Guidance for the antithrombotic management of persons with haemophilia and cardiovascular disease

Owing to the continuous progress of therapies for the haemophilias in the last 50 years,1 persons with these congenital coagulation disorders have attained a life expectancy very close to that of their unaffected peers. This fulfilment is inevitably accompanied by an increase of such age-related illnesses as cardiovascular disease (CVD).2 Until the last 10−15 years, health care providers of persons with haemophilia (PWH) addressed relatively little attention to these comorbidities,3-7 because prevention and treatment of bleeding were their primary and compelling goals. Moreover, it was felt that their hypocoagulable state would protect PWH from atherothrombotic and thromboembolic CVD. This paradigm was subsequently challenged by the demonstration that PWH have the same degree of atherosclerosis of their unaffected peers8, 9 and that arterial and venous thrombosis do occur in them, even though somewhat less frequently than in the general population.10, 11 Some of us have indeed faced the challenge of managing PWH who developed CVD and provided advice on how to handle the contrasting risks of thrombosis and bleeding, the latter enhanced by antiplatelet and anticoagulant drugs.12-14 Early How to Treat articles were based on the experience of large haemophilia centres and focused on how to tailor the management of the coagulation defect to the challenge of antithrombotic therapies prescribed for acute events and secondary prevention.12-19 Further, the French network of haemophilia centres elected to start and run a prospective registry (COCHE) of incident PWH who needed antithrombotic medications owing to CVD.20 Moreover, since 2008 the European Haemophilia Safety Surveillance program (EUHASS) is collecting information on adverse events occurring in haemophilia treatment centres and incident episodes of thrombosis are gathered.21 However, unmet needs remained pertaining to the antithrombotic management of PWH, because recommendations were largely informed by expert opinions in the absence of high quality data.12-19 Furthermore, the most recent therapeutic advances, such as emicizumab and gene transfer,1 were not taken into account. With this background and gaps of knowledge, the European Hematology Association (EHA) chose in 2021 to critically evaluate the published data on PWH with CVD and supply guidance for the concomitant management of the bleeding disorder and CVD by appointing an expert panel representing learned scientific organisations such as the International Society for Thrombosis and Haemostasis (ISTH) and the European Association for Haemophilia and Allied Disorders (EAHAD). Furthermore, the European Society of Cardiology (ESC) and the European Stroke Organisation (ESO) contributed with input from cardiologists and neurologists. The ensuing publication22 offers the most recent and comprehensive guidance that can be practically employed by those confronted with the painstaking scenario of handling at the same time thrombosis and bleeding in PWH. The clinical practice guidelines stem from the analysis of publications of non-randomised studies, observational studies including case series and case reports, as well as consensus documents based upon the Delphi methodology.22 Aware of the limitations inherent in these reports, the authors of the guidance document chose of not adopting the GRADE nomenclature but instead a simple, three-level ranking system offering from strong to weak recommendations.22 The whole clinical practice guidance contains six sections with 24 clinically relevant questions (Table 1). The answers to the questions have been discussed and reviewed among panel members during virtual meetings and correspondence, so that unanimous consensus was ultimately reached. Are PWH naturally anticoagulated? What is the FVIII/FIX threshold to safely start aspirin or oral anticoagulation in PWH? What is the bleeding risk in PWH using antiplatelet or oral anticoagulant therapy? Should clotting factor prophylaxis be adapted in PWH in need for anticoagulation therapy? If the decision for oral anticoagulation in PWH has been made, is there a preference for a specific type of drug? If the decision for oral anticoagulation in PWH has been made, is there a need for monitoring anticoagulation treatment and dose adjustment? Does the use of emicizumab suggest a safe threshold for antithrombotic therapy? What tool can be used for ischemic stroke risk assessment in PWH with AF? What tool can be used as bleeding risk assessment in PWH with AF? Is there a place for aspirin in the treatment of AF in PWH? What is the role for alternative strategies in PWH with AF, such as left atrial appendix closure or pulmonary vein isolation? Can systemic thrombolysis be given in PWH? Is there an indication for pretreatment with antiplatelet therapy in PWH with ACS before invasive (PCI) treatment? Is there an indication for clotting factor replacement in PWH before cardiac intervention? Which anticoagulant is preferred in PWH before and during PCI? Is there a formal bleeding risk assessment tool for bleeds in PWH with ACS? What type of stent is preferred in PWH with ASC? What DAPT regimen is preferred in PWH? How to manage valve replacement in PWH? Is routine thromboprophylaxis needed in PWH undergoing surgery or who are medically ill? Is the recommendation for routine thromboprophylaxis in PWH different according to the haemostatic product that is used (bypassing agents/emicizumab)? What is the management of an acute venous thromboembolic event in PWH? What is the optimal antithrombotic management of transient ischaemic attack in PWH? What is the antithrombotic management of acute ischemic stroke in PWH? The present commentary on the article by Schutgens et al.22 is written by a long-standing insider in haemophilia care,12, 19 who chose to enlist the input of a cardiologist and geriatrician with specific expertise on the aging PWH. Impressed by the clarity of the settings of the guidance blueprint (Table 1), we are convinced that it is a badly needed handbook to be widely consulted by those confronted with the clinical situations epitomised by the comprehensive and well-focussed clinical questions. We are also convinced that the current lack of RCT warranted to produce GRADE recommendations is unlikely to change in the next future, because it is difficult to envisage a scenario for funding and conducting RCTs on the optimal management of CVD in a rare disease such as haemophilia. With this preamble, we offer some comments about a few specific clinical questions. Clinical question 7 deals with the safe threshold of anticoagulants or antiplatelets in PWH who, while on prophylaxis with emicizumab, need these medications for the treatment of acute thrombotic episodes or their secondary prevention. The recommendation suggests an individualised approach based on the clinical indication that led to antithrombotic prophylaxis, as well as a word of caution for the long-term use of antithrombotic drugs in this situation. We believe that, at least in PWH without inhibitor, the issue is not that of the safety and duration of antithrombotic medications but that discontinuation of emicizumab should be implemented when these agents are warranted, with return to FVIII prophylaxis. Although the risk of arterial, venous and microvascular thrombosis has been scaled down following real-life use worldwide,23, 24 emicizumab-related safety concerns for an increased risk of thrombogenesis remain. The lack of a natural regulation of the FVIII mimicking activity of emicizumab and the long-term steady state of coagulation activation without the peaks and troughs associated with factor replacement are the pathophysiological basis for our concern.25 Further, in a recent real-world study analysing data from the EudraVigilance database, our Milan colleagues found a higher rate of thrombotic complications for emicizumab than extended half-life factor VIII products, although one third occurred during the concomitant administration of bypassing agents, particularly rFVIIa.26 On the whole, owing to the tiny number of older patients included in the pivotal trials and the scarcity of real-world data, further data are warranted to assert the safety of emicizumab in older PWH at very high risk of CVD. Thus, in PWH who need antithrombotic medications for whichever CVD and thus are by definition at a very high risk of thrombosis or re-thrombosis, we suggest to withdraw emicizumab, at least in PWH without inhibitors, because the recent availability of a FVIII product such as efanesoctocog with an ultra-extended plasma half-life allows these patients to continue prophylaxis with efficacy and acceptable quality of life.27 The clinical question 20 addresses the option of routine anticoagulant prophylaxis of venous thromboembolism (VTE) in PWH undergoing surgery. The substantially negative guidance of the panel is based on the alleged low prevalence of VTE in PWH, even though a recent report based on a claims database comparing 3490 PWH with 16.380 individuals in the general US population found that venous thrombosis was more frequent in PWH.10 We question that the conservative guidance of the panel regarding perioperative thromboprophylaxis is applicable to PWH undergoing hip and knee arthroplasty, that are the epitome of the surgical procedures that warrant thromboprophylaxis owing to a high risk of postoperative VTE. The approach of the panel not favouring prophylaxis is mainly based on an expert consensus that predicted a low DVT prevalence of .5% in PWH undergoing joint arthroplasty.28 This consensus is at variance with a prospective study that in 46 PWH undergoing hip or knee arthroplasty recorded a 4.3% prevalence of symptomatic VTE (both DVT and PE), similarly to that of a control non-haemophilia cohort off thromboprophylaxis.29 Considering that arthroplasty is frequently performed in PWH who are usually treated post-operatively for prolonged time periods and with very high doses of factors, we believe that pharmacological thromboprophylaxis should be implement in most cases, also because the alternative of mechanical prophylaxis is often not available in surgical theatres and wards. Clinical question 8: As reported by a meta-analysis30 CHADS2 and CHA2DS2-VASc scores have the same utility in predicting the risk of stroke and thromboembolism in atrial fibrillation (AF). Even though CHA2DS2-VASc includes a wider spectrum of stroke risk factors and is able to identify very low risk cases, we consider reasonable to prefer CHADS2 owing to the greater simplicity and practicality of this tool, maintaining the recommended cut-off value of ≥2 to start anticoagulation. Clinical question 9: We agree to consider all PWH at high risk of bleeding independently from scores, so that no prediction tools are warranted. However, as recommended by the ESC guidelines,31 in “high bleeding risk patients” treated with anticoagulants or antiplatelet agents it is important to implement a close monitoring and management of “potentially modifiable” or “modifiable” risk factors of bleeding such as severe frailty with risk of falls, anaemia, low platelet count, renal impairment, elevated systolic blood pressure and hazardous hobbies/occupations. Clinical question 11: Left atrial appendage occlusion (LAAO) is an effective alternative strategy in PWH with chronic AF, allowing the avoidance of long-term anticoagulation treatment. Thus we believe that LAAO should be the first-line choice in PWH with AF: particularly in those undergoing PCI or with ACS, with the goal of discontinuing anticoagulation in favour of DAPT and thus reducing the prohibitive risk of bleeding of a dual antithrombotic regimen. The management of antithrombotic medication in PWH is a formidable challenge that warrants long-standing experience and a multidisciplinary approach. Considering the growing prevalence of older PWH with CVD, a comprehensive assessment should be performed in those in need of antithrombotic medications, independently from their chronological age but taking into account frailty, concomitant cardiovascular risk factors and comorbidities, chronic polypharmacy and related drug-drug interactions, life expectancy and patietns' preferences and priorities in the context of a shared personalised approach. The authors declare no conflicts of interest. Not applicable. For original, deidentified data, please contact the corresponding author.