This week, Friday Feedback takes a look at The BMJ's investigation into alleged suppression of information supporting routine drug level monitoring and dose adjustment for the oral anticoagulant dabigatran (Pradaxa).
Internal documents obtained through freedom of information requests and litigation showed that drugmaker Boehringer Ingelheim determined that keeping plasma levels within the optimal 40-to-200 ng/mL range could cut bleeding risk by up to 20% compared with unadjusted use and by 40% compared with well-controlled warfarin (Coumadin) without sacrificing effectiveness in cutting risk of ischemic stroke in atrial fibrillation.
But the company didn't share those analyses with regulators or physicians in an apparent bid to boost dabigatran's commercial success by marketing a simpler treatment strategy.
Boehringer Ingelheim maintains that the unadjusted strategy still has clinical benefit as demonstrated by the RE-LY trial and that it released the full dataset to regulators.
Shocked
We reached out to a diverse group of healthcare professionals and experts and found equally diverse opinions on the BMJ conclusions.
'The promise of Pradaxa, and other newer drugs of the same class, was that positive results could be achieved without the variability seen with warfarin, and with no need for routine monitoring. If, in fact, this is not the case, as the investigation suggests, then one of the primary reasons to use this drug would be void. Further, since it would appear that the efficacy is closely comparable, adding the need for monitoring to a branded, that is expensive, drug in favor of the more commonly used generic warfarin would seem to be another impediment to its use.' -- Marc I. Leavey, MD, primary care physician, Mercy Medical, Baltimore
Not Surprised
'I am very surprised the FDA approved the drug despite having reservations from the initial evaluation. All the data came from a single study, the RE-LY trial. My main concern is safety of the patients.' -- Miguel Escobar, MD, hematologist, University of Texas Medical School at Houston
'Not surprising at all. A lot of evidence has slowly been leaked about the harms of this drug that were known and hidden. I think a lot of doctors are going to feel very bad that they ever started these meds. We in the ED have always been very opposed (in general). Easier if you don't have to monitor but no reversal agent. We've seen a number of bad head bleeds on dabigitran.' -- Anand Swaminathan MD, MPH, emergency medicine physician, Bellevue/NYU Langone Medical Center, New York City
'Not surprised. The trauma surgery and emergency medicine community has been skeptical for some time of a medication that could be a 'better blood thinner' for stroke but without causing a 'thinning of your blood' that makes you bleed more. Some investigators have suspected issues with missing/under-reported adverse events. Others suggested significant heterogeneity among people taking the medications .... As a clinician on the receiving end of the drugs complications, I will dislike it even more and continue to advocate for its FDA approval to be reconsidered. I don't prescribe this for my patients for afib or for VTE.' Bryan Cotton, MD, MPH, acute care surgeon, University of Texas Health Science Center, Houston
'The medical community has already been aware that certain patient profiles such as elderly patients and those with mildly reduced kidney function may be at higher risk of bleeding with dabigatran and that the 'one size fits all' approach may not be appropriate. I am not surprised that heterogeneity exists based on differences in metabolism between patients. What concerns me is that the company may not have passed this information regarding drug monitoring over to the medical community to allow the opportunity for further independent research to occur.' -- Michael Field, MD, director of clinical electrophysiology and cardiac arrhythmia service, University of Wisconsin Hospital and Clinics, Madison, Wis.
Not Concerned
'I am troubled by the findings. ... If it is identified that valuable -- if not critical -- information was withheld from practicing physicians, this will certainly undermine the confidence in the FDA and the drug manufacturer. Hopefully this will not be the case.' -- Howard Weintraub, MD, clinical director, NYU Langone Center for the Prevention of Cardiovascular Disease, New York City
'I have no changes to my comments [to MedPage Today in November 2012] based on the material.' -- Elliott Antman, MD, cardiologist, Brigham and Women's Hospital, Boston, past American Heart Association president
A Change for Clinic?
'While the charges are interesting, the BMJ piece is necessarily incomplete and biased. The FDA did a full analysis with ALL of the data available, not just the bits of data leaked by the BMJ, and established that the drug was safe and effective. This piece of journalism is not science, nor medicine. It raises regulatory questions, not scientific questions, and has no clinical relevance whatsoever. All NOACs offer a significant benefit and improvement over warfarin, save lives, and should be used.' -- Patrick D. Lyden, MD, chair of neurology, Cedars-Sinai Medical Center, Los Angeles
'Many physicians were unaware of the drug monitoring levels in dabigitran. The fact that there are ways of monitoring and adjustment of the medication are a positive indicator to support its use.' -- Albert Favate, MD, division chief of vascular neurology, NYU Langone Comprehensive Stroke Center, New York City
'Checking the blood level of a drug such as dabigatran, which should not be necessary repeatedly, would seem to be a small price to pay to enhance the safety of the drug.' -- Anne Curtis, MD, electrophysiologist, University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, N.Y.
'I am not sure that this will influence my practice habits in the short term. Actually, I was a late adopter of these medications. I waited for the 'smoke to clear' before using it readily in patients. I select the patients carefully and have actually been very satisfied and successful in using this class of drugs.' -- Weintraub
Want Further Action
'Based on the investigation, I believe it is justified to have drug level monitored. A 30% to 40% reduction in bleeding is a big deal. If proven true, we should not prescribe the medicine until monitoring is available. There are several similar medications available now, and we certainly have options. Having said that, it is conceivable that other new anticoagulation medications also need monitoring.' -- David Zhao, MD, section chief of cardiology, Wake Forest Baptist Medical Center, Winston-Salem, N.C.
'The article and editorial suggest monitoring drug levels and changing the dose could further lower bleeding risk, but this article did not reveal the data either, so I am still unable to judge the importance. ... So the first step would be to make available the data that the BMJ writers say was withheld. The next step would be to study whether or not measuring drug levels and adjusting medication dose improves outcomes.' -- James Froehlich, MD, MPH, cardiologist and medical director of the University of Michigan Anticoagulation Service, Ann Arbor
'We need to know the detailed analysis in full and transparent fashion so we can make intelligent decisions on behalf of our patients.' -- Zhao
'The FDA should review the use of the lower dose [110 mg] as it may prove effective, and ... ordering blood levels should be an option for the physician as a means to adjust the dabigitran dose.' -- Favate
Entities 0 Name: FDA Count: 5 1 Name: BMJ Count: 5 2 Name: New York City Count: 3 3 Name: Pradaxa Count: 2 4 Name: Houston Count: 2 5 Name: Boehringer Ingelheim Count: 2 6 Name: Marc I. Leavey Count: 1 7 Name: Change for Clinic Count: 1 8 Name: Patrick D. Lyden Count: 1 9 Name: Buffalo School of Medicine and Biomedical Sciences Count: 1 10 Name: Wis. Count: 1 11 Name: NYU Langone Center for the Prevention of Cardiovascular Disease Count: 1 12 Name: Michael Field Count: 1 13 Name: Howard Weintraub Count: 1 14 Name: Anand Swaminathan Count: 1 15 Name: Brigham and Women 's Hospital Count: 1 16 Name: Anne Curtis Count: 1 17 Name: Bryan Cotton Count: 1 18 Name: Albert Favate Count: 1 19 Name: Miguel Escobar Count: 1 20 Name: Ann Arbor Count: 1 21 Name: Los Angeles Count: 1 22 Name: University of Michigan Anticoagulation Service Count: 1 23 Name: Weintraub Count: 1 24 Name: Cedars-Sinai Medical Center Count: 1 25 Name: VTE Count: 1 26 Name: American Heart Association Count: 1 27 Name: NYU Langone Comprehensive Stroke Center Count: 1 28 Name: N.C. Count: 1 29 Name: ED Count: 1 30 Name: Langone Medical Center Count: 1 31 Name: David Zhao Count: 1 32 Name: Elliott Antman Count: 1 33 Name: Zhao Count: 1 34 Name: University of Wisconsin Hospital Count: 1 35 Name: University of Texas Health Science Center Count: 1 36 Name: James Froehlich Count: 1 37 Name: Buffalo Count: 1 38 Name: Baltimore Count: 1 39 Name: Winston-Salem Count: 1 40 Name: Madison Count: 1 41 Name: Boston Count: 1 42 Name: MPH Count: 1 43 Name: Wake Forest Baptist Medical Center Count: 1 44 Name: University of Texas Medical School Count: 1 45 Name: N.Y. Count: 1 Related 0 Url: http://ift.tt/Um5R3H Title: Big Data Peeps At Your Medical Records To Find Drug Problems Description: Katherine Streeter for NPR No one likes it when a new drug in people's medicine cabinets turns out to have problems - just remember the Vioxx debacle a decade ago, when the painkiller was removed from the market over concerns that it increased the risk of heart attack and stroke.
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