] The study enrolled more than 25,000 people. Patients had significantly more bleeding and a higher number of infections than researchers had expected. A Merck spokesman said there "was nothing to add."
When it was announced that the drug, Tredaptive, had failed to prevent heart attacks, strokes and death in heart patients also taking drugs to lower bad LDL cholesterol, Merck said it would not seek U.S. approval and would stop selling it in the dozens of other countries where it was already available.
Fenofibrate, including AbbVie's TriCor, has also failed to show benefit in two separate studies, Krumholz said. The $2 billion-a-year drug is used to lower low-density lipoprotein, or LDL, the unhealthy cholesterol, and triglycerides and to raise high-density lipoprotein, or HDL, the healthy cholesterol.
AbbVie's cardiovascular products "help patients with abnormal cholesterol levels reach their cholesterol treatment goals," the company said in an emailed statement. "Physicians need to consider the results of clinical trials, available treatment guidelines, and each patient's cardiovascular and benefit/risk profile to determine the best possible treatment regimen."
Other drug companies including Sanofi, Bristol-Myers Squibb Co and Pfizer declined to comment.
BLOCK THAT BLOCKER?
Beta-blockers are absolutely necessary for some patients, said Dr. Sripal Bangalore, a cardiologist at New York University, but are probably prescribed too widely and for too long a period of time. Examining three distinct patient groups from a data registry of 44,000 patients, he said the drug did not reduce the risk of heart attack, stroke or death after 3.5 years.
Yet the American Heart Association (AHA) and American College of Cardiology guidelines recommend heart attack survivors take beta-blockers for at least three years. Those recommendations, several doctors noted, are based on data collected two decades ago. "We don't know if they are providing benefit for one year or three years," Bangalore said.
Today, blocked arteries are cleared right away with angioplasty, and the patient is typically put on a statin to keep harmful cholesterol from building up in the artery walls. For those whose hearts are not badly damaged, beta-blockers do not help.
Then there are blood thinners, like Warfarin, commonly used to treat some types of heart disease by preventing clots. Dr. Robert Harrington, a cardiologist at the Stanford School of Medicine, said patients were at risk of bleeding when they were on more than one. "We've had recent trials where we've gone from one to two to three agents," he said. "There's got to be a way to start peeling away, and maybe it's over a period of time, or as the clinical status changes."
MARKET SIDE EFFECTS
Clinical trials that have called into question the drugs' benefits have affected sales. Combined sales of AbbVie's TriCor and Trilipix were $1.4 billion in 2012, down from $1.7 billion in 2011. Sales of Niaspan were $911 million in 2012, down from $976 million in 2011.
Cowen and Co estimates the 13 main classes of drugs used to treat various types of cardiovascular disease had U.S. sales of almost $75 billion in 2011. The brokerage expects sales to shrink to about $59 billion in 2016 because of recent and looming patent expirations on branded products.
Even if doctors aggressively cut back the number of heart medicines they prescribe, however, it would have only a limited impact on drugmaker revenue because many would be the generic older drugs that are far cheaper, according to analyst Barbara Ryan, of Barbara Ryan Advisors.
Dr. Richard Stein, a professor of medicine at New York University and spokesperson for the AHA, estimated the average patient with heart disease truly needs to take from seven to nine pills each day in order to control the various risk factors, including cholesterol, high blood pressure and diabetes. Beyond that, he said, it makes sense to be restrictive.
"Doctors should look for combination pills if they can, and exclude pills that don't critically help patient care," he said. "To live your life taking that many pills, the danger is you'll stop taking the critical ones, because how many pills can you take several times a day?"
Source : Reuters
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FDA Warns of Liver Injury Risk with Tolvaptan/Samsca
Samsca is used to treat hyponatremia (low levels of sodium in your blood) in people with heart failure, liver disease, and certain hormonal imbalances. Samsca improves urine flow without causing the body to lose too much sodium as you urinate. Tolvaptan is also in fast-track clinical trials for polycystic kidney disease
Three cases of serious but reversible increases in hepatic enzymes in a clinical trial involving tolvaptan (Samsca) have prompted the FDA to warn of potential liver injury with the drug.
Tolvaptan's manufacturer, Otsuka America Pharmaceutical, has also sent a "Dear Healthcare Provider" letter to physicians with the warning.
According to the letter, dated Jan. 22, three patients out of some 1,400 participating in a clinical trial of tolvaptan, a selective vasopressin V2-receptor antagonist, in autosomal dominant polycystic kidney disease (ADPKD) developed increases in serum alanine aminotransferase (ALT) three times above the upper limit of normal, as well as elevated serum total bilirubin above twice the upper limit of normal.
"An external panel of liver experts assessed these three cases as being either probably or highly likely to be caused by tolvaptan. These findings indicate that Samsca (tolvaptan) has the potential to cause irreversible and potentially fatal liver injury," Otsuka said in the letter.
The company indicated that all three patients improved after the drug was stopped.
Also of concern, according to Otsuka, was that the incidence of seriously elevated ALT was significantly greater with tolvaptan versus placebo in the trial. ALT increases three times above the upper limit of normal were detected in 42 of 958 patients receiving the drug, compared with five of 484 patients in the placebo group.
In these patients, "the elevations gradually improved after discontinuation of tolvaptan," Otsuka said.
Although tolvaptan is not approved for ADPKD -- its current approved indication is for treating clinically significant hypervolemic or euvolomic hyponatremia -- Otsuka and the FDA determined that the risk of liver injury seen in the trial could carry over to other patients.
Otsuka pointed out that liver enzyme elevations had not been noted in clinical trials with tolvaptan for the hyponatremia indication.
But, the company said, "these data are not adequate to exclude the possibility that patients receiving Samsca for its indicated use of clinically significant hypervolemic and euvolemic hyponatremia are at a potentially increased risk for irreversible and possibly fatal liver injury."
Patients with underlying liver disease that may cause or contribute to hyponatremia may be less able to recover from drug-induced liver injury, Otsuka said.
"Limiting the duration of Samsca therapy may reduce the risk of developing liver injury," the company suggested.
It also recommended that healthcare providers order liver tests in patients with symptoms consistent with hepatic injury. These include fatigue, anorexia, discomfort in the upper right abdomen, dark urine, or jaundice.
"If hepatic injury is suspected, Samsca should be promptly discontinued, appropriate treatment should be instituted, and investigations should be performed to determine probable cause," Otsuka said.
"Samsca should not be re-initiated in patients unless the cause for the observed liver injury is definitively established to be unrelated to treatment with Samsca."
Source : MedPage Today
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FDA Drug Safety Communication: Review update of Multaq (dronedarone) and increased risk of death and serious cardiovascular adverse events
The U.S. Food and Drug Administration (FDA) has completed a safety review of the heart drug Multaq (dronedarone). This review showed that Multaq increased the risk of serious cardiovascular events, including death, when used by patients in permanent atrial fibrillation (AF). The review was based on data from two clinical trials, the PALLAS trial (Permanent Atrial FibriLLAtion Outcome Study Using Dronedarone on Top of Standard Therapy) and the ATHENA trial (which supported Multaq's approval for treatment of non-permanent AF).1,2 FDA is providing new information and recommendations for the use of Multaq to manage the potential serious cardiovascular risks with the drug. The Multaq drug label has been revised with the following changes and recommendations [see the revised Multaq label for all changes]:
- Healthcare professionals should not prescribe Multaq to patients with AF who cannot or will not be converted into normal sinus rhythm (permanent AF), because Multaq doubles the rate of cardiovascular death, stroke, and heart failure in such patients.
- Healthcare professionals should monitor heart (cardiac) rhythm by electrocardiogram (ECG) at least once every 3 months. If the patient is in AF, Multaq should be stopped or, if clinically indicated, the patient should be cardioverted.
- Multaq is indicated to reduce hospitalization for AF in patients in sinus rhythm with a history of non-permanent AF (known as paroxysmal or persistent AF)
- Patients prescribed Multaq should receive appropriate antithrombotic therapy.
FDA is reviewing the risk evaluation and mitigation strategy (REMS) for Multaq to determine the changes necessary to ensure that the benefits of Multaq outweigh the risks of cardiovascular death, stroke, and heart failure.
Source : FDA
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FDA Drug Safety Communication: Multaq (dronedarone) and increased risk of death and serious cardiovascular adverse events
Multaq is used to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors, who are in sinus rhythm or who will be cardioverted [Refer to Multaq label]
From approval in July 2009 through June 2011, approximately 1 million Multaq prescriptions were dispensed and approximately 241,000 patients received Multaq prescriptions from U.S. outpatient retail pharmacies.2
[07-21-2011] The U.S. Food and Drug Administration (FDA) is reviewing data from a clinical trial that was evaluating the effects of the antiarrhythmic drug Multaq (dronedarone) in patients with permanent atrial fibrillation. The study was stopped early after the data monitoring committee found a two-fold increase in death, as well as two-fold increases in stroke and hospitalization for heart failure in patients receiving Multaq compared to patients taking a placebo. Currently Multaq is approved for use in a different, but related patient population (see Facts about Multaq box). The approval of Multaq was based on another trial (ATHENA) in which use of Multaq was associated with a decreased number of deaths compared to placebo.1
The Permanent Atrial fibriLLAtion Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS) study, sponsored by Sanofi Aventis (the maker of Multaq), was being conducted to assess the potential clinical benefit of Multaq in patients over 65 years of age with permanent atrial fibrillation in the reduction of:
- Major cardiovascular (CV) events (stroke, systemic arterial embolism, myocardial infarction or cardiovascular death), or
- Unplanned cardiovascular hospitalization or death from any cause
At this time, patients taking Multaq should talk to their healthcare professional about whether they should continue to take Multaq for non-permanent atrial fibrillation. Patients should not stop taking Multaq without talking to a healthcare professional. Healthcare professionals should not prescribe Multaq to patients with permanent atrial fibrillation.
FDA previously issued a Drug Safety Communication (DSC) in January 2011 regarding cases of rare but severe liver injury that have been reported with the use of Multaq.
Today's communication is in keeping with FDA's commitment to inform the public about its ongoing safety review of drugs. FDA will update the public when more information is available.
Additional Information for Patients
- Talk to your healthcare professional about whether you should continue to take Multaq for paroxysmal or persistent atrial fibrillation. Do not stop taking Multaq without talking to your healthcare professional.
- Discuss any questions or concerns about Multaq with your healthcare professional.
- Report any side effects you experience to the FDA MedWatch program using the information in the "Contact Us" box at the bottom of the page.
- Do not prescribe Multaq to patients with permanent atrial fibrillation.
- FDA is evaluating whether and how the preliminary results of the PALLAS study apply to patients taking Multaq for paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL).
- The PALLAS study results are considered preliminary at this time because the data have not undergone quality assurance procedures and have not been completely adjudicated.
- Report adverse events involving dronedarone to the FDA MedWatch program, using the information in the "Contact Us" box at the bottom of the page.
Sanofi Aventis conducted "A randomized, double blind, placebo controlled, parallel group trial for assessing the clinical benefit of dronedarone 400 mg BID on top of standard therapy in patients with permanent atrial fibrillation and additional risk factors" (PALLAS). This study was a large outcome trial intended to evaluate the effectiveness of dronedarone in patients with permanent atrial fibrillation.
The patients eligible to enroll in PALLAS were 65 years or older, in permanent atrial fibrillation (defined by the presence of atrial fibrillation/atrial flutter for at least 6 months prior to randomization without plans to restore sinus rhythm), and had at least one additional cardiovascular (CV) risk criterion.
In July 2011, the data monitoring committee reviewed the preliminary data and concluded that there was a significant excess of CV events in the Multaq group for both co-primary endpoints (CV death/myocardial infarction/stroke/systemic embolism; death/unplanned CV hospitalization) as well as other CV events (see Table 1 below). As a result, the PALLAS study was stopped.
FDA has received and is currently reviewing preliminary results from the PALLAS study and will review the final results when they become available. Because the review is ongoing, FDA has not concluded whether the results of the PALLAS study are applicable to patients taking Multaq for paroxysmal or persistent atrial fibrillation or atrial flutter. However, healthcare professionals should not prescribe Multaq to patients with permanent atrial fibrillation. FDA will update the public when further information is available.
- Hohnloser SH, Crijns HJ, van Eickels M, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 2009 Feb 12;360(7):668-78.
- Source: SDI, Vector One®: National (VONA) and Total Patient Tracker (TPT). July 2009 – June 2011. Extracted 7-18-2011.
Source : FDA (July 2011)
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FDA Drug Safety Communication: Severe liver injury associated with the use of dronedarone (marketed as Multaq)
The U.S. Food and Drug Administration (FDA) is alerting healthcare professionals and patients about cases of rare, but severe liver injury, including two cases of acute liver failure leading to liver transplant in patients treated with the heart medication dronedarone (Multaq).Dronedarone is a drug used to treat abnormal heart rhythm in patients who have had an abnormal heart rhythm (atrial fibrillation or atrial flutter) during the past 6 months. Dronedarone can reduce the risk of being hospitalized for these heart problems. Since dronedarone's approval in July 2009 through October 2010, around 492,000 dronedarone prescriptions were dispensed and around 147,000 patients filled dronedarone prescriptions at outpatient retail pharmacies in the United States.1 Additional usage can occur in the hospital setting.
Dronedarone was approved with a Risk Evaluation and Mitigation Strategy (REMS) with a goal of preventing its use in patients with severe heart failure or who have recently been in the hospital for heart failure. In a study of patients with these conditions, patients given dronedarone had a greater than two-fold increase in risk of death.
Information about the potential risk of liver injury from dronedarone is being added to the WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS sections of the dronedarone labels.
Today's communication is in keeping with FDA's commitment to inform the public about its ongoing safety review of drugs. FDA is continuing to review reports of possible adverse events and drug interactions with dronaderone submitted to our Adverse Event Reporting System.
Additional Information for Patients
- Contact your healthcare professional if you develop itching, yellow eyes or skin, dark urine, loss of appetite, or light-colored stools. These may be signs of liver injury.
- Talk to your healthcare professional about any concerns you have with this medication.
- Do not stop taking dronedarone unless told to do so by your healthcare professional.
- Report any side effects you experience to the FDA MedWatch program using the information in the "Contact Us" box at the bottom of the page.
- Read the Medication Guide when picking up a prescription for dronedarone. It will help you understand the potential risks and benefits of this medication.
Additional Information for HCPs
- Advise patients to contact a healthcare professional immediately if they experience signs and symptoms of hepatic injury or toxicity (anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant pain, jaundice, dark urine, or itching) while taking dronedarone.
- Consider obtaining periodic hepatic serum enzymes, especially during the first 6 months of treatment. However, it is not known whether routine periodic monitoring of serum liver enzymes (ALT, AST, and alkaline phosphatase) and bilirubin in patients taking dronedarone will prevent the development of severe liver injury.
- If hepatic injury is suspected, dronedarone should be promptly discontinued and testing of serum liver enzymes and bilirubin should be performed. If hepatic injury is found, appropriate treatment should be initiated.
- Dronedarone should not be restarted in patients who experience hepatic injury without another explanation for the observed liver injury.
- Report adverse events involving dronedarone to the FDA MedWatch program, using the information in the "Contact Us" box at the bottom of the page.
FDA has received several case reports of hepatocellular liver injury and hepatic failure in patients treated with dronedarone, including two post-marketing reports of acute hepatic failure requiring transplantation. Because these reactions are reported voluntarily from a treatment population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The two cases of acute hepatic failure requiring transplantation occurred at 4.5 and 6 months after initiation of dronedarone in patients with previously normal hepatic serum enzymes. Both patients were female and approximately 70 years of age. In the first case, the patient had underlying intermittent atrial fibrillation, arterial hypertension and stable coronary artery disease. She was treated with dronedarone for 4.5 months. Two weeks prior to hospitalization she reported increased exhaustion and tiredness. One week prior to admission she discontinued dronedarone, and at the time of admission she was noted to have jaundice, coagulopathy, transaminitis and hyperbilirubinemia, which progressed to hepatic encephalopathy over the next nine days. A pre-transplant workup did not reveal another etiology of liver failure. In the second case, the patient had a medical history of paroxysmal atrial fibrillation and Sjogren's syndrome. Following 6 months of treatment with dronedarone she developed weakness, abdominal pain, coagulopathy, transaminitis and hyperbilirubinemia. She was transplanted 1 month later; no alternative etiology for liver failure was identified in the transplant work-up. In both cases, the explanted liver showed evidence of extensive hepatocellular necrosis.
Multaq (dronedarone) is approved to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent history of AF/AFL and associated cardiovascular risk factors (age >70, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter ≥ 50 mm or left ventricular ejection fraction <40%) who are in sinus rhythm or who will be cardioverted.
Dronedarone is contraindicated in patients with NYHA Class IV heart failure or NYHA Class II - III heart failure with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic. In a placebo-controlled study in patients with severe heart failure requiring recent hospitalization or referral to a specialized heart failure clinic for worsening symptoms (the ANDROMEDA Study), patients given dronedarone had a greater than two-fold increase in mortality. Such patients should not be given dronedarone.
Source : FDA
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