Hugo Ten Cate ^1,2*

• ¹ Internal medicine, Maastricht University Medical Centre, Maastricht, Netherlands
• ² University Medical Centre, Johannes Gutenberg University Mainz, Mainz, Rhineland-Palatinate, Germany

Introduction Over the past decades, anticoagulant medication has changed dramatically. During the past century (1950 onwards) the use of heparins and vitamin K antagonists (VKA) became common practice for prevention and treatment of venous thromboembolism (VTE), prevention of stroke in atrial fibrillation (AF), and other indications (1). From the 80-ies onwards, the introduction of low molecular weight heparins (LMWH) led to rapid replacement of unfractionated heparin for prevention and (initial) treatment of VTE (2). Subcutaneous administration of LMWH allowed for ambulatory management of many patients (3). From the 90-ies onwards, the introduction of direct oral anticoagulants (DOAC, also known as “NOAC”) led to a similarly rapid replacement of VKA for the major indications involving prolonged oral anticoagulation, VTE and AF (4,5). The basis for this pharmaceutical transition was established by the immense gain in knowledge of structure and function of coagulation enzymes and their natural inhibitors. Many years of research by academics and pharmaceutical companies alike paved the way for the successful marketing of LMWH, danaparoid and the synthetic glycosaminoglycan molecule fondaparinux (6,7). The development of DOAC was led by company-based researchers that spent many years on identifying suitable small molecules with the desired specificity for their target (thrombin or factor Xa), but also with the appropriate characteristics to allow oral ingestion and adsorption from the gastrointestinal tract, and with pharmacological properties enabling once or twice daily dosing (8-10). The high quality of this research and the successful translation to clinical trials and subsequent implementation cannot be overestimated. Large clinical trials comparing DOAC with VKA showed non-inferior or superior efficacy as well as safety, vs VKA (warfarin), with a class effect of reduced intracranial bleeding for all DOAC (11,12). Due to these encouraging features, coupled with strong marketing publicity, DOAC flooded the “markets”; the large volumes of patients with VTE and particularly AF, meant big business worldwide. The downside of this success story may have been that there was little time left for reflection on possible hurdles and caveats. Which caveats could have been foreseen? One of the key differences between the “old” (heparins, VKA) and “new” anticoagulants was moving from a laboratory guided therapy towards a fixed dose policy. For heparins, aPTT controlled therapy had been important (in case of iv dosing), for VKA determination of the prothrombin time (translated into International Normalized Ratio, INR) was and remains pivotal to titrate the optimal dose for the individual patient (13,14). Ideally, VKA management is supported by trained anticoagulation service personnel; in countries like the Netherlands there still is an efficient network of anticoagulation clinics (“Trombosediensten”). With the introduction of DOAC, these anticoagulation clinics did not play any role of importance, leaving DOAC management to the prescriber and general practitioner with support from the pharmacy. In practice, my impression is that this vulnerable system of follow up of patients on DOAC is suboptimal. My international colleagues have oftentimes done the suggestion to use the system of existing anticoagulation clinics for organizing annual checks for patients on DOAC and to serve as a helpdesk for questions from patients and caregivers. However, the Dutch insurance companies have consistently deferred any serious discussions on such initiatives, on basis of the added costs of these clinics to the already expensive DOAC; now that most of these drugs are or will be generic, the cost argument becomes less important. In fact, even today one insurer actively promotes to replace remaining VKA use as much as possible by DOAC and to scale down anticoagulation clinics into centralized “desks” for dosing, which is bizarre as remaining patients on VKA are even more complex than before. How to improve DOAC management? Patients on DOAC deserve proper drug management, like for drugs taken to treat diabetes, hypertension or hypercholesterolemia. So-called cardiovascular risk management for patients with AF, is a successful instrument in our country. DOAC control is only occasionally part of this system, while general knowledge on indications, mode of action, drug-drug interactions (DDI), pharmacology, and side effects, is poor among patients and caregivers (DUTCH-AF study, submitted). It is probably a combination of these factors that underlies the surprising outcomes of the Dutch FRAIL-AF study in frail elderly patients with AF, showing that the conversion from VKA to DOAC led to more bleeding complications as compared to continued VKA, without any reduction in thromboembolic complications (15). While there can be debate about several trial elements, including selection bias (only patients already on VKA enrolled), the outcomes should have triggered concern about the quality of DOAC care in this country, at this moment. Most likely, DOAC are suitable drugs also in frail patients, as shown by others (16), but the demonstrated inferior safety, even for hemorrhagic stroke, is alarming. A consequence must be to critically revise our follow up system for DOAC, focusing more on proper patient information and guidance, addressing avoidable problems like suboptimal dosing, based on inappropriate subjective arguments (frail patient, prone to fall and bleed), but also based on lack of insight in individual pharmacodynamics, especially in an aging population. A place for DOAC monitoring? There has been much debate about the need for laboratory monitoring of DOAC and it is a pity that this discussion wasn’t more broadly held at the introduction of these agents (17). It could be foreseen, as is recognized in most current guidelines, that at least in acute settings like major bleeding or thromboembolism, while on DOAC therapy, or in peri-procedural settings like surgery, or thrombolysis, there would be a need for determination of a DOAC plasma level, preferably even by point-of-care (POC) device; the INR still is an undisputed biomarker for VKA in the emergency setting. Still, the adagio remained “no monitoring necessary” for a long time. The result is that even after > 15 years of DOAC use, a POC assay is still lacking, except for a rapid urine test (18). Another assumption at onset was that DOAC would be markedly safer, driven by the class effect of less intracranial bleeds. The implicit conclusion was that reversal agents would not be really needed, in absence of frequent life-threatening bleeding complications, an unfortunate misconception. The positive exception was the Boehringer company that rapidly after introducing dabigatran decided to also develop a specific reversal agent; the monoclonal antibody fragment idarucizumab is a rapidly acting reversal agent without intrinsic procoagulant properties (19). Factor Xa inhibitor producing companies decided not to invest in developing reversal agents, maybe understandable from their short-term financial outlook, but not from a societal perspective where thousands of patients take a daily dose of a potentially harmful Factor Xa inhibitor without proper antidote available. The idea that in case of major bleeding prothrombin concentrate would be sufficient has been essentially refuted by the recent Andexa-I study outcomes, showing superior hemostatic effect of the reversal agent Andexia for intracranial bleeding, as compared with prothrombin complex concentrate (20). The fact that there still is debate on the costs and adverse effects of Andexia is relevant and the need for refinement of this and other reversal agents is evident, but the fact that this discussion takes place while most DOACs are already getting out of patent illustrates the lack of careful thinking upfront when developing these potent factor Xa targeted DOAC. Anticoagulation in a frail elderly population Except for acute situations like major bleeding, there should be further discussion and study regarding application of DOAC in frail elderly patients, as this population is increasing among those with AF. Our recent work and that of others clearly show concerning deviations of plasma DOAC levels when compared with on-therapy ranges derived from the initial large trials (21-23). Importantly, excess plasma levels are associated with bleeding risk (24,25). Most concerning is that it is not immediately evident what the reasons are for deviating, especially too high, plasma concentrations; mostly it is not directly linked to wrong dosing or renal insufficiency. For the time being this may mean that in practice, a check of plasma level over the age of 75 years or so, may be worth to explore whether a specific DOAC is appropriate for a given subject, certainly in case of frailty and other potential factors like DDI and renal impairment. While this policy may raise criticism based on lack of proper pharmacokinetics when sampling single blood draws, inappropriate use of on-therapy ranges and so forth, common sense may suffice to at least estimate whether the used DOAC is reasonable to begin with, or should be replaced by another, or tailored in dose within registered ranges. Obviously, clinical trials need to address the potential utility of DOAC laboratory monitoring for establishing long term safety among frail DOAC users. Lastly, one should be aware of VKA as a more than reasonable alternative. VKA remains a proper alternative for DOAC Many starting physicians will have hardly any experience with VKA, so this alternative to DOAC is hardly ever considered in practice, is my observation. Many think that VKA are old fashioned (correct), complex (partially correct) and dangerous (not correct, at least not much worse than DOAC). However, important indications for VKA remain in place, as DOAC were inferior in patients with mechanical heart valves, antiphospholipid antibody syndrome (at least in those with triple positive antibodies) and moderate to severe mitral valve stenosis associated AF (26). Moreover, the practical advantage of VKA is the managed care, which, when organized properly provides individual tailoring that considers all possible factors including DDI and renal impairment. For patients with anticipated poor drug adherence, this may also be an advantage of VKA over DOAC. VKA have the disadvantage of increased vascular calcification and perhaps negative impact on renal function in those with renal insufficiency (27,28). Surprising advantages of VKA may be increased survival in subjects with cancer (maybe due to inhibition of specific proteins like Gas-6) (29), as well as in patients with AF, at least while on phenprocoumon, the single VKA in Germany (partially explained) (30); as compared to Factor Xa inhibitors, patients on dabigatran had a comparable survival advantage. This possible survival benefit, while prone to bias, sheds new light on this old class of agents and may be reassuring for those who feared that VKA, when indicated, would cause more harm (eg vascular calcification) than benefit. Altogether, one should not discard VKA as a treatment alternative even in frail elderly with AF, provided that a good time in therapeutic range is achieved; the latter is best obtained with phenprocoumon, but this medication is not available in many countries, unfortunately. The German colleagues appropriately call for a randomized trial to assess the merits of phenprocoumon against DOAC (30). Place for new anticoagulants? Finally, following initial enthusiasm about DOAC, we are entering a period of greater realism regarding the limitations in safety of DOAC (and VKA), with remaining annual risk of major bleeding of at least 2-3% on average, and substantial variation among individuals that is hard to predict with current risk scores. The hope among pharmaceutical companies (and their investors) is that safety can be further enhanced by addressing other targets, including factor XIa (31). On the one hand, this wishful thinking stems from observational data from patients with congenital factor XI deficiency showing that it is associated with a low risk of spontaneous bleeding, in contrast to other hemophilias. On the other hand, epidemiological, genetic and experimental evidence indicates that FXI is associated with thrombus formation and is specifically linked to cardioembolic stroke and VTE. Data on atherothrombosis remain controversial (32-34). A proof of principle human study showed that FXI gene silencing with siRNA technology markedly reduced FX levels in blood and also achieved a substantial reduction in postoperative venous thrombosis in knee replacement surgery (35). A comparable efficacy was shown for other approaches, including monoclonal antibodies and the small oral molecule milvexian (36). Based on these studies phase 2 trials were designed in patients with VTE, but also with arterial vascular disease, including AF, acute stroke and acute coronary syndrome (ACS). Last year, the outcomes of several phase 2 trials were published. The data unequivocally show reduced bleeding risk as compared with apixaban, or rivaroxaban in the AF studies, and acceptable bleeding rates in patients with ACS or stroke (discussed in 37-39). However, none of these studies gave a clear signal about efficacy, which although not accounted for in phase 2, would have been of interest. Driven by optimism, phase 3 was initiated with studies in AF, the OCEANIC-AF and LIBREXIA-AF, with asundexian and milvexian, respectively (40,41). While the LIBREXIA-AF trial is still ongoing, the OCEANIC-AF trial was arrested after inclusion of close to 15,000 patients, due to excess ischemic strokes in the asundexian arm. The main paper was recently published, discussing potential reasons for failure (40). These included too low dosing (although in plasma samples there was well over 90% inhibition of FXIa), escape mechanisms that were not alluded to, but may include bypass activation of FIX by kallikrein (42); finally, the authors note that the background population may have markedly changed with less AF burden, explaining the overall low rate of embolic stroke. A final option, that FXI activation may not be so relevant in all subjects with AF, was not mentioned. All arguments shed doubt on the design of such large studies, where the contribution of FXI to thrombosis risk, the impact of the drug (dose) and possible escape mechanisms, including the kallikrein driven activation of FIX bypassing FXI, were apparently not sufficiently explored or considered. Unfortunately, the negative trial outcome may lead to scepsis regarding the concept of FXI inhibition, that may be preliminary and unjustified, in absence of mechanistic data. Conclusion and perspective Although anticoagulant treatment has improved markedly from a practical perspective, its safety remains at stake as the follow up of patients on DOAC is insufficient. This certainly concerns frail elderly with AF where VKA may even be better than DOAC, if VKA care is well managed. Attention must be on improving the quality of DOAC, including adherence to therapy, which may also require occasional assessment of DOAC plasma level in frail patients, to assess the suitability of drug and dose. When moving forward with novel anticoagulants, e.g factor XIa inhibitors, one should not only rely on wishful thinking but also carefully consider disease related thrombosis mechanisms in the very diverse patients, to be better prepared for and hopefully avoid, more large study failures.