Talk:Dabigatran

Older comments
the only downside of warfarin is that it has to be taken for one month??!!! (77.102.24.67 (talk) 21:38, 9 August 2008 (UTC))

150 mg bd for stroke - publication awaited. JFW | T@lk  07:56, 1 August 2006 (UTC)


 * 2% got abnormal LFTs, better than with ximelagatran. JFW | T@lk  07:57, 1 August 2006 (UTC)


 * More on the PETRO and PETRO-Ex trials. JFW | T@lk  07:59, 1 August 2006 (UTC)

Animal model: JFW |  T@lk  20:12, 27 March 2007 (UTC)

VTE post knee replacement
- RE-MODEL trial showed non-inferiority to enoxaparin and no difference in liver enzymes. JFW | T@lk  21:32, 2 September 2007 (UTC)


 * Lancet study (RE-NOVATE) shows comparable efficacy to enoxaparin. JFW | T@lk  00:25, 16 September 2007 (UTC)

I edited the IUPAC Name to simplify it...--ChemSpiderMan (talk) 19:21, 16 December 2007 (UTC)

When you edited the IUPAC Name, did you notice, that it contaíns a (2-pyridinyl)-group and in the picture above it´s a 3-pyridinyl? I suppose the picture is wrong. Besides, it shows the pro-drug Dabigatran-etexilat and not Dabigatran itself. —Preceding unsigned comment added by 88.116.119.194 (talk) 14:40, 16 May 2008 (UTC)

Bags of trials
http://www.pradaxa.com/HCP/Home/clinical_trials/index.htm (for non-US based healthcare professionals only, apparently). JFW | T@lk  20:31, 12 May 2008 (UTC)

The British Heart Foundation.
At present the article states: "Charities, including the British Heart Foundation are campaigning for the drug to be widely prescribed in place of Warfarin..." The BHF in an email to me say: "Currently we have no active campaign for this medication to be distributed and await evidence for its further use." So what is the source for what the article says? robert2957 (talk) 18:26, 7 April 2009 (UTC)

RE-COVER
Free full text. Fvasconcellos (t·c) 15:29, 6 December 2009 (UTC)

change links to refs?
I added two paragraphs today (drug added to US guidelines, and 30 day expiry). But I don't quite remember how to include refs, so I made them as links instead. Maybe somebody can change them to refs. Kenmcl2 (talk) 17:03, 16 February 2011 (UTC)

Clinical trials bias
Both studies were sponsored by the drug developer; I don't believe this section makes that clear. Secondly, the use of the term "non-inferior" sounds like a weasel word trying to give the impression that dabigatran is significantly better than warfarin in areas where the trial shows no significant difference. <-- read the trial again, higher dabi dose superior in terms of efficacy, no difference in major bleeding. That's superior to most healthcare professionals

The section on RE-LY also leaves out the very relevant result (for an expensive drug marketed as a warfarin alternative) that rates of death by myocardial infarction were significantly higher in both of the dabigatran groups compared to the warfarin group which was then not significantly different, albeit after a post-hoc incorporation of events that were adjudicated after database closure (Connolly et al NEJM 2010. Tomorrow I'm going to revise this section to include this data and more neutral wording ("not significantly different" instead of "non-inferior"). Dallas (talk) 13:05, 2 April 2011 (UTC)

I agree that we should mention that the trials were sponsored by the drug company.

I don't think that we should change the term "non-inferior". "Non-inferior" is not a weasel word in this context, but a design of a type of clinical trial. See http://www.ncbi.nlm.nih.gov/pmc/articles/PMC59590/ Please do not change this wording, as it is  descriptive of the type of trial.

Regarding the MI statistics and death from cardiovascular causes, I don't agree with your assessment. Table 2 on pg 1144 from the RE-LY study in NEJM shows increased MIs in the Dabigatran 150 vs warfarin, but not the dabigatran 110 vs warfarin. This table also states that the relative risk of  DEATH from cardiovascular causes was slightly LOWER in the dabigatran 150 group vs warfarin, and not statistically different in the dabigatran 110 group vs warfarin.

Anyway, I think the more relevant statistic is the all-cause mortality was not different between the warfarin and either of the two doses of dabigatran.

Wawot1 (talk) 02:22, 3 April 2011 (UTC)

Incorrect. Please refrain from using incorrect interpretations and terminology when discussing trial data. RE-LY found that there was NOT a significant difference in terms of MI rates between the groups. If you read closely you will discover this yourself. Do not assume a standard p-value here. It is spelled out in the trial. MI rates were found to be higher in both dabigatran groups, however they were NOT significantly higher. This is even pointed out in a later sub-group analysis. ALSO the term "non-inferior" is not another way of saying "not significantly different". These are not interchangeable and SHOULD NOT BE USED THAT WAY. Non-inferiority trials should be displayed as such... and therefore you should continue to use terminology that conveys this. Here is the title of the subgroup analysis that spells out more clearly the fact that the increase in MI rates was not statistically significant. "Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: a subgroup analysis of the RE-LY trial" Outcomer (talk) 03:58, 3 April 2011 (UTC)

This is a very inadequate page in that it does not list contraindications, adverse events (other than bleeding) and drug interactions. (you coiuld almost believe it was written entirely by the pharmaceutical company.) I'm currently looking for a good source on these. This report lists drug-drug interactions: www.tga.gov.au/pdf/auspar/auspar-pradaxa.pdf. The drug is also not available through the public health system in Australia, having been turned down. It is available on private prescription.

According to my local sources mild-moderate renal failure and increased ALT are contraindications, and risk:benefit ratio is poor in the 80+ age range.

From an emergency medicine perspective the drug is a serious risk as it cannot be reversed in time to prevent fatal hemorrhage in trauma or other acute bleeding. Current advice is to give prothrombinex and FFP, though neither has been demonstrated to reverse anticoagulation in an acute clinical setting.

123.2.102.243 (talk) 11:24, 16 November 2011 (UTC)Alex

Pharmacovigilance of dabigatran
Three times I changed the following text, to be more neutral. "According to new data compiled by QuarterWatch, in 2011 the FDA received more safety reports about dabigatran than any other drug. Dabigatran was the subject of 3,781 serious adverse events reported to the FDA in 2011. This included 542 patient deaths , 2.367 hemorrhages, 291 acute renal failures and 644 stroke. Warfarin  was the subject of  1,106 serious adverse events, including 72 deaths. These results emphasize that anticoagulant drugs used in a vulnerable older population are resulting in thousands of serious injuries and death, and these must rank among the highest risk of all outpatient drug therapies. Additional steps to achieve safer use of these drugs—especially dabigatran—should be an important priority.[48] According to Dr. Robert Temple, FDA spokesman few doctors notify the agency about incidents from warfarin because its risks are already well known. There were 33 million U.S. prescriptions filled for warfarin for atrial fibrillation and other uses in 2011, and some 2.2 million prescriptions for Pradaxa according to IMS Health.[49]" 48 May 2012 Anticoagulants the Leading Reported Drug Risk in 2011 http://www.ismp.org/QuarterWatch/pdfs/2011Q4.pdf 49 Reuters Insight: Top heart doctors fret over new blood thinners http://www.reuters.com/article/2012/06/14/us-drugs-bloodthinners-idUSBRE85D06G20120614 After 3 changes this was again deleted by JfdWolf

JfdWolf. "I have removed one of your additions, which is the observation from the FDA about the absolute number of adverse events. The source was a lot more balanced (see WP:NPOV), in the sense that it made a point about the fact that warfarin use might have led to a similar number of adverse events but they would not be reported to the FDA because it's been around since the 1960s. I would have no objection to returning the content, but only if it can be presented in a more neutral version" And later on: "With a number of these sources, there is a very real risk of falling foul of the guidance from WP:MEDRS. These are primary sources, often methodologically very weak. I am also concerned about WP:RECENTISM - a lot of safety signals from postmarketing surveillance turn out to be untrue. Do we need to alarm the general public about something that (in the fullness of time) will turn out to be wrong?"

My questions are: 1.could JfdWolf make above text more balanced? 2. could JfdWolf give some methodologically strong secundary sources for dabigatran?; in the absence we have to analyse very critically company based primary sources, on which worldwide authorisation is based, based on analyses of reviewers from FDA and EMA. — Preceding unsigned comment added by Janbaekelandt (talk • contribs) 13:31, 24 August 2012 (UTC)

I don't get an answord from JfdWolf. Know you can find exactly the same text about dabigatran in a systematic review of the annals of internal medecine situated here http://annals.org/article.aspx?articleid=1355171

FDA Reports

QuarterWatch, a public service of the Institute for Safe Medication Practices, monitors adverse events reported to the FDA through MedWatch. Recently, QuarterWatch published its annual report and concluded that 2 anticoagulants—dabigatran and warfarin—ranked first and second among suspect drugs in direct reports to the FDA. Collectively in 2011, there were 3781 domestic reports of adverse events attributed to dabigatran, including 2367 hemorrhages, 291 cases of acute renal failure, 644 strokes, 542 deaths, and 15 suspected cases of liver failure (57). The adverse events occurred more often in elderly patients (median age, 80 years), prompting the FDA to recommend that the manufacturer reevaluate the dose of dabigatran for elderly patients and those with moderate renal impairment (59). Warfarin was associated with 1106 adverse events in 2011, including 72 deaths.

So i ad this? jan baekelandt — Preceding unsigned comment added by Janbaekelandt (talk • contribs) 20:54, 29 August 2012 (UTC)


 * Do me a favour and read WP:MEDRS. Quarterwatch is a primary source, and methodologically very weak. If you can find a systematic review that says the same, then it stands to reason that you would want to reference the systematic review. JFW &#124; T@lk  23:59, 2 September 2012 (UTC)

Clotcare
I don't think the website Clotcare is suitable as a reference. It does not seem to meet the criteria from WP:MEDRS. JFW &#124; T@lk  23:59, 2 September 2012 (UTC)

I agree; I removed itJanbaekelandt (talk) 14:32, 8 September 2012 (UTC)

Several sections of this article violate WP:MOS, specifically:
 * Try to avoid cloning drug formularies such as the BNF and online resources like RxList and Drugs.com. Extract the pertinent information rather than just dumping low-level facts in a big list. For example, a long list of side effects is largely useless without some idea of which are common or serious. It can be illuminating to compare the drug with others in its class, or with older and newer drugs. Do not include dose, titration or pricing information except when they are extensively discussed by secondary sources, or necessary for the discussion in the article. Wikipedia is not an instruction manual or textbook and should not include instructions, advice (legal, medical or otherwise) or "how-to"s

The sections on Dosing, Contraindications and probably Adverse effects violates that paragraph. Wikipedia isn't a package insert or drug monograph. It's not supposed to tell people how to practice medicine. Anything that tells what you "should" do apparently violates that. Even the section on Major trials is close to a data dump.

Don't forget, Wikipedia is written for the average reader, not the specialist. Even for specialists, I read clinical trial reports every day, and I have a hard time reading through this section. It would be easier to read the original literature.

Is it effective? How effective? Is it safe? How safe? How effective and safe is it compared to warfarin? What are the important issues here?

What does it mean to a patient that dabigatran is not inferior to warfarin? Suppose you have a trial with 18,000 patients, 3% major bleeds with warfarin and 3% major bleeds with dabigatran. What's the confidence interval of that 3%? In a larger trial, could it more accurately turn out to be 2.5% with warfarin and 3.5% with dabigatran?

I would start the Major trials section with a discussion of the systematic reviews, including Cochrane.

BTW there's a story about this in the New York Times http://www.nytimes.com/2012/11/03/business/a-rising-anti-stroke-drug-is-tied-to-risk-of-bleeding-deaths.html They do a reasonably good (not perfect) job of explaining the issues. --Nbauman (talk) 17:54, 3 November 2012 (UTC)

Change of name in Canada
Hi everyone. This is just a short insert to explain the recent edit of the Pradaxa intro text. Recently, the name in Canada changed from Pradax to Pradaxa. Here is a link with the official information for reference as well http://www.boehringer-ingelheim.ca/content/dam/internet/opu/ca_EN/documents/humanhealth/Pradaxa_name_Change_HCP_Letter.pdf. --Judith von Gordon (talk) 09:49, 4 February 2013 (UTC)

Hi everyone. We added the name change in Canada again - but explained that the previous name before January 2013 was Pradax. --BIGlobalComms (talk) 11:40, 21 February 2013 (UTC)

Additions by Truebreath
made a number of additions that seem to imply that real-world bleeding in people using dabigatran is higher than in study setting. I am extremely concerned that this might well reflect methodology rather than incontrovertible fact. If I encounter a patient who has suffered a major haemorrhage while taking warfarin, I would not want to report this well-known association to local drug safety monitoring organisations. In contrast, if the same patient had been taking a novel anticoagulant, I believe many practicioners would want to report this. The result would be a marked overrepresentation of novel anticoagulants in safety reports. It would be entirely unbecoming for an encyclopedia to say that "the FDA doesn't seem to be taking it seriously" (or something along those lines) without attributing this to a very strong secondary source.

There are numerous ways to engage with drug safety and regulation, but we can only report work done elsewhere, not stimulate debate by ourselves. JFW &#124; T@lk  10:11, 3 November 2013 (UTC)


 * I only now see your remarks. Ok I remove this part.
 * But did you eliminated me from making additions?
 * Truebreath (talk) 19:03, 6 November 2013 (UTC)


 * In this edit, I have restored changes I had made to the section headings for the following reasons:
 * "Important: you can start but don't stop taking pradaxa" → "Discontinuation". Wikipedia is  not a how to guide.  See also Medical disclaimer and MEDMOS.  The entire article needs to be carefully edited to remove medical advice and to replace with simple statements of fact.
 * "No reversal of action and lack of a reliable blood test in possible overdosis or bleeding" – way too long for a section heading. "Overdose" is much more concise.
 * "Hemorrhage and gastrointestinal hemorrhage" Redundant and wordy. "Hemorrhage" is much more concise and covers both the general topic of Hemorrhage and the more specific topic of gastrointestinal hemorrhage. Boghog (talk) 22:00, 10 November 2013 (UTC)

I agree with your changes Truebreath (talk) 15:10, 11 November 2013 (UTC)

Bleeding
10.1136/emermed-2012-201976 Emerg Med J review about bleeding in people taking dabigatran. Secondary source and open access. JFW &#124; T@lk  08:28, 16 January 2014 (UTC)


 * Is there a problem with BMJ open access? Should i delete this?--Truebreath (talk) 11:00, 8 February 2014 (UTC)


 * No, it is a good source. Open access means our readers can look at the reference without paying $$$. JFW &#124; T@lk  21:35, 8 February 2014 (UTC)

Conflicts of interest
added a section on conflicts of interests in the guideline development process. On the one hand, we know this to be true from some other areas of medicine. On the other hand, this is not supported by high-quality secondary sources and mostly seems to reflect the author's own opinion. If a secondary source can be produced, the content will stand. JFW &#124; T@lk  20:48, 26 January 2014 (UTC)


 * Is a ESC guideline a primary or a high-quality secondary source?--Truebreath (talk) 11:26, 7 February 2014 (UTC).
 * I only resumed what the guideline contributors declared themselves. It is simple counting and dividing. --Truebreath (talk) 11:03, 8 February 2014 (UTC)


 * Potential COI is not the same as actual COI. Many authors advise loads of different companies and probably don't give a hoot which one manages to succesfully market a NOAC before the others. Copying the information from the guideline to the Wikipedia article creates the suggestion that these are actual conflicts of interest. That is, unless a secondary source makes the observation that these are actual COIs that invalidate the conclusions of the guideline. JFW &#124; T@lk  21:35, 8 February 2014 (UTC)

It is important to know that all 8 contributors of the revised ESC guideline 2012 have potential financial conflicts of interest with the anticoagulant and medical device industry, 7 of them with the anticoagulant industry. From 25 reviewers only 4 have no possible financial conflicts. Al this is part of the guideline. I didn't suggest anything else. There was no suggestion of actual COI's. On the contrary later on in the text the word possible was present. The meta-analysis about coi's in medical guidelines treated possible conflicts of interest, not actual conflicts of interest. So i don't understand why the text was removed. And : Is a ESC guideline a primary or a high-quality secondary source? --Truebreath (talk) 14:29, 9 February 2014 (UTC)


 * International clinical guidelines that use evidence-based grading of its recommendations are regarded as WP:MEDRS-compliant secondary sources.
 * There is however a problem with pointing out the conflict of interest. These declarations are present in almost every guideline ever published, and pointing them out to the reader ("look, it's a guideline but they're basically just pushing these drugs for their own gain") is a clear case of WP:WEIGHT. I don't deny that there are problems with COI in guideline development panels, but this article is not the place to deal with that.
 * In general, I think you need to start removing primary sources from the article, because there are loads of secondary sources available on the subject. Your editing is almost exclusively to articles on the new anticoagulants; I am happy to assist in making these articles of excellent and dependable quality. JFW &#124; T@lk  13:46, 10 February 2014 (UTC)

Moved from article
This whole section needs copyediting to be encyclopedic - it's talking to the reader. The intro sentence is also suggestive of WP:SYNTH.

Prevention of ischaemic stroke in avalvular atrial fibrillation
If we try to translate the results from clinical trials into practise, we have to consider necessarily some facts.

On the one hand, thrombotic and haemorrhagic events in the real-world anticoagulated atrial fibrillation population are higher than those reported in clinical trials, probably due to the strict selection of population and close follow up applied in clinical trials.

In particular, patients aged 75 years or older were under represented in clinical trials (range: 31% to 43% of patients) compared with real-world atrial fibrillation cohorts (range: 47% to 64% of patients). This issue may have important implications in bleeding risk, as renal function declines with age and all NOAC undergo renal elimination to a greater or lesser extent. Post marketing reports of serious bleedings have frequently involved patients generally not qualified for the NOAC (i.e., severe renal insufficiency). This finding, accompanied by the current unavailability of specific antidotes, emphasizes the need for their appropriate use according to product labelling in order to minimise bleeding risk.

Finally, there is a need for strategies that could optimize anticoagulation quality and improve clinical outcomes in atrial fibrillation. Beyond the use of NOAC in selected patients, these strategies may include systems facilitating algorithm-based warfarin dosing in the anticoagulation clinics as well as the use of home-monitoring and self-management of anticoagulation with VKA in suitable candidates.

Following studies are prospective cohort studies and can only be hypothesis generating or confirming, because of inherent biases.

Effect in new onset dabigatran against new onset warfarin patients: in a Danish cohort study of new onset dabigatran users against new onset warfarin users stroke, systemic embolism and bleeding risks were equal to warfarin. Adjusted mortality, pulmonary embolism and intracranial bleedings were lower against warfarin. Also the risk of myocardial infarctions and gastro-enteric bleedings with low dose was lower, contradicting the clinical trials. The study was limited by short follow up (10,5 month). Compared to Re-Ly it was a low risk population with mean CHADS score of 1,2, patients were younger (70 year) and had less co morbidities (e.g., heart failure, prior myocardial infarction, diabetes mellitus, hypertension). Overall, 8 deaths were reported 7 of these 8 patients were age >80 years  and 6 of the 8 were female, 7 of the 8 were taking dabigatran 110mg twice  day, one was taking dabigatran 150mg twice a day.

Effect in a global cohort: in the overall Danish atrial fibrillation cohort, unexpectedly it was found that the adjusted risk of thromboembolic events was increased among users of both doses of Dabigatran against warfarin users.

Overtreatment with double and triple therapy: in the real world pan-European PREFER in AF registry only 10% took combined anticoagulant anti-platelets therapy, and only 0,5% needed them, not being given because of recent stenting or acute coronary syndrome event. Only 1,3% of the PREFER cohort received triple combined therapy, of wich only 0,6% had an appropriate indication. So there is massive over treatment of aspirin and anti-aggregants in atrial fibrillation patients On the contrary in the US ORBIT AF registry 35% received combined aspirin and oral anticoagulants. More than one-third of the patients on OAC and aspirin had no history of atherosclerotic disease. Major bleeding and bleeding hospitalizations were significantly higher in those patients on OAC and aspirin versus those on OAC alone. In the new anticoagulant trials initially 30 to 40% took aspirin.

Discontinuation: in real life discontinuation can be quite high. In a US study 40% of patients discontinued dabigatran therapy within 6 months, and the majority of these patients were not anticoagulated with warfarin upon discontinuation. A 2012 Medco Health Solutions report found the actual stroke and bleeding rates found at four months for dabigatran were equivalent to or higher than the stroke and bleeding rates per year for warfarin from the RE-LY trial, partly by early discontinuing dabigatran. They conclude patients need to be monitored closely to prevent bleeds or blood clots.

Switching from warfarin to dabigatran: in real life switching from warfarin to dabigatran can be risky the first 4 months: thromboembolic risk associated with dabigatran was 250% to 470% higher for low and high dose dabigatran than with warfarin in a Danish nationwide study. This was unexpected and could reflect patient selection and ‘drug switching’ practices. No such risk was reported in the Re-Ly trial, in which 50% of patients switched from long-term warfarin treatment to dabigatran. There was also an increased risk of bleeding when switching from warfarin to a 110 mg dose of dabigatran. Warfarin naïve patients had no increased risks. In the overall cohort, unexpectedly it was found that the adjusted risk of thromboembolic events was increased among users of both doses of Dabigatran. In the first two months after switching there was also a 200% increased risk of myocardial infarction compared with continued warfarin usage.

Dosing errors: in the ORBIT-AF cohort more than half of patients with severe kidney disease were not prescribed reduced dosing of dabigatran, whereas 10% with preserved renal function received lower dosing.

Drug interactions: a survey among 100 hospitalized AF patients showed that 42% of hospitalized AF patients and 48% of VKA-receiving patients take P-gp-affecting drugs. The fatality rate of haemorrhages after a first major bleeding event in 5 phase 3 trials of dabigatran was favourable for dabigatran: 9% against 13% for warfarin. In contrast the case fatality rate of bleeding events from dabigatran reported to the FDA was inverse: 16% against 8% for warfarin. The author works out that if fewer than 1 in 3 adverse bleeding events were reported to the FDA, this fatality rate may signal an increased risk for bleeding death compared with that seen in RE-LY. Anyway the FDA reporting system suffers from reporting bias and accuracy and duplication problems, so that any definitive conclusions can be drawn. The study suggests the drug is being used in a different profile of patients as that in the RE-LY trial: the mean age of patients who had an adverse event with dabigatran reported to the FDA (75 years) was greater than that in the RE-LY trial (71 years), and more patients with FDA-reported events were female (48%) than those included in RELY (36.7%).

Prevention of venous thromboembolism perioperative
Following studies are prospective cohort studies and can only be hypothesis generating or confirming.

In real life the use of dabigatran can led to a significant increase in post-operative wound leakage (20% with dabigatran, 5% with a multimodal regimen; p < 0.001), which also resulted in an increased duration of hospital stay. There were similar results in an earlier study. On the contrary, in the randomized RE-NOVATE II trial, patients after hip arthroplasty no difference in postoperative insertion of drains or total wound drainage was observed between patients who received dabigatran versus enoxaparin, but more wound secretion. Doc James (talk · contribs · email) (if I write on your page reply on mine) 23:34, 15 March 2014 (UTC)

Pharmacovigilance
On August 12, 2011, the Ministry of Health, Labour and Welfare in Japan required Nippon Boehringer Ingelheim Co., Ltd. to include a new boxed warning and to revise precautions of the package insert, because several fatal cases resulting from severe haemorrhagic adverse effects, including gastrointestinal haemorrhages, had been reported in patients treated with Prazaxa.

On December 7, 2011, the U.S. FDA initiated an investigation into serious bleeding events associated with dabigatran, stating, "[the] FDA is working to determine whether the reports of bleeding in patients taking Pradaxa are occurring more commonly than would be expected, based on observations in the large clinical trial that supported the approval of Pradaxa [RE-LY trial]." In November 2011, Boehringer Ingelheim confirmed 260 fatal bleeding events worldwide between March 2008 and October 2011 of which 21 in Europe.

The Therapeutic Goods Administration in Australia published a Safety Advisory on 3 November 2011 regarding the risk of bleeding in people using dabigatran. The analysis of these reports shows some of the bleeding adverse events occurred during the transition from warfarin to dabigatran; many of the adverse events are occurring in patients on the reduced dosage regimen; and the most common site of serious bleeding for dabigatran is the gastrointestinal tract, whereas for warfarin it is intracranial. Risk factors for bleeding are: age ≥ 75 years, moderate renal impairment (30-50 ml/min) - severe renal impairment is a contraindication, concomitant use of aspirin (approximately twice the risk), clopidogrel (approximately twice the risk), non-steroidal anti-inflammatory drugs including COX-2 inhibitors (50% more risk).

On 25 May 2012, the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP)(Europe) found the frequency of occurrence of fatal bleedings with Pradaxa seen in postmarketing data was significantly lower than what was observed in the clinical trials that supported the authorisation of the medicine, but considered this issue should nonetheless be kept under close surveillance.

Until recently, the most often cited cause for drug-related mortality by the FDA was warfarin. In October 2006, the FDA issued a black box warning for warfarin due to its hazards. According to data compiled by QuarterWatch, in 2011, the FDA received more safety reports about dabigatran than any other drug. Dabigatran was the subject of 3,781 serious adverse events reported to the FDA in 2011, including 542 patient deaths, 2,367 hemorrhages, 291 acute renal failures and 644 strokes. Warfarin was the subject of  1,106 serious adverse events, including 72 deaths. Quarter Watch and other groups have raised concerns or made recommendations for adjusting dosage to age or renal function. According to Dr. Robert Temple, FDA spokesman, few doctors notify the agency about incidents from warfarin because its risks are already well known. There were 33 million US prescriptions filled for warfarin for atrial fibrillation and other uses in 2011, and some 2.2 million prescriptions for Pradaxa according to IMS Health The unexpectedly large number of reports of hemorrhage in patients receiving dabigatran could reflect differences between the clinical trial setting and the community setting, including differences in monitoring and perhaps heightened reporting and differences in patient populations.

On Dec. 19, 2012, the FDA began requiring a contraindication (a warning against use) of Pradaxa (dabigatran) in patients with mechanical heart valves (also called mechanical prosthetic heart valves).The RE-ALIGN clinical trial in Europe was recently stopped because Pradaxa users were more likely to experience strokes, heart attacks, and blood clots forming on the mechanical heart valves than were users of the anticoagulant warfarin. There was also more bleeding after valve surgery in the Pradaxa users than in warfarin users.

In April 2013 the FDA Office Director Ellis F. Unger wrote a “Perspective” article in the New England Journal of Medicine, discounting the post-marketing reports. The authors believed that the large number of reported cases of bleeding associated with dabigatran provided a salient example of stimulated reporting. However, the FDA Pilot Mini-Sentinel database study captured only 25 intracranial and gastrointestinal bleeding events during 14,5 months in dabigatran patients with atrial fibrillation, and the results were not adjusted for confounders. The study explores new onset Dabigatran bleeding events compared to new onset warfarin in atrial fibrillation. It doesn't explore bleeding events from peri-operative thromboprofylaxe, switching from warfarin to dabigatran (approximately 50% of new dabigatran users) and off-label uses of dabigatran. The reliability of the Mini-Sentinel Program is unknown, but observational studies are inherent problematic owing to several sources of bias. A meta-analysis of 4 trials with dabigatran compared the results of this program regarding the gastrointestinal (GI) tract bleeding risk of dabigatran vs warfarin with the results of randomized clinical trials (RCTs). In this meta-analysis dabigatran significantly increased risk of gastrointestinal bleeding, compared with warfarin. Risk was 41% increased in the meta-analysis of trials, whilst in the mini-sentinel program there was a 54% decreased risk. End 2013 the FDA proposes a new protocol for assessment of dabigatran and selected safety outcomes, using data from the same Mini-Sentinel Distributed Database, although "preliminary data suggest that ambulatory INR test results will be incomplete... which will limit power for assessing outcomes".

A draft version of a company study from 2011, discovered after litigation, reveals a five fold variation in dabigatran plasma levels, possibly requiring blood monitoring in some patients at risk, according The New York Times. A certain segment of patients, the paper found, absorb too little of the drug to effectively prevent strokes, while another group absorbs so much that they are at a higher risk for bleeding. It concerns the elderly and the patients with renal impairment. Ultimately the study was published online in september 2013, 1,5 years after the draft version was finished with omission of this core conclusion and without references to a patient’s optimal blood-level range. According a series of internal emails and memos unsealed by a federal judge in Illinois, employees of Boehringer Ingelheim, continued to express concern in 2011 and 2012 over whether sales of their blood thinner, Pradaxa, could be harmed if the public learned that some patients might need regular testing for safety reasons and whether the study should be published. After this discovery the company said the change between the draft and final version represented an evolution in the scientists' thinking on the topic, and was not motivated by marketing concerns. Doc James (talk · contribs · email) (if I write on your page reply on mine) 23:47, 15 March 2014 (UTC)

RE-LY study:
For understanding trials of new oral anticoagulants in avalvular atrial fibrillation (rivaroxaban ROCKET AF trial, apixaban ARISTOTLE trial and edoxaban ENGAGE AF-TIMI 48) it is essential to understand the RE-LY trial.

The RE-LY trial is a Boehringer Ingelheim, phase III study. It evaluated the efficacy and safety of two different doses of dabigatran relative to warfarin in over 18,000 patients with atrial fibrillation. They were randomized to one of three arms: (1) adjusted dose warfarin, (2) dabigatran 110 mg twice daily, or (3) dabigatran 150 mg twice daily. The warfarin arm was open label, but adverse events were adjudicated by reviewers blinded to treatment.


 * Dabigatran 110 mg was not inferior to warfarin for the primary efficacy endpoint of stroke or systemic embolization, while dabigatran 150 mg was significantly more effective than warfarin or dabigatran 110 mg. Analyses by EMA demonstrated the benefits observed in the comparison of dabigatran to warfarin diminished if INR control was good, with time in therapeutic range TTR >70%. In Re-ly INR values were within the target range 64.4% of the time. In other trials with new anticoagulants mean TTR (Time in Therapeutic Range) was only 55% in ROCKET for rivaroxaban, 62% in ARISTOTLE for apixaban, 66% in SPORTIF 3 and 68% in SPORTIF 5 for meligatran, median (not mean) TTR was 68,4% in ENGAGE AF-TIMI 48 for edoxaban. On the contrary in AuriculA, the Swedish national quality registry for atrial fibrillation and anticoagulation the mean TTR for all patients was 76.2%. In the US patients spent a mean 55% of their time in the therapeutic INR range.


 * Major bleeding occurred significantly less often with dabigatran 110 mg than warfarin; dabigatran 150 mg showed similar major bleeding to warfarin. The global INR control in RE-LY, although being comparable to contemporary trials in this indication, was not optimal from a Northern/Western European standard. When major bleeding events were analysed by time in therapeutic range (TTR), the outcome of warfarin treatment for the overall population improved with increasing TTR. For centres with TTR ≥ 70% (such as Western Europe) the major bleeding event rates were marginally higher for dabigatran 150 twice a day vs. warfarin, and for the elderly ≥ 75 years the risk was significantly higher.


 * A post hoc analysis from RE-LY showed patients over 75 with atrial fibrillation at risk for stroke have lower risks of intra-cranial bleeding but higher risk of extra-cranial (gastrointestinal) bleeding with high-dose dabigatran when compared with warfarin.
 * At the beginning of the trial approximately 40% of patients took aspirin and 7% took clopidogrel. Taking either anti-platelet drug doubled the incidence of major bleeding events, an absolute increase of > 2% per year. This effect was similar for both doses of dabigatran and for warfarin. A favourable risk–benefit ratio for the use of aspirin (in terms of reduction in vascular events, including stroke) with warfarin has been reported only for patients with mechanical heart valves, not for nonvalvular atrial fibrillation. In practice physicians seldom co-prescribe anticoagulants and aspirin because of risk of bleedings. In other trials with new anticoagulants as in ARISTOTLE for apixaban 30,5% took aspirin at inclusion, in the ROCKET-AF trial for rivaroxaban 38,5% and in ENGAGE AF-TIMI 48 for edoxaban 29%. The baseline prevalence of prior myocardial infarction was 17% in RE-LY and 12% in ENGAGE, respectively, raising questions regarding the indication for aspirin among these patients.
 * Apart from inadequate warfarin treatment, high antiplatelets consumption in RE-LY leaded to high rates of major bleeds in warfarin-treated patients, despite being a low-risk population, and the rates of major bleeds were higher than historic warfarin trials. The rate in RE-LY was 3,36% a year, and 3,57% a year, after revision of data. This was much higher than in the meta-analyses with RCTs about warfarin and atrial fibrillation 1.3%  and recently 2,1% (0.9–3.4) in trials and 2% (0.2–7.6) in observational studies.
 * The rate of major bleeding in RE-LY is much higher than previously reported by the same author (1.78 to 2.92%) and than reported for warfarin groups in clinical trials of anticoagulants such as ximelagatran (1.8%) and idraparinux (1.4%). This effect was expected because in an analysis of the SPORTIF 3 and 5 trials in 2006 aspirin combined with warfarin was associated with an incremental rate of major bleeding of 1.6% (P=0,01) per year against warfarine alone, whilst there was no incremental risk for ximelagatran.
 * Also in trials with other NOACS (new oral anticoagulants) the rates of major haemorrhages were clearly higher than in older warfarin studies. They were 3.45% a year in ROCKET (rivaroxaban study), 3.36% in RE-LY (dabigatran study ), 3.09% in ARISTOTLE (apixaban study), and 3,43% in ENGAGE AF-TIMI 48 (edoxaban study) against the BAFTA-study 1.6%, the ACTIVE-W-study 2.21% or in the earlier meta-analyses with RCTs about atrium fibrillation 1.3% and 1% for controle treatment.
 * Intracranial hemorrhages were significantly fewer with dabigatran compared to warfarin. But in RE-LY, an unusually high incidence of intra-cranial haemorrhages by warfarin occurred, 0.76% per year, which is much more than meta-analyses from cochrane 0.3% and 0.45% or individual trials 0.53% in SPORTIF III (10% aspirine, multicenter world) and 0.28% in SPORTIF V (18,5% aspirin use, multicenter Northern-America). Also in other multicenter world trials with new oral anticoagulants risk was higher: risk for warfarin in ROCKET AF was 0,7% per year, in ARISTOTLE 0,8% per year and in ENGAGE AF-TIMI 48 0,85% per year. Already in 1999, a meta-analysis found the use of aspirin with oral anticoagulants was associated with more than double the frequency of intra-cranial haemorrhage (relative risk = 2.4, 95% CI = 1.2-4.8, p = 0.02). In RE-LY, independent predictors of intra-cranial haemorrhage were assignment to warfarin, aspirin use, age and previous stroke/transient ischemic attack. Concomitant aspirin use was the most important modifiable independent risk factor for intra-cranial haemorrhage. Aspirin nearly doubled the risk for warfarin-associated spontaneous intracerebral haemorrhage.
 * Also in trials with other NOACS (new oral anticoagulants) the rates of major haemorrhages were clearly higher than in older warfarin studies. They were 3.45% a year in ROCKET (rivaroxaban study), 3.36% in RE-LY (dabigatran study ), 3.09% in ARISTOTLE (apixaban study), and 3,43% in ENGAGE AF-TIMI 48 (edoxaban study) against the BAFTA-study 1.6%, the ACTIVE-W-study 2.21% or in the earlier meta-analyses with RCTs about atrium fibrillation 1.3% and 1% for controle treatment.
 * Intracranial hemorrhages were significantly fewer with dabigatran compared to warfarin. But in RE-LY, an unusually high incidence of intra-cranial haemorrhages by warfarin occurred, 0.76% per year, which is much more than meta-analyses from cochrane 0.3% and 0.45% or individual trials 0.53% in SPORTIF III (10% aspirine, multicenter world) and 0.28% in SPORTIF V (18,5% aspirin use, multicenter Northern-America). Also in other multicenter world trials with new oral anticoagulants risk was higher: risk for warfarin in ROCKET AF was 0,7% per year, in ARISTOTLE 0,8% per year and in ENGAGE AF-TIMI 48 0,85% per year. Already in 1999, a meta-analysis found the use of aspirin with oral anticoagulants was associated with more than double the frequency of intra-cranial haemorrhage (relative risk = 2.4, 95% CI = 1.2-4.8, p = 0.02). In RE-LY, independent predictors of intra-cranial haemorrhage were assignment to warfarin, aspirin use, age and previous stroke/transient ischemic attack. Concomitant aspirin use was the most important modifiable independent risk factor for intra-cranial haemorrhage. Aspirin nearly doubled the risk for warfarin-associated spontaneous intracerebral haemorrhage.
 * Intracranial hemorrhages were significantly fewer with dabigatran compared to warfarin. But in RE-LY, an unusually high incidence of intra-cranial haemorrhages by warfarin occurred, 0.76% per year, which is much more than meta-analyses from cochrane 0.3% and 0.45% or individual trials 0.53% in SPORTIF III (10% aspirine, multicenter world) and 0.28% in SPORTIF V (18,5% aspirin use, multicenter Northern-America). Also in other multicenter world trials with new oral anticoagulants risk was higher: risk for warfarin in ROCKET AF was 0,7% per year, in ARISTOTLE 0,8% per year and in ENGAGE AF-TIMI 48 0,85% per year. Already in 1999, a meta-analysis found the use of aspirin with oral anticoagulants was associated with more than double the frequency of intra-cranial haemorrhage (relative risk = 2.4, 95% CI = 1.2-4.8, p = 0.02). In RE-LY, independent predictors of intra-cranial haemorrhage were assignment to warfarin, aspirin use, age and previous stroke/transient ischemic attack. Concomitant aspirin use was the most important modifiable independent risk factor for intra-cranial haemorrhage. Aspirin nearly doubled the risk for warfarin-associated spontaneous intracerebral haemorrhage.
 * Intracranial hemorrhages were significantly fewer with dabigatran compared to warfarin. But in RE-LY, an unusually high incidence of intra-cranial haemorrhages by warfarin occurred, 0.76% per year, which is much more than meta-analyses from cochrane 0.3% and 0.45% or individual trials 0.53% in SPORTIF III (10% aspirine, multicenter world) and 0.28% in SPORTIF V (18,5% aspirin use, multicenter Northern-America). Also in other multicenter world trials with new oral anticoagulants risk was higher: risk for warfarin in ROCKET AF was 0,7% per year, in ARISTOTLE 0,8% per year and in ENGAGE AF-TIMI 48 0,85% per year. Already in 1999, a meta-analysis found the use of aspirin with oral anticoagulants was associated with more than double the frequency of intra-cranial haemorrhage (relative risk = 2.4, 95% CI = 1.2-4.8, p = 0.02). In RE-LY, independent predictors of intra-cranial haemorrhage were assignment to warfarin, aspirin use, age and previous stroke/transient ischemic attack. Concomitant aspirin use was the most important modifiable independent risk factor for intra-cranial haemorrhage. Aspirin nearly doubled the risk for warfarin-associated spontaneous intracerebral haemorrhage.


 * Dabigatran trended to decreased mortality compared to warfarin. The FDA clinical reviewer found the trend toward increased mortality with warfarin was entirely due to investigator sites where INR monitoring was inferior. At sites where INR was within therapeutic range ≥ 67% of the time, relative risk for mortality (RR 1.05) favoured warfarin over dabigatran. Overall in the RE-LY study annual mortality rate was 3.84%. Cardiac deaths (sudden cardiac death and progressive heart failure) accounted for 37.4% of all deaths, whereas stroke and haemorrhage-related deaths represented only 9.8% of the total mortality. The majority of deaths (90%) are not related to stroke in a contemporary anti-coagulated AF population. These results emphasize the need to identify interventions beyond effective anticoagulation, in order to further reduce mortality in atrial fibrillation and that antithrombotic therapy only modestly reduces mortality in atrial fibrillation. Thus management of CV co-morbidities (heart failure, hypertension, intra-ventricular conduction delay, diabetes mellitus, obesitas and renal impairment) may be more effective. In a meta-analysis NOACs decreased all-cause mortality significantly in AF with 12%.


 * Significantly more patients withdrew from dabigatran, due to serious adverse events (RRI 56%) and to any adverse event (RRI 26%), compared to warfarin and significantly more adverse events occurred with dabigatran (RRI 3%) compared to warfarin. There was 100% more dyspepsie with dabigatran. Absolute numbers of serious adverse events were not reported. Because total serious adverse events include benefit and harm, total % serious adverse events provides a useful single measure of the overall health impact of a particular intervention. In a meta analysis of 3 new oral anticoagulants discontinuation due to adverse events was significantly increased by 23% against warfarin and there were limited data on harms.


 * There were significantly more heart infarctions (RRI 33% ARI 0,4%) in the initial analysis of the RE-LY trial. A meta analysis confirmed that the oral direct thrombin inhibitors were associated with significantly higher rates (RRI 32-35%) for myocardial infarction as compared to warfarin.


 * In the Re-ly study health-related quality of life was equal in warfarin and dabigatran treated patients who didn't experience strokes or bleedings. This was unexpected given the known complexities of warfarin treatment.


 * Exclusion criteria included severe heart-valve disorder, stroke within 14 days or severe stroke within 6 months, conditions that increase risk for hemorrhage, creatinine clearance < 30 ml/min, active liver disease, and pregnancy. Both the RE-LY and ROCKET-AF trials have important inclusion/exclusion criteria that limit their ability to be generalized or at least raise questions in regard to how well they will perform in the real world of nonselected AF patients.


 * Some reviewers argue, because of major flaws in RE-LY, a double-blinded trial should be performed testing dabigatran against warfarin to verify the results of the RE-LY trial. A meta analysis about the impact of double-blind vs. open study design on the observed treatment effects of new oral anticoagulants in atrial fibrillation found a significant 67% enhancement of treatment effect with PROBE/open-label trials compared with double blind trials (interaction test, P = 0.05) for hemorrhagic stroke. No other interaction was significant. There are doubts about the netto clinical effect of dabigatran in the absence of data concerning total adverse events. Other authors raise concerns about the design of the RE-LY trial, including selection bias (low risk patients), co-interventions (aspirin), adverse events (myocardial infarction) and generalisability (overrepresentation of stroke, underrepresentation of myocardial infarction) al leading into a bias in favour of dabigatran, causing its benefit to be overstated when generalising to a broader population. The same selection bias including low risk patients was present in the ARISTOTLE trial. Co-interventions with aspirin and problems with generalisability bij overrepresentation of stroke and underrepresentation of myocardial infarction were present in ARISTOTLE, ENGAGE AF-TIMI 48 and ROCKET AF trials. In ARISTOTLE the ratio of previous stroke against previous myocardial infarction was 19,5% against 14% of participants, in ROCKET AF the ratio was 55% against 17% and in ENGAGE AF-TIMI 48 the ratio was 28,3% against 11,5%. In a real world population there is more myocardial infarction than stroke.   Another factor favourising dabigatran (and other NOACs) was seen by EMA reviewers pointing to inadequate warfarin control in much trial centers, considering North- and Western-European standards. The same problem was seen in the rivaroxaban and the apixaban study.

Venous thromboembolism
Dabigatran is indicated for the prevention of venous thromboembolic events in patients who have undergone elective hip or knee replacement surgery (based on the RE-NOVATE, RE-NOVATE 2, RE-MODEL, and RE-MOBILIZE trials).

A 2009 Boehringer Ingelheim, randomized, double-blind trial by the RE-COVER study group demonstrated no inferiority of dabigatran 150 mg twice daily compared to warfarin in the treatment of acute venous thromboembolism for prevention of recurrent venous thromboembolism, with a similar rate of major bleeding after 6 month. Both groups received first 9 days of LWMH. Patients randomized to dabigatran had more dyspepsia and more drug discontinuation.

A systematic review found new oral anticoagulants are effective for the extended treatment of venous thromboembolism and may reduce the risk of all-cause mortality against placebo. Dabigatran and rivaroxaban, but not apixaban, may cause more major or clinically relevant bleeding. Another systematic review about 4 new oral anticoagulants found no difference in risk with warfarin for recurrences of venous thromboembolism, mortality, and fatal pulmonary embolism. Risk of major bleeding was lower with number needed to treat of 149.

Negative trials
The RE-ALIGN clinical trial in Europe for patients with mechanical heart valves (also called mechanical prosthetic heart valves) was recently stopped because Pradaxa users were more likely to experience strokes, heart attacks, and blood clots forming on the mechanical heart valves than were users of the anticoagulant warfarin. There was also more bleeding after valve surgery in the Pradaxa users than in warfarin users.

In the RE-DEEM trial dabigatran was used after acute coronary syndromes on top of dual antiplatelet therapy during six months. Dabigatran, in addition to dual antiplatelet therapy, was associated with a dose-dependent increase in bleeding events against placebo. For the 150 mg twice a day dose the risk was 327% higher.

In patients with a recent acute coronary syndrome, the addition of a new oral anticoagulant to antiplatelet therapy results in a modest reduction in cardiovascular events but a substantial increase in bleeding, most pronounced when new oral anticoagulants are combined with dual antiplatelet therapy. The use of anti-Xa or direct thrombin inhibitors is associated with a dramatic increase in major bleeding events (2- to 3-fold higher odds), which might offset all ischemic benefits in patients receiving antiplatelet therapy after an ACS. There is no net clinical benefit, calculated as the sum of composite ischemic events and major bleeding events for different doses of new anticoagulants. Doc James (talk · contribs · email) (if I write on your page reply on mine) 23:51, 15 March 2014 (UTC)
 * This content should be merged into either "medical uses" or "adverse effects" if not already covered there which most of it appears to be. Doc James  (talk · contribs · email) (if I write on your page reply on mine) 23:53, 15 March 2014 (UTC)

Suggested dabigatran edit
I would like to propose some minor updates to the current article for dabigatran (http://en.wikipedia.org/wiki/Dabigatran) as some of the information on this page is now factually inaccurate or out dated. As of January 2013, the brand name for dabigatran in Canada was changed from ‘Pradax®’ to ‘Pradaxa®’.

In the ‘Medical Uses’ section, it states that dabigatran is used to prevent strokes in those with atrial fibrillation due to non heart valve causes. In addition to this, please be aware that dabigatran has been approved to treat and prevent recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE). Outside of the US dabigatran is also used to prevent blood clots (venous thromboembolic events) in adults who have undergone elective total hip or total knee replacement surgery. Please see below links to the dabigatran prescribing information pages on the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) websites for information about medical uses

I would be grateful for any advice you are able to offer with regards to updating these factual inaccuracies. Tvrdonova (talk) 08:25, 21 October 2014 (UTC)


 * Thank you for using this page to make suggestions, which is a best practice when you have a conflict of interest (thank you as well for acknowledging that on your user page). We should correct inaccuracies, but I would not characterize lack of inclusion of all approved uses as an inaccuracy, and I don't think we are bound to be inclusive. That said, these are constructive and we should consider your suggestions seriously. -- Scray (talk) 13:07, 27 November 2014 (UTC)

Updating Approvals in History sections
Dear Wikipedia Community,

In order to supplement the completeness of this Wikipedia article, I was wondering whether readers would appreciate a more complete list of regulatory approvals for dabigatran to be added in the “History” section. Currently, the “History” section does not reflect the approvals listed in the “Medical Uses” section. I could imagine that the article would benefit if the two sections were aligned. If you would like further information or dates, I would be happy to provide them here.

Tvrdonova (talk) 14:04, 16 March 2015 (UTC)
 * I saw your post at WP:PHARM alerting to this proposal and am replying.
 * I cannot say whether readers would appreciate it because we do not have access to surveys of the readers on this topic, but I can say that based on March 2015 traffic this is a fairly popular Wikipedia article by any standard, so readers do care about this topic.
 * Wikipedia does not usually present information about the approvals of medical uses because we usually cannot easily get access to this information. In any case, we accept all kinds of information, and my thought is that if you have a reliable source which provides this kind of information then it would be useful to share it in the history, especially if that can create a match to the indications already listed in the "medical uses" section.
 * This starts with having a source to cite, though. Can you share a reliable source which presents this information?  Blue Rasberry   (talk)  13:54, 28 April 2015 (UTC)

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