trombosi - emostasi

Abstract

Initially conceived as an abstract, due to the enormous number of papers published continuosly, and due to the great controversy about laboratory monitoring of dabigatran, and probably of all other Direct Oral Anticoagulants (DOACs), this abstract has become day by day a chapter. The problem of laboratory monitoring is so an important issue because of the large number of patients who are involved, and of the tremendous impact that eventually its introduction may have on their health and their lives, that exceptionally deserves a large and detailed analysis of the most important papers published about this topic, also at the beginning of this review before all the other sections. For these considerations, this abstract could be called Chapter One : Increased evidence of the clinical utility of laboratory monitoring in dabigatran treatment.

Dabigatran  etexilate  is  a  direct  thrombin  inhibitor  that has  been  approved  for  prevention of  stroke  and  systemic  embolism  in  patients  with  non  valvular  atrial  fibrillation in U.S.A., Canada and Europe,and  for  post-operative thromboprophylaxis  in  patients  who  have  undergone  a  knee  or  a  hip  replacement  surgery only in Europe. Recently at the end of march 2014, by the Food and Drug Administration (FDA) and after by European Medical Agency (EMA) dabigatran has been approved for treatment of deep vein thrombosis (DVT) and of pulmonary embolism (PE) and to prevent these conditions from reoccuring in adults. In  the  RE-LY trial, a non-inferiority trial, (1) (NEJM  2009  vol.361  pp.1139-1151) stroke and systemic embolism were  1.71% patients  per  year in the  warfarin group and 1.11% patients per  year in  the  group  treated with  150 mg. of dabigatran etexilate   twice  daily  and 1.54% patients per year  in  the group  treated  with  110 mg. twice daily.  The rate of major  bleeding in the warfarin group was 3.57% patients per year,  and in  the dabigatran etexilate group was  3.32% patients  per year  with  a  dosage of  150 mg.twice  daily and 2.87% patients per year  with a dosage of 110 mg. twice daily. The mortality rate was 4.13% patients per year in the warfarin group and 3.65% patients per year with 110 mg. of dabigatran and 3.75% patients per year with 150 mg of dabigatran always twice daily.(2) (Thrombosis and Hemostasis 2013 vol  110  pp. 496-500)
In patients  with atrial fibrillation dabigatran at  a dosage of  110 mg. twice daily  was  associated  with  similar rates of stroke and systemic embolism obtained  with  warfarin treatment but with lower rates of major  hemorrhage. Dabigatran etexilate at a dosage of 150 mg twice daily was associated with lower rates of stroke and systemic embolism than warfarin but with similar rates of major hemorrhage. (RE-LY Trial) (1) (NEJM 2009  vo.361  pp.1139-1151)  The  RE-LY trial, a non-inferiority trial, sponsored  by  dabigatran  etexilate  manufacturer,  is  a large  trial conducted in  44  different  countries  with  different  healths  systems. Are non-inferiority trials unethical compared with superiority trials ? Some key leaders in the pharmacological research field, think they are unethical because they disregard patients' interests. Use of non-inferiority rather than superiority trials, implies the intention of not tryng to prove any additional value of  new drugs. Drug manufacturers argue that there is no reason to know whether a new drug is more effective than an older one. It is enough to show that they are similar. The added value is based on the probability of a better compliance. Non-inferiority trials allow new products to compete with older ones on the basis of small differences made to seem to benefit patients. In addition, non-inferiority trials expose patients to clinical experiments without any assurance that the experimental drug is not worse than the standard treatment, and without really exploring whether it is better.The subsequent statements of Garattini and Bertelé are so strong, so effective and so clear that I think to be obliged to use exactly their words : " We believe that non-inferiority studies have no ethical justification, since they do not offer any possible advantage to present and future patients, and they disregard patients' interests in favour of commercial ones. This situation betrays the agreement between patients and researchers set out in any fair informed consent form that presents randomised trials as the only ethical way to address clinical uncertainty. Non-inferiority trials claim minor advantages for the test drugs, but do not prove their efficacy compared with older products. Few patients would agree to participate if this message were clear in the informed consent form : as we said before, why should patients accept a treatment that, at best, is not worse, but could actually be less effective or less safe than available treatment ?. In conclusion we believe that non-inferiority trials fail to meet the commitments of good clinical research : Ask an important question, and answer it reliably ". (3) (The Lancet 2007 vol. 370 pp. 1875-1877) Others authors think they are useful and can be ethically justified in some cases. In addition, an author thinks that would be useful to ban the improper application of the non-inferiority design such as setting wide inferiority limits or using statistical rather than clinical difference  as a basis for concluding that a drug is non-inferior, not the design itself. (4) (The Lancet 2008 vol. 371 pp. 895-897) It is undeniable that superiority trials are the gold standard in clinical trial research. Having difficulties to find more powerful drugs on the market, the pharmaceutical industry has been forced to look for drugs that may not improve the current efficacious treatments but may be better on other aspects of treatment such as adverse reactions. However, different definitions of non-inferiority may be a difficult obstacle for clinical decision maker to decide the true message of a non-inferiority trial. (5) (Bullettin of the NYU Hospital for Joint Disease 2008 vol. 66 (2) pp. 150-154) The noninferiority margin is taken into account in the formulation of the sample size calculation. The margin must be smaller than or equal to "the smallest value that would represent a clinically meaningful difference, or the largest value that would represent a clinically meaningless difference ". The determination of this margin must be based on both statistical reasoning and clinical judgement. For analysis, intent-to-treat (ITT) and per-protocol analyses should be performed. ITT analysis may lead to biased conclusions because protocol violations and withdrawals. In addition, dropouts and nonadherent participants from the 2 groups are potentially different, which may also bias a per-protocol analysis. Thus both analyses are required to draw a conclusion. Reporting the results of only one of the analyses may reflect a deliberate intention to mask some of the results, potentially modifying the interpretation of the results. (6) JAMA 2006 vol. 295 (10) pp. 1147-1160) For details see section on "Conclusions". At  the  moment,  we  do not have  an antidote  to neutralize  the  anticoagulant  effect  of  dabigatran.  PCC  concentrates  that are very  useful in  warfarin  bleedings, and Recombinant  Activated  Factor  VII  are unsuccessfull  in  dabigatran  bleedings,  only  FEIBA probably may reduce dabigatran anticoagulant effect as reported recently in anedoctal cases. (7) (British Journal of Haematology 2014 vol. 164 pp. 308-310) (8) (British Journal of Haematology 2014 doi: 10.1111/bjh.12831) Also tranexanic acid IV may be efficacious in reducing bleedings. The  only procedure that  reduces   the  anticoagulant  effect  of  dabigatran  removing  it  from  plasma, is  dialysis but, in  patients  with  important  bleeding  that  frequently  are  in unstable  clinical  conditions,  performing this  procedure  can  be  very  challenging  also  in  the  best  emergency  departments.
Less drug interactions  compared with warfarin are described, but these few interactions are very important,  considered  that  amiodarone  and  verapamil  for example,  are  very  used  in  atrial  fibrillation and  the  approved  principal  use  for  dabigatran is to  prevent  stroke or  systemic  embolism  in  patients  with  non  valvular  atrial  fibrillation.
The manufacturer of dabigatran is facing more than 4,000 law suits in the US, claiming dabigatran caused severe and fatal bleeding and in January 2014 the New York Times reported that the employees were worried about publishing a research paper suggesting that patients taking dabigatran might require blood monitoring. (9) (www.medscape.com/viewarticle/821116) (see section on "Discussion"). The FDA (Food and Drug Administration) has given the designation of breakthrough therapy to Idarucizumab, an experimental drug that is in evaluation as an antidote for the oral anticoagulant Dabigatran. In a study of phase 1, it has been demonstrated that Idarucizumab has produced an immediate, complete and prolonged reversal of the anticoagulation induced by Dabigatran in healthy people. A study of  phase 3, RE-VERSE AD, is evaluating Idarucizumab in patients who are taking Dabigatran and are showing an uncontrolled bleeding or are undergoing an emergency surgery or other invasive procedures. Just recently, The New England Journal of Medicine published a human volunteer study of 80 individuals who received PER977 (Aziparine) which is a synthetic small molecule (D-arginine compound)  which has broad activity against various old (heparin, low molecular weight heparin) and new oral anticoagulants (dabigatran, rivaroxaban, apixaban end edoxaban). (10) (New England Journal of Medicine 2014 vol. 371 pp. 2141-2142) see section on "Adverse reactions". At the moment there are not antidotes approved by FDA or EMA to reverse the effects of the new oral anticoagulants. More time passes and more questions about safety of Dabigatran raise. As it was pointed out in this review since last year, and in the reviews about rivaroxaban, apixaban and edoxaban, the fact that the new oral anticoagulants do not need laboratory monitoring is not correct, because probably they need less monitoring compared to warfarin, but in any case they do. It was emphasized that the new oral anticoagulants do not need laboratory monitoring because they have a predictable pharmacokinetics and pharmacodynamics but, in a new RE-LY substudy, was found that plasma dabigatran levels for either dose in RE-LY ranged over 5-fold for the 10th to 90th percentile (11) (Journal of The American College of Cardiology 2014 vol. 63 pp. 321-328) The authors concluded that considered that the primary analysis of the whole population, without consideration of plasma levels showed that the two doses of dabigatran in the RE-LY were safe and effective, this suggested that there is a wide therapeutic range. In 2010 was published a study in which the authors identified some sources of inter- and intra-individual variability, such as renal and/or hepatic function, advanced age, and certain clinically relevant drug-drug interactions. (12) (Journal of Thrombosis and Haemostasis 2010 vol. 8 pp.621-626) For details see section on "laboratory tests". On 23 july 2014, was published by the British Medical Journal an interesting article written by Dr. Deborah Cohen, the investigations editor at the BMJ, with the following title : Dabigatran : how the drug company withheld important analyses.  I think that just the title do not need any comment, considered that Dabigatran achieved blockbuster status, with sales of over 1 billion US dollars by april 2012 and of 2 billions by 2014 despite increasing concerns about safety.
Boehringer Ingelheim, the maker of dabigatran,did not 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. Analyses that calculated how many major bleeds dose adjustment could prevent were also withheld. The company replied that this information was not comunicated to the regulatory agencies because the analysis did not provide a reliable prediction of patient outcomes. Internal documents of Boehringer show that major bleeds with dabigatran may be reduced by 30-40% if the plasma levels of the drug were measured and the dose was adjusted accordingly. It has also identified the plasma level at which the dose adjustment should occur to reduce the risk of a major bleed. The analysis concluded that "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". During litigation was revealed an internal email discussions about the potential merits of drug plasma monitoring in which one Boehringer employee, whose name has been reducted, said : "This may not be a onetime test and could result in a more complex message (regular monitoring) and a weaker value proposition". On the contrary, in an FDA press statement in 2010 at the time of its US approval, Norman Stockbridge, director of the division of cardiovascular and renal products in the FDA's Center for Drug Evaluation and Research, said : "Unlike warfarin, which requires patients to undergo periodic monitoring with blood tests, such monitoring is not necessary for Pradaxa (dabigatran)". Differently 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 market the drug, but also later when widespread use of the drug led to safety concerns. As test to monitor drug level was chosen the Hemoclot test. 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". A spokeperson for Boehringer said that the company "never told EMA or any regulatory authority that 200 ng/mL was a level not to be exceeded". 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 a 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".  A QuarterWatch report analysed all the adverse events submitted to the FDA's reporting system in 2011. 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. (13) QuarterWatch 2012 Quarter 4) Although the RE-LY protocol did not require monitoring of blood levels in patients taking dabigatran, the investigators collected drug plasma concentrations during the trial. Internal documents of the company in August 2011 show that employees completed a subgroup analysis of these data. Some of the conclusions of this analysis were published in the Journal of the American College of Cardiology as cited above. Internal emails released during US litigation show that 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. 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 discussion in the regulatory bodies".  Clemens also wrote : "The world is crying for this information but the tricky part is that we have to tailor the message 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 Health Authorities extremely difficult (i.e. Health Canada, TGA) and undermine our efforts to compete with other NOACs. 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. As the number of fatal bleeds accumulated, the EMA asked to Boehringer to "discuss and suggest appropriate monitoring frequency and laboratory tests". On 9 March 2012, Boehringer gave a presentation to the EMA committee. The EMA's minutes show that routine monitoring of anticoagulant activity was discussed "in depth" by the committee. However, most experts voted against it. Some of the analyses and conclusions pointed out in Reilly's 2011 paper, which was produced over six months before EMA's safety, were absent from the company's presentation to the committee. In particular there was not in the company's presentation a graph showing that beyond a certain plasma concentration of the drug major bleedings events continued to increase as the plasma levels increased with little effect on rates of stroke and systemic embolism. 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. 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 BMJ asked to Boehringer if had comunicated to the EMA 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 woul be required to identify these patients. A dose adjustment could improve the benefit-risk ratio", as had been described in the draft publication. A company spokesperson said that the company did not comunicate to the EMA these information because they were "hypotheses in drafts of a paper that the authors of that paper rejected as they refined their analysis". 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". 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. An employee from the cardiology division of the company who wanted to develop such a device in a email 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 ".  At a certain point the company started to evaluate to prescribe monitoring for dabigatran therapy especially after that by 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". But after considering regulatory and other obstacles, the company decided to continue to support the position that dabigatran does not need laboratory monitoring. In their mid to long term strategy document, company officials also considered 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 ?. 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. "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.  (14) (British Medical Journal 2014 vol. 349 pp. g4670)  Another article appeared on August 18, 2014 in the New York Times with the following title : Weighing Pradaxa's risks. For other comments and other articles about this very important problem, see section on " Adverse reactions" and " Discussion" . 
On September 25, 2014, Chest Journal published on line an article in which the author points out that direct thrombin inhibitor anticoagulants, used for the treatment of cardiac and venous thromboembolism, have repeatedly associated with a significantly increased frequency of thrombosis on abnormal cardiac endothelium when compared with indirectly-acting therapeutic anticoagulants in studies of sufficient patients number and duration. The author concludes that " Although there is uncertainty as to mechanism, the weight of evidence as a class effect warrants prescribing effective anticoagulants other than direct thrombin inhibitors". (15) (Chest 2015 vol. 147 (1) pp. 21-24) For other comments, see section on " Adverse reaction" and section on "Conclusions".  Recently (16) Circulation 2015 vol. 131 pp. 157-164 and (17) JAMA November 3, 2014, published two analyses of Medicare database to evaluate the efficacy and safety of dabigatran in clinical pratice, comparing it to warfarin in patients with nonvalvular atrial fibrillation.The studies attain divergent conclusions.The investigators of the first study published by Circulation conclude that dabigatran has a more favorable effect compared to warfarin. On the contrary, the investigators of the second study published by JAMA conclude that dabigatran should be prescribed with caution, especially among high risk patients. The two studies did not evaluate the quality of warfarin anticoagulation by TTR (Time in the therapeutic range). For details, see section on "Adverse reactions" and on "Conclusions". Also recently, on november 28, 2014, BMJ published an editorial about ties between medical journals and industry that can cause clinical decisions based on information biased by commercial interest. Its editors decided to start to accept in 2015 only clinical educational articles by experts without financial ties to companies producing drugs, devices, or test and medical education companies. They hope to extend this policy to the state of the art reviews and diagnostic and therapeutic series by the end of 2016.  For over two decades the journal American Family Physician which principally publishes clinical reviews, has not accepted articles by authors who have financial ties with industry. "Many clinical practice guidelines are little more than industry marketing tools because of the financial competing interests of their authors and sponsors". (18) (British Medical Journal 2014 vol. 349 pp. g7197)  For details, see section on "Conclusions". 
A very important paper which has practical clinical implications was published by Journal of Thrombosis and Haemostasis in July 2014, in which Poller and collegues compared the results obtained with warfarin and Dabigatran in the RELY study (6022 patients) with the results obtained with warfarin in the European Action on Anticoagulation (EAA) study (5939 patients). Morbidity and mortality were much higher in RE-LY in all three groups than with warfarin in the EAA study, and better results for stroke, major bleedings and minor bleedings were obtained in the EAA study, compared with patients treated with warfarin and with patients treated with both Dabigatran doses in the RE-LY study. In the RE-LY study, in warfarin patients, overall events (% per year) were 1.57, 3.36, 16.37, and 4.13 for stroke, major bleedings, minor bleedings and death respectively. In dabigatran patients were 1.44, 2.71, 13.16 and 3.75 in the 110 mg. group and 1.01, 3.11, 14.84 and 3.64 in the 150 mg. group. On the contrary, in the EAA study overall events (% per year) for stroke, minor bleedings, major bleedings and death were 0.30, 2.70, 0.86 and 0.75 per year respectively. These impressive results obtained in the EAA study although the "Time in INR range" was marginally better than in RE-LY may be explained by the lack in RE-LY of two important assessments of INR control, local ISI calibration and external quality control of INR. (19) (Journal of Thrombosis and Haemostasis 2014 vol. 12 pp. 1193-1195) Now a precise local INR may be obtained easily using the prothrombin time/international normalized ratio (PT/INR) Line which is a simple method that uses only five certified European Concerted Action on Anticoagulation (ECAA) plasmas to derive local INR. The PT/INR Line does not require manual PT testing, an International Sensitivity Index (ISI) and Mean Normal Prothrombin Time (MNPT) and can be used in place of local ISI calibration. It can be performed with the assistance of a spreadsheet freely available online from www.anticoagulants.co.uk. (20) (Journal of Clinical Pathology 2011 vol. 64 pp. 930-932) In addition, in RE-LY there was only a recruitment of 6.3 patients per centre against a recruitment of 182 patients per centre in the EAA study. The larger number of centres participating in the RE-LY study, compared with the EAA study, would result in a greater between-centre variation in the quality of oral anticoagulation treatment and this could also be another reason for the impressive results obtained in the EAA study. In addition the higher incidence of events in the RE-LY study may be due to the participation of less experienced centres and a subgroup analysis stratifying centres by size or proficiency may prove this.  (19) (Journal of Thrombosis and Haemostasis 2014 vol. 12 pp. 1193-1195) see details in the sections "Indications" and "Conclusions".  As more time passes, more papers are published by key physician opinion leaders too, emphasizing the tremendous advantage of the new oral anticoagulants in long term anticoagulation and in particular emphasizing the fact that can be given in fixed doses without routine coagulation monitoring, and that will replace warfarin for more and more indications.  (21) (Journal of thrombosis and thrombolysis 2015 vol. 39 pp. 264-272)  (22) (ATVB 2015 DOI : 10.1161/ATVBAHA.115.303397) (23) (Blood 2014 vol. 124 (12) pp. 1968-1975) Unfortunately, although the fact that they do not need a laboratory monitoring would be really an important advantage over warfarin, this is not true. As written above, these new drugs need a laboratory monitoring, may be less times than warfarin, but in any case they do, and differently from vitamin K antagonists in which using the INR we can decide to let perform a surgery or not, with these drugs, we do not have a drug concentration that let us decide if a patient can receive or cannot receive a surgery, in particular a major surgery, although EMA marketing authorization holder informed that a dabigatran concentration below 48 ng/ml should be reached before an invasive procedure and although the "Groupe d'Intéret en Hémostase Périopératoire (GIHP) indicates a threshold at 30 ng/ml. (24) (Archives of Cardiovascular Diseases 2013 vol. 106 pp. 382-393) Also with low concentrations we cannot exclude a probable surgical bleeding. We will be sure that the patient can undergo a major surgical procedure safely only when the drug will be completely disappeared. In case of an emergency surgery, trying to antagonize the anticoagulant effect of these drugs using Prothrombin Complex Concentrates (PCCs) or FEIBA, are we able to say with certainty that the patient will not bleed ? Certainly not. Is this last aspect correctly explained to the patient before give him one of these drug? I hope yes. And if it is explained, how many patients do you think would be willing to take these drugs, considering that they could be in serious troubles in case of an emergency surgical procedure? Thomas Moore, senior scientist at the US Institute for Safe Medication Practices, and collegues raise concerns about the differences in how US and European regulatory agencies manage the safety problems of dabigatran and ask both FDA and EMA to think again and mandate plasma monitoring of dabigatran. In fact, they say that FDA pursued a policy making the new drug easier to use with just one primary dose, even though it would increase the risk of haemorrhage in older patients. But the FDA also believed its actions might slightly improve the efficacy of dabigatran in preventing stroke. On the contrary, EMA showed continuing concerns about reducing the risk of bleeding and pursued multiple risk reductions policies. Although results were not published until late 2013, the RE-LY trial had included a large sub-study (n= 9183) which showed that a fixed dose of dabigatran had a wide variability in plasma levels that were directly related to risk of bleeding. After a month of treatment, the 150 mg twice daily dose could produce peak levels as low as 2.3 ng/mL and as high as 1000 ng/mL. A conservative measure that omitted 20% patients at the extremes and used log transformed data indicated a 5.5 fold variability. They correctly affirm that "dabigatran's high variability was not a desirable characteristic for a drug where not enough anticoagulation means loss of benefit in stroke prevention and too much anticoagulation increases the risk of haemorrhage". Clearly the variability of dabigatran may be explained by its low bioavailability (3-7%), two metabolic steps to convert the pro-drug into the active drug and a single primary route of elimination, the kidneys. (25) (BMJ 2014 vol. 349 pp. g4517) Variability can also be explained by genetic variants that could contribute to interindividual variability in blood concentrations of the active metabolite of dabigatran and influence the safety and efficacy of dabigatran. (26) (Stroke 2013 vol. 127 pp. 1404-1412) These characteristics were not found in rivaroxaban and apixaban , which have much higher bioavailability (50-80%) and multiple routes of elimination.  As the company stated, dabigatran showed a wide therapeutic range in effects on stroke, with about a similar efficacy from around 50 ng/mL through 300 ng/mL, but the probability of major bleeding rises rapidly from around 2-3% at 50 ng/mL to more than 9% for the typical patient around 300 ng/mL, and to more than 12% at the extremes. One member of the advisory committee of the FDA focused on the fact that with high plasma level variability, did not dabigatran really need plasma level monitoring? " I am struck by what my eyeball tells me about a five-fold variability within the 90 percent confidence interval of the 150 mg. dose. That seems awfully big to me in a drug that we are proposing to use without therapeutic monitoring", said Darren McGuire, a cardiologist on the panel. But an agency pharmacologist told him, "We did not see a need for monitoring the concentration because we saw in a study, a favorable result in all subgroups". The FDA recommended the indication for any patient with nonvalvular atrial fibrillation and showed a strange narrow view in pursuing a reduction in stroke rate of a fraction of 1% on the basis of a single trial whose data quality the agency had already changed without caring of the bleeding risk. On the contrary, the EMA committee reviewed and expressed concern about the large variability in plasma levels and bleeding risk found in the then-unpublished RE-LY sub-study data. EMA requested, received and published a therapeutic range (48-200 ng/mL). It also ensured that an accurate assay was available and validated, the Hemoclot direct thrombin inhibitor assay, but did not oppose to Boehringer's will to market dabigatran as a drug that did not require blood level testing to establish the optimal level of anticoagulation. As of December 2011, the company summary cited 9049 reported bleeding events in its global experience, including 368 deaths. At least 10% of patients had peak plasma level concentrations >/= 383 ng/mL when taking the 150 mg. dose. This is about seven times (48-50 ng/mL) the minimum level needed for stroke prevention, according to Boehringer. The EMA on the other hand, considered whether to require plasma level testing for dabigatran.
As described above, EMA had already obtained a therapeutic range from Boehringer Ingelheim, 48-200 ng/mL, which was included in the European Union (EU) approved product information. However, at the end, the company position that routine monitoring of the anticoagulant activity is not necessary, was accepted. A review of the EMA meeting materials shows that the company slide presentation did not include all their relevant data on plasma level variability of dabigatran. (24) (BMJ 2014 vol. 349 pp. g4517) An internal document of Boehringer Ingelheim showed a significant reduction of bleeding events with dabigatran titration.There are some key documents referred to the BMJ investigation conducted by Deborah Cohen on how the company withheld important analyses, showing modelling which Boeringher Ingelheim carried out on dabigatran. (www.bmj.com/investigation/dabigatran) In 2012, a second risk of dabigatran become visible. At the low end of the variability range, plasma levels in some patients were insufficient to reduce the risks of stroke and other thromboembolic events. When Boehringer planned a new trial to study the effect of dabigatran on patients with mechanical heart valves decided to individualise the dose for each patient and selected a minimum of 50 ng/mL to be effective. The company revealed that 17% of RE-LY patients had ended up with plasma levels that were lower than 50 ng/mL.  (27) (American Heart Journal 2012 vol. 163 pp. 931-937) The heart valve study using dose adjustment showed that at least 8% of participants had plasma levels below the 50 ng/mL target even when prescribed double the maximum approved dose up to 300 mg twice daily. The dabigatran study in mechanical heart valves was stopped for safety. A Boehringer unpublished simulation model compared the 150 mg. dose twice daily with a hypothetical treatment programme in which dose would be optimised for each patient to achieve a plasma concentration of 90-140 ng/mL. The model showed that only 45% of patients would receive the 150 mg. standard dose; 26% should be reduced to 75 mg and 30% to 110 mg.
The model projected that major bleeding could be reduced by 20% compared with the 150 mg dose without having a statistically significant effect on rates of ischemic stroke and serious embolism. Compared with warfarin the hypothetical reduction in risk of major bleeding was 40% and the risk of stroke or serious embolism was not statistically different. These results showed benefits in adjusting dose to optimise the level of anticoagulation in each patient.
Most patients could benefit from a lower dose and reduced bleeding risk with no loss of efficacy. Moore and collegues concluded that the manufacturer, the FDA, and EMA need to agree on a therapeutic range and recommend initial dose adjustment based on plasma measurements. (25) (BMJ 2014 vol. 349 pp. g4517) Hugo ten Cate argues that the safety of all the new oral anticoagulants can be potentially improved through documenting a therapeutic range for each agent, individualising dose in many patients subsets, and improving adherence. The title of his editorial is :"New oral anticoagulants : discussion on monitoring should start now ! ". The development and implementation in quantitative laboratory assays will enable further dose optimization and the conduction of the treatment by a patient centered manner would prevent non-adherence, especially in elderly patients. (28) (Thrombosis Journal 2013 vol. 11 pp. 8) Published data show the range in responses to dabigatran for the indication stroke prevention (150 mg bd), with average peak and trough levels of 175 and 91 ng/mL (assayed by TT-hemoclottest), with 25-75th percentile (ng/ml) of 117-275 and 61-143 ng/mL, respectively. (29) (Pradaxa product monograph, revised 2012). (30) (Van Zuiden Communications BV; 2012, Dutch language)  Ten Cate concludes that for NOACs therapeutic ranges of each agent should become available based on concentrations and/or dose response effects in laboratory tests. This will ultimately provide a means of optimizing dose adjustment in individual patients, more so than by current algorithms.(28) (Thrombosis Journal 2013 vol. 11 pp. 8)  In another paper published on BMJ in July 2014 (31) (BMJ 2014 vol. 349 pp. g4747) Deborah Cohen reported that academics who wrote the Therapeutics Letter expressed concern about RE-LY trial because it was an open label trial, meaning that clinicians and trial participants knew which drug was being given. This can lead to a risk of bias as was well demonstrated in the clinical trial of another direct thrombin inhibitor, ximelagatran, that did not receive regulatory approval. In an unblinded clinical trial similar to RE-LY, ximelagatran was associated with numerically fewer strokes and systemic emboli compared with warfarin. However, in a follow-up double blinded trial, there were more strokes and systemic embolisms with ximelagatran. All this leads to questions about the regulatory decision to licence a drug on the basis of a single open label trial when the regulators had identified serious concerns. A transcript of the FDA's advisory committe shows that the US agency found "that knowledge of treatment arm, by doctors and patients, may have led to important differences in the treatment of subjects. For example if a subject experienced an ischemic stroke, TIA (a non-end point event) or minor bleed, she was more likely to have her study medication permanently discontinued in the dabigatran than in the warfarin treatment arms". (www.fda.gov/ downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/) The authors of the Therapeutic Letters correctly noted that the incidence of intracranial haemorrhage (ICH) observed with warfarin was higher (0.76% per year compared with 0.27% per year with dabigatran) than that observed in other trials such as SPORTIF III (0.53%), SPORTIF V (0.28%) and 0.3% or 0.45% in two Cochrane reviews. (32) (Cochrane Database of Systematic Reviews 2005, Issue 3. Art. No : CD001927) (33) (Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No : CD006186) These authors conclude that "Licensing of dabigatran 150 mg BID for atrial fibrillation is premature, pharmacologically irrational and unsafe for many patients. The optimal dose for non-valvular atrial fibrillation is not yet clear. An independent audit of RE-LY is needed to check for irregularities in conduct, sources of bias and the cause of the unusually high incidence of intracranial hemorrhage in the warfarin arm. An independently conducted double-blind RCT comparing dabigatran with warfarin in patients with non-valvular atrial fibrillation is required." (34) (Therapeutics Letter 2011 vol. 80 www.ti.ubc.ca/letter80) On 28 May 2014, the company announced that it had settled about 4000 cases for 650 million dollars, but denied wrongdoing saying that it had settled the lawsuit to avoid lengthy litigation. Two men who participated to RE-LY trial had major bleeds immediately before their deaths, but neither was counted as having had one in the company's original submission to the regulator when applying for approval in 2009. Nor were they identified in the FDA mandated review in 2010. In the cases of Barndt and Duncan, the two patients who died because major bleedings, the unblinded clinicians whose care they were under during the trial, listed them as having died from a cardiovascular event. Documents released during US litigation, however, showed that in neither case did clinicians fill in a major bleed case report form. Completion of the form, to be sent to the blinded adjudicator along with the patient's medical history, was required by the trial protocol, and both Duncan and Barndt were in the dabigatran arm of the trial. Three times the number of bleeds in the RE-LY trial had been evaluated, the first time during the trial itself , the second time in the FDA mandated review, and the third time in a recently "targeted" review prompted by information uncovered by lawyers acting for the families. The third evaluation found eight unreported fatal bleeds, three in the dabigatran 110 mg. arm of RE-LY, two in the 150 mg. arm, and three in the warfarin arm. Both the FDA and the EMA are aware of this review. It has also emerged, and Boehringer Ingelheim has confirmed it to the BMJ, that the FDA mandated review was conducted by company scientists and overseen by the company's most senior executive, Andreas Barner, who was spokeperson for the board of managing directors and responsible for research and development in medicine at that time. Deborah Cohen , the author of this paper published on BMJ,  asks : "Why did the regulators allow this level of involvement from senior executives when so much was at stake? And is this acceptable?". Steve Nissen, department chair of cardiovascular medicine at the Cleveland Clinic and one of the members of the FDA's advisory committe considering dabigatran for use in non-valvular atrial fibrillation said to BMJ : "With regard to collection of cardiovascular event data, it is imperative that ascertainment of cardiovascular events be performed by a committe completely independent of the sponsor and fully blinded with respect to the assigned treatment group. Involvement by the sponsor in the adjudication process undermines the scientific integrity of any trial and can potentially result in inaccurate conclusions. Such involvement is not acceptable". (31) (BMJ 2014 vol. 349 mpp. 4747) Another consideration is the great difference of number of patients recruited in different cities in the RE-LY trial. For example Joué-Lès-Tours in France (Population of about 40000 people) ranks as the 1st by the number of patient recruitment centres (n=18) among RE-LY locations distributed across 43 countries (according to the clinical trials.gov.registry) or 44 Countries according to the RE-LY trial. A close city to Joué-Lés-Tours (Angers population about 300000 people) ranks 3rd by the number of locations (n=11) and only one patient recruitment centre was located in Paris. France also ranks 1st in Europe by number of RE-LY locations (clinicalTrials.gov) but the country is absent in the EudraCT registry. Israel is not a location of patient recruitment in the RE-LY registry but appears in the registry of their extension study RELY-ABLE (26 patient recruitment centres) and the NEJM 2009 publication (24 investigators recruited at least 12 patients). There are many other inconsinstencies in the ClinicalTrials.govlocations of RE-LY and RELY-ABLE. (www.bmj.com/content/349/bmj.g4747/rapid-responses)  Another paper published always by BMJ in July 2014, described that analyses conducted by Boehringer Ingelheim showed that in August 2011 the company had calculated that there was an optimal plasma concentration range of the drug. In June 2012 another analysis showed that measuring blood dabigatran concentrations and changing the dose as needed could reduce major bleeds by 30-40% in comparison with well controlled warfarin. The analysis concluded : "Optimally used (=titrated) dabigatran has the potential to provide patients an even better efficacy and safety profile than fixed dose dabigatran and also better safety and efficacy profile than a matched warfarin group". But the results of these studies were not comunicated to the regulatory agencies and emails showed that Boehringer Ingelheim employees were reluctant to release the information as it could affect sales. Thomas Moore of the US Institute for Safe Medication Practices and collegues, already cited above, said that regulators should recommend plasma concentration testing in all new patients and eliminate the recommendation that dabigatran "does not in general require routine anticoagulant monitoring". (35) BMJ 2014 vol. 349 pp.g4756) Charlton Blake and Rita Redberg, professor of Medicine at the University of San Francisco, in a paper published in July 2014 by BMJ made some considerations. The RE-LY trial was the single pivotal trial for dabigatran. Boehringer Ingelheim applied for fast track approval premised on the novelty of fixed dose rather than an assessment after the completion of two randomised clinical trials as required under standard approval procedures. (36) (BMJ 2014 vol. 349 pp. g4681) In addition the FDA issued a reassuring "drug safety communication" after data from its pilot electronic programme (Mini-Sentinel, www.mini-sentinel.org) indicating that dabigatran's risks were less than warfarin's. However a meta-analysis of randomised controlled trials examining risk of gastrointestinal bleeding with dabigatran and warfarin obtained completely different results. In this study a total of 4 total Randomised Clinical Trials (RCTs) enrolling 26076 patients were included. On meta-analysis, dabigatran significantly increased the risk of GI tract bleeding, compared with warfarin and the results remained the same with the random-effects model. In this study there were 16074 GI tract bleeding events with dabigatran and 10002 events with warfarin. On the contrary, using the Mini-Sentinel Database, the FDA obtained a GI tract bleeding rate of 1.6 with dabigatran and 3.5 with warfarin (per 100,000 days at risk). With this analysis, the agency concluded that GI tract bleeding rates are not higher, and indeed lower with dabigatran, releasing a reassuring report about the bleeding risk of this drug. The discrepancy between these results is really wide. The meta-analytic results of the RCTs have very narrow confidence intervals and no heterogeneity, demonstrating the increased risk of GI tract bleeding with dabigatran compared with warfarin undoubtedly. However, the Mini-Sentinel Program reports a greater than 50% decrease in GI tract bleeding with dabigatran compared with warfarin. Observational studies like the Mini-Sentinel Program have several sources of bias and because of their limitations, the approval process of drugs is based on RCTs only. The authors conclude that in case of dabigatran, the results generated by this program are contradicted by the results obtained using RCTs which represent the "gold standard" to evaluate the efficacy and safety of a drug. Examination of the reasons behind this contradiction by the FDA, may help to understand and improve the reliability of this program. (37) (JAMA Internal Medicine 2014 vol. 174 (1) pp. 150-151) In addition to bleeding risks identified in RE-LY, other methodological concerns include the fact that dabigatran was blinded while warfarin was not blinded and that RE-LY used an intention to treat analysis, which may bias it toward non-inferiority. Litigation revealed internal documentation that the company failed to disclose that monitoring might reduce risk of stroke and bleeding. The investigators conclude that a more transparent process of data collection and review would make important clinical data available without waiting for litigation as it happened with Boehringer in case of dabigatran and as it is also described in an article of The New York Times ( February 7, 2014) www.nytimes.com/2014/02/08/business/new-emails-in-pradaxa-case-show-concern-over-profit.html) (36) (BMJ 2014 vol. 349 pp. g4681)  Chan and collegues conducted a prospective observational study of 100 patients with atrial fibrillation (AF), peak and through levels of dabigatran were measured with the Hemoclot assay at baseline and every 2 months thereafter with a maximum of four visits. The results of their study showed that there is greater between-patient variability (gCV = 51-64%) than within-patient variability (gCV = 33-40%) in plasma dabigatran levels as measured by Hemoclot assay. They affirmed that the inter-patient variability was consistent with that observed in other studies including the RE-LY substudy (11) (Journal of The American College of Cardiology 2014 vol. 63 pp. 321-328) and was similar in magnitude to the variability reported with low-molecular-weight heparin and fondaparinux which are given in fixed doses like dabigatran. I think that we cannot compare variability of drugs that have different pharmacokinetics and pharmacodynamics and consequently the fact that LMWH and fondaparinux are given in fixed doses, this certainly does not mean that we can also use dabigatran in fixed doses without laboratory monitoring. They say that their findings are in contrast with those of RE-LY because in the RE-LY study, patients were randomly assigned to the two doses of 150 mg and 110 mg. and on the contrary, in their study informed physicians selected the lower dose based on known clinical characteristics of patients which could be correlated with increased bleeding risk and consequently with drug levels. In my opinion, it is not possible to obtain correct information on such an important issue like laboratory monitoring of a drug, affirming that were obtained similar levels of drug exposure in patients given dabigatran dose of 110 mg or 150 mg. because physicians correctely selected patients who, in their opinion, needed the lower dosage of 110 mg., due to the variability of physicians opinion in the so called "real world". I do not think that this is a correct scientific approach. On the other hand, I am really surprised by their other conclusion that because serial measurements of drug concentrations over a 6-month periods showed that up to 40% of patients whose baseline trough levels were in the upper 20th and 10th centiles had subsequent levels that no longer fell within these respective extremes and that an even 80% of patients with a single low trough measurement did not have subsequent levels in the low extremities, the use of a single Hemoclot measurement does not identify patients with extreme drug levels, considered the large variability related to the time of blood collection for trough levels (median of 13.3 +/- 4.7 hours after the last ingested dose). In any case I hope that in the future we will have more information on how and when correctely perform a laboratory monitoring of dabigatran, not only to identify high or low responders. After having emphasized the results of their study, they concluded that however there were two limitations. The first was related to the intra-patient variability because only 50% of subjects underwent testing at all four time-points, and the second was due to the low sensitivity of the Hemoclot test  (30 ng/mL) which was not able to distinguish between low drug levels and absence of the drug. Other objections about their study are well point out by a subsequent comment.  (38) (Journal of Thrombosis and Haemostasis 2015 vol. 13 pp. 353-359) Douxfils and collegues commented that Chan and collegues revealed an impressive 17 fold variation in plasma concentrations (from < / = 30 to 510 ng/mL) at trough (median of 13.3 +/- 4.7 hours after the last drug intake) with an interpatient geometric coefficient of variation (gCV) of 63.8%. This variation was also important when plasma level was assessed at peak (median of 2.5 +/- 0.2 hours) after the drug intake) with an interpatient gCV of 50.9%. In addition they said that plasma levels were similar at baseline and 2, 4, and 6 months. (39) (Journal of Thrombosis and Haemostasis 2015 DOI: 10.1111/jth.12880) The greater variability observed at C trough is questionable as a study of Douxfils and collegues  (40) (Thrombosis and Haemostasis 2015 vol. 113 pp. 862-869) and another study (41) (Journal of Thrombosis and Haemostasis 2011 vol. 9 pp. 2168-2175) showed lower variability in samples taken at trough. The variability of the median delay since the last drug intake is more important for blood taken at trough (4.7 h) than at peak (0.2 h), which certainly explains an important part of this discrepancy. This is a very important limitation of Chan and collegues' study. In addition Douxfils and collegues affirmed that results of the intraindividual variability are even more equivoque. Chan et al. found gCVs of 32.9% and 39.5% for trough and peak levels, respectively. Based on the 100 patients screened at baseline, they defined the upper 20th centiles (n = 20 patients) as equal to 129 ng/mL . Trough plasma levels remained above that threshold in 88.2%, 80.0%, and 70.0% of  patients at the 2, 4, and 6 month visit, respectively. Similar analyses were performed for the upper 10th centiles (Plasma level of 180 ng(mL and n= 10 patients) and in the lower 20th percentiles (Plasma level of 38 ng/mL and n= 20 patients). Based on these results, they affirmed that "over the six months measurement of drug concentrations up to 40% of patients whose baseline trough level were  in the upper 20th and 10th centiles had subsequent levels that no longer fell within these respective extremes. In addition about 80% of patients with a single low trough measurement did not have subsequent level in the low extreme and for this, as cited above, a single Hemoclot measurement does not identify patients with extreme drug levels. Douxfils and collegues believe that these conclusions must be interpreted with caution for many reasons. First, the lack of individual data does not let us make firm conclusions regarding the concept of a single Hemoclot Thrombin Inhibitor measurement. Namely, it is not possible to assert if it was the same patient  who no longer fell within these respective extremes. In addition, from the 20 patients identified on the threshold of 129 ng/mL (the 20th centiles at baseline), data at 2, 4, and 6 months were available for only 17, 10, and 10 patients, respectively and the fact that 50% of patients were not included at all stages of follow-up is a limitation. Another important limitation, for trough plasma data, is the median value of the delay since the last drug intake had an impressive variation of +/- 4.7 hours. Thus, a patient initially identified above the threshold of 129 ng/mL can be normalized due to the  fact that delay since the last intake is more important at the 2, 4, or 6 month visit. For the 20th lower percentiles, Chan and collegues said that the test used had a limit of quantitation of 30 ng/mL. (39) (Journal of Thrombosis and Haemostasis 2015 DOI: 10.1111/jth.12880) The recent study of Douxfils and collegues demonstrated  that for concentrations of < / = 30 ng/mL, it is more appropriate to use a test dedicated [Hemoclot Thrombin Inhibitors LOW (HTI LOW) kit or the STA -ECA II (ECA-II) kit, a chromogenic variant of the ecarin clotting time] to measure these low levels and probably not only < 30 ng/mL.  (41) (Thrombosis and Haemostasis 2015 vol. 113 pp. 862-869). (see section on "Laboratory Tests"). Moreover, other preanalytical and analytical laboratory key information is still lacking. For example it is not possible to know if different batches of the Hemoclot Thrombin Inhibitor assay have been used, and also the delay between the blood sampling and the congelation is not stated.  Douxfils conclude that these limitations clearly highlight that the conclusion of Chan and al. need to be "toned down". Several criteria should be taken into consideration when considering proper drug monitoring : 1) a high intraindividual and 2) high interindividual variability in drug level, both justifying identification of the optimal dose for each patient at the start of treatment; 3) a low variability and good reproducibility in the assay method; 4) a correlation between drug level and clinical event; 5) the demonstration of the value of the therapeutic drug monitoring.(13) (Jourmal of Thrombosis and Haemostasis 2010 vol. 8 pp.621-628) Although a previous simulated pharmacokinetic analysis from the RE-LY study stated that a 6 hours delay might put trough level outside the variability of a typical AF patient, (42) (Journal of Thrombosis and Haemostasis 2011 vol. 9 pp. 2168-2175) Douxfils and collegues concluded that a well designed study, assessing the plasma level with adequate coagulation tests and restricting the delay since the last drug intake for the trough measurement at 12 +/- max 1 hour, is required to obtain accurate information on the usefulness of a single measurement to identify high or low responders. (39) (Journal of Thrombosis and Haemostasis 2015 DOI: 10.1111/jth.12880) They pointed out that as cited above, the high intraindividual and interindividual variabilities in dabigatran plasma levels are clearly demonstrated. (11) (Journal of the American College of Cardiology 2014 vol. 63 pp. 621-628) Chan and collegues reply that the study by Douxfils et al. restricted inclusion to patients (n = 33) with plasma dabigatran levels < 200 ng/mL  and they say that because they enrolled unselected clinic patients, their results are likely to be more representative of the variability in through level seen in clinical practice. In addition they say that Douxfils et al. propose that the differences in sampling times may have led to overstimation of interindividual and intraindividual variabilities in trough level and recommend that trough levels should be measured at 12 hours +/-  max 1 hour.  They found difficult to standardize trough sampling times (median time of collection was 13.3 + / - 4.7 hours after last dose) but they think that this did not affect their results because in the study of Liesenfeld et al. (41) (Journal of Thrombosis and Haemostasis 2011 vol. 39 pp. 2168-2175) sampling at 18 hours after dabigatran administration for a typical patient should not result in the pre-dose level falling outside the 80% confidence interval for a 12 hours trough level and similarly, sampling at 6 hours after administration should not result in a pre-dose level outside the 80% confidence interval for a 12 hours trough level. May this be considered a scientific approach ? Absolutely not. In addition they conclude saying that they wanted estimate variability in drug levels within and among patients over time, but not to examine clinical outcomes, as the correlation between drug levels and clinical outcomes were a secondary problem. Contrary to the assertions by Douxfils et al. they believe that their results for interindividual and intraindividual variabilities in dabigatran levels are robust but I absolutely do not think that their statement is correct. (42) (Journal of Thrombosis and Haemostasis 2015 DOI: 10.1111/jth.12906) Papers celebrating the advantages of new oral anticoagulants also in thromboprophylaxis after elective hip and knee arthroplasty, continue to be published. (43) (ATVB 2015 vol. 35 pp. 771-778) (see also review on rivaroxaban) However dabigatran has been approved for thromboprophylaxis in patients undergoing a hip or knee replacement surgery in Europe and Canada but not in the United States. Although it seems that there is a certain advantage in the use of rivaroxaban and apixaban in these cases, considered the less incidence of the primary efficacy outcome, which was the composite of deep vein thrombosis (either symptomatic or detected by bilateral venography if the patient was asymptomatic), non fatal pulmonary embolism, or death from venous thromboembolism, this advantage is clear when as thromboprophylaxis is used a dosage of 40 mg. of enoxaparin daily on the basis of  European guidelines, and is less clear when it is used a dosage of 30 mg. of enoxaparin twice daily on the basis of US guidelines. On the other hand, until an antidote will not be commercial available I do not think to use these drugs in these indications, considered the short period of tromboprophylaxis (14 days in case of knee replacement surgery and 35 days in case of hip replacement surgery) and the deep knowledge of enoxaparin that we have, due to many years of its clinical use.
Recently, Dr. Darlene Elias MD, Director, Anticoagulation Services, Division of Pulmonary and Critical Care Medicine, Scripps Clinic and Scripps Green Hospital, La Jolla, CA, USA, during the 8th North American DAWN AC user group meeting, 21^st november 2014, showed an analysis of the percentage of adverse events by severity per patient year in their large patient base of about 3,000 patients. The percentage of major bleedings per patient year was much lower than the warfarin major bleed percentages reported by the DOACs trials such as RE-LY (TTR 64.0%), RECOVER (TTR 60.0%), ROCKET-AF (TTR 55.0%), EINSTEIN-DVT (TTR 57.7%), EINSTEIN-PE (TTR 62.7%), ARISTOTLE (TTR 62.2%), and AMPLIFY (TTR 61.0%). As can be seen, in none of these trial was reached an optimal TTR that can considerably reduce the incidence of all adverse events, notably major bleedings in patients in treatment with vitamin K antagonists.  In conclusion, the dabigatran "saga" continues, but it is becoming increasingly difficult to hide the truth, and that is that dabigatran treatment and very probably treatments with all the other direct oral anticoagulants such as direct factor Xa inhibitors, need laboratory monitoring.    

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