Anticoagulanti Orali Diretti
During these last years many papers about new oral anticoagulants have been published.
Drugs manufacturers invested a lot of money in the development of these drugs and clearly now they want to recover their money and eventually to earn other money. The pressure of these powerful pharmaceutical companies which naturally are profit organization, is really impressive. The money involved in the treament of patients with these new oral anticoagulants is a very big amount, billion of dollars. It easy to understand that when is involved such a big amount of money, “shadowy behaviours” on behalf of pharmaceutical companies, health Institutions and physicians who are “ key opinion leaders” are very probable, especially when some health institutions receive an important percentage of their budget from donations from the medical industry. The fact that a drug is approved for the treatment of patients with a certain disease by regulatory agencies, does not mean that this drug must be used in all the patients with that disease. Probably that drug will be useful in a small amount of those patients with that disease as is the case of Non Vitamin K Antagonists Oral Anticoagulants (NOACs) or using a better definition, Direct Oral Anticoagulants (DOACs), but if we use correctly these drugs in selected cases in which they are really useful,clearly the pharmaceutical companies will not earn a lot of money. For this reason, the pressure of drug manufacturers is so impressive through sponsorizations of National and International Meetings, of Medical Societies, through consultancies of physicians who are key opinion leaders, through donations to well-known Medical Research Institutions, through sponsorization of clinical studies which in the majority of cases are non-inferiority trials and not superiority trials which are “the gold standard” to demonstrate without any doubt the superiority of a drug compared with another drug 1. However, the pharmaceutical companies are not interested to demonstrate the superiority of new oral anticoagulants compared with vitamin K antagonists but just to try to demonstrate that they are more manageable principally because they do not need laboratory monitoring. Unfortunately for them and for their official and “non official employees” now we know that this is not true. For dabigatran we know from an internal report of Boehringer Ingelheim of 2011 , that there is a reduction of 30-40% of bleeding events by laboratory monitoring and 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” 2 , confirmed by two papers 3,4 and because of a marked intra- and inter-individual variability now demonstrated also for rivaroxaban 5,6 , apixaban 6,7,8 and very probably for edoxaban too. In a recent large study a high intra-and inter-individual variability for dabigatran, rivaroxaban and apixaban was demonstrated 9 . Their laboratory monitoring very probably will reduce adverse events, in particular bleeding events. For this, we need clinical studies in which should be compared patients in treatment with new oral anticoagulants without laboratory monitoring with patients in treatment with the same drugs but with laboratory monitoring by appropriate tests. Only by these studies we will able to show the incidence of the adverse events, in particular bleeding events, in the two group of patients and, as showed for dabigatran, if will be showed a significant reduction of bleeding events without an increase of stroke events in patients controlled by laboratory monitoring, will they continue to say that these drugs do not need laboratory monitoring ?. Why the pharmaceutical companies do not sponsor these studies ?
Because very probable they already know the favorable results which can be achieved by laboratory monitoring and clearly these direct oral anticoagulants would lose their principal commercial appeal. In fact, during litigation was revealed an internal mail discussion about the potential merit of dabigatran 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” 2 .EMA documents from early 2010 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 risk of bleeding”. A spokerperson for Boehringer said that the company “never told EMA or any regulatory authority that 200 ng/ml was a level not to be exceeded” 2 . In addition, internal emails released during US litigation show that Andreas Clemens, a medical leader for the drug dabigatran, stated that he was “phobic” and “not happy with the conclusion” that an optimal balance between benefit and risk occurs in a range of concentrations between 40 ng/ml and 215 ng/ml. Clemens also wrote “ The world is crying for this information but the tricky part is that we have to tailor the message smart” 2 . (For details see the abstract section of Dabigatran review)
Now what is really strange is that if for politicians in Europe and North America to avoid constant criticism is much better not have conflicts of interests, also because in some cases they can be forced to resign, in case of physicians this unwritten rule does not exist. As a consequence, physicians who received consultancy fees or other kind of honoraria for conferences, etc. from pharmaceutical companies and in some cases even if they are included in the board of these pharmaceutical companies, they can write and publish on leading medical journals papers about drugs manufactured by the companies from which they received honoraria and in addition in many cases the same publication is funded by the pharmaceutical companies. This is really unbelievable. Is it possible to be reliable just declaring the conflicts of interests at the end of the paper ? I think not. Transparency is essential , but is not sufficient to eliminate bias or perception of bias. Now I report exactly the words used by the authors in an article published by the British Medical Journal whose title Is : Medical journals and industry ties. Zero tolerance on education articles with financial links to industry 10 . The words are : “This risk of bias is particularly important for clinical educational articles that are designed to guide patient care, when authors’ biases may be less visible to general medical readers. For some years we have sought to minimise as well as declare competing interests for these articles. Recently we introduced more active management of competing interests, requiring authors to complete a more detailed declaration and excluding authors with close ties. From the next year our clinical educational articles will be authored by experts without financial ties to industry. By industry we mean companies producing drugs, devices, or tests; medical education companies; or other companies with an interest in the topic of the article. We are phasing in this policy to start with editorials, clinical reviews, and most practice series. We hope that by the end of 2016, this will have extended to the rest of our education section : our specialist state of the art reviews and diagnostics and therapeutics series” 10 . The authors say that the principal reason for doing this is that “making clinical decisions based on information biased by commercial interests can cause harm, as happened with cardiotoxicity from rosiglitazone and rofecoxib “ 10,11,12 . Another medical journal, the American Family Physician, which primarily publishes clinical reviews, for over twenty years has not considered articles by authors who have financial ties with industry. I report the words written in the conflict of interest form of this journal : “ To avoid bias or the perception of bias, AFP will not consider manuscripts sponsored directly or indirectly by a pharmaceutical company, medical education company, or other commercial entity or those written by an author who has a financial relationship with or interest in any commercial entity that may have an interest in the subject matter of the article within the previous 36 months or in the foreseeable future. It also includes serving on a commercial speaker’s bureau or advisory board, or receiving commercial research support related to the subject matter of the article, as well as other relationships detailed in our conflict of interest policy” 13 . Considering the policies of these journals, all the articles about new oral anticoagulants should not have been accepted for publication. I hope that in the future all the leading medical journals will adopt the same policy adopted by these two journals to restore dignity to clinical medical research and to give our patients really the best of medical progress. Public and private research institutes should not forget their key role in the modern society and should adopt a strict ethical policy accepting funds from governmental institutions and from private donations only, refusing any kind of financial support from the medical industry. On the other hand, governmental institutions should start to fund all the clinical trials which involve the efficacy and safety of a new drug although this may be expensive, because the public money they will invest will return to the society in terms of improved public health.
The health and life of only one patient, are much more important than the budget of many pharmaceutical companies.
1) Garattini Silvio, Bertelè Vittorio : Non-inferiority trials are unethical because they disregard patients’ interest. The Lancet 2007; 370 : 1875-1877
2) Cohen Deborah : Dabigatran : How the drug company withheld important analyses. British Medical Journal 2014; 349:g467023)
3) Douxfils J., Mullier R., Robert S. et al. : Impact of dabigatran on a large panel of routine or specific coagulation assays. Laboratory recommendations for monitoring of dabigatran etexilate. Thrombosis Haemostasis 2012; 107 : 985-997
4) Reilly P.A., Lehr T., Haertter S. et al. : The effect of dabigatran plasma concentration and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients : The RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). Journal of the American College of Cardiology 2014; 63: 321-328
5) Samama M.M., Guinet C., Le Flem L. et al. : Measurement of dabigatran and rivaroxaban in primary prevention of venous thromboembolism in 106 patients who have undergone major orthopedic surgery : an observational study. Journal of Thrombosis and Thrombolysis 2013: 35 : 140-146
6) Gong Inna Y. and Kim Richard B. : Importance of pharmacokinetic profile and variability as determinants of dose and response to dabigatran, rivaroxaban, and apixaban. Canadian Journal of Cardiology 2013; 29: S24-S33
7) Freyburger Geneviève, Macouillard Gèrard, Khennoufa Karim et al. : Rivaroxaban and apixaban in orthopaedics : is there a difference in their plasma concentrations and anticoagulant effects ? Blood, Coagulation and Fibrinolysis 2015; 26 : 925-933
8) Skeppholm Mika, Al-Aieshy Fadiea, Berndtsson Maria et al. : Clinical evaluation of methods to monitor apixaban treatment in patients with atrial fibrillation. Thrombosis Research 2015; 136 : 148-153
9) Testa Sophie, Tripodi Armando, Legnani Cristina et al. : Plasma levels of direct oral anticoagulants in real life patients with atrial fibrillation : Results observed in four anticoagulation clinics. Thrombosis Research 2016; 137 : 178-183
10) Chew Mabel, Brizzel Catherine, Abbasi Kamran et al. : Medical journals and industry ties. Zero tolerance on education articles with financial links to industry. BMJ 2014; 349 : g7197 doi: 10.1136/bmj.g7197
11) Krumholz H., Ross JS, Presler AH et al. : What have we learnt from Vioxx ? BMJ 2007; 334 : 120
12) Moynihan R. : Rosiglitazone, marketing, and medical science. BMJ 2010; 340 : c1848
13) Conflict of interest form – American Family Physician www.aafp.org/journals/afp/authors/guide/coi.html