key: cord-1024064-pte4w0li
authors: Bencivenga, Leonardo; Sepe, Immacolata; Palaia, Maria Emiliana; Komici, Klara; Corbi, Graziamaria; Puzone, Brunella; Arcopinto, Michele; Cittadini, Antonio; Ferrara, Nicola; Femminella, Grazia Daniela; Rengo, Giuseppe
title: Antithrombotic therapy in patients undergoing transcatheter aortic valve replacement: the complexity of the elderly
date: 2020-11-06
journal: Eur J Prev Cardiol
DOI: 10.1093/eurjpc/zwaa053
sha: 2135d77d203309b47ffd95c6c42e2b5415171a8d
doc_id: 1024064
cord_uid: pte4w0li

Along with epidemiologic transitions of the global population, the burden of aortic stenosis (AS) is rapidly increasing and transcatheter aortic valve replacement (TAVR) has quickly spread; indeed, it is nowadays also employed in treating patients with AS at intermediate operative risk. Nonetheless, the less invasive interventional strategy still carries relevant issues concerning post-procedural optimal antithrombotic strategy, given the current indications provided by guidelines are not completely supported by evidence-based data. Geriatric patients suffer from high bleeding and thromboembolic risks, whose balance is particularly subtle due to the presence of concomitant conditions, such as atrial fibrillation and chronic kidney disease, that make the post-TAVR antithrombotic management particularly insidious. This scenario is further complicated by the lack of specific evidence regarding the ‘real-life’ complex conditions typical of the geriatric syndromes, thus, the management of such a heterogeneous population, ranging from healthy ageing to frailty, is far from being defined. The aim of the present review is to summarize the critical points and the most updated evidence regarding the post-TAVR antithrombotic approach in the geriatric population, with a specific focus on the most frequent clinical settings.

Aortic stenosis (AS) represents the most common valvular heart disease in Europe and North America, with a steadily growing prevalence due to the ageing population. 1 Indeed, although the predictable variability among data derived from epidemiological studies and the slight contribution of bicuspid aortic valve and congenital forms, this condition particularly affects elderly patients. It is estimated that about 5% of the population at age 65 suffers from AS and it is becoming increasingly frequent in clinical practice. 2 Calcific degeneration of valve structure constitutes the most common cause of AS in the Western world, whereas rheumatic AS still remains the main aetiology in developing countries. 3 The pathophysiological mechanisms leading to valve stenosis are considered to be similar to those involved in the development of atherosclerotic plaques, with emerging therapeutic implications. 4 Actually, advanced age, male gender, dyslipidaemia and systemic inflammatory status represents shared risk factors between coronary artery disease and AS. 5 Initially, aortic degeneration insidiously progresses, then symptoms' onset is paralleled by a fast worsening of valvular stenosis and calcifications. The symptomatologic manifestations, including breathlessness, angina, palpitations and syncope, are crucial for the assessment of aortic valve replacement therapy, though the heterogeneity of clinical presentation also poses controversies in approaching asymptomatic patients with instrumental evidence of severe AS. 6 

According to European Society of Cardiology (ESC) and American Heart Association (AHA) guidelines for the management of valvular heart disease, severe AS is currently defined as aortic valve area <1.0 cm 2 and/or a mean transaortic pressure gradient >40 mmHg and/or a peak aortic jet velocity (V max ) >4 m/s, together with evaluation of flow rate, ventricular function, size and wall thickness. 7 Transthoracic and/or transoesophageal echocardiography constitute the diagnostic gold standards, with exercise testing recommended for unmasking asymptomatic patients.

Since the first procedure performed in 2002, TAVR was supported by scientific evidence, showing superiority or non-inferiority compared to SAVR. Moreover, TAVR has rapidly spread and it is nowadays also employed in treating patients with intermediate operative risk. The decision-making process in elderly patients requires tailored considerations and should include a comprehensive geriatric evaluation. Indeed, despite unquestionable advantages, TAVR is burdened by many relevant complications, such as paravalvular regurgitation, aortic injury, heart block, vascular access haemorrhages, and thrombosis/embolization of the prothesis. 3 Ischaemic/embolic and bleeding complications are strongly related to mortality, thus the optimal antithrombotic approach after TAVR still remains debated. Despite no strong evidence exists yet, dual antiplatelet therapy (DAPT) is warranted for the first 3-6 months, followed by single antiplatelet therapy (SAPT) lifelong. 1 A recent analysis of 16 694 patients undergoing TAVR showed an increase in bleeding risk with DAPT as compared to SAPT without any significant difference regarding 1-year mortality, myocardial infarction, or stroke. 8 The Aspirin Versus Aspirin plus Clopidogrel Following Transcatheter Aortic Valve Implantation (ARTE) trial confirmed DAPT to increase the rate of complications compared to SAPT. 9 Accordingly, ESC guidelines for the management of Valvular Heart Disease states that SAPT may be the preferred choice compared to DAPT in patients with high risk of bleeding (Class IIb), especially for elderly patients with several comorbidities. 1 In this scenario, the management of elderlies undergoing TAVR is particularly complex: older patients suffer higher thromboembolic and bleeding risks, comorbidities and various degrees of disability and dependency, which make the correct choice of antithrombotic strategy after TAVR particularly challenging 10 ( Figure 1) .

Key points: DAPT prescription should be indicated for the first 3-6 months after TAVR, followed by SAPT lifelong. Consider SAPT in high bleeding risk (e.g. frail elderly, several comorbidities).

Cerebrovascular complications in patients undergoing TAVR, whose rates appear to be relatively unchanged over time although improvements in device technology, are very relevant due to great impact on both outcomes and quality of life. 11 The pathophysiology underlying cerebrovascular injuries typically comprises embolic, haemorrhagic, and atherothrombotic events. 12 Neurological complications mainly occur in the periprocedural period and they are primarily related to valve positioning, deployment, and valvuloplasty balloon. 13 Indeed, a fertile substrate for thrombogenicity is constituted by the presence of tissue factor and thrombin on calcific native aortic valve, whose manipulation in the context of the procedure may facilitate embolization. Furthermore, blood flow turbulence can be generated by the mechanical interaction between the prosthesis and the native valve, and the device itself may induce platelet aggregation and coagulation cascade activation. This scenario is intuitively aggravated in the elderly by the frequent concomitance of chronic conditions [e.g. atrial fibrillation (AF), hypertension, diabetes] which represent risk factors for ischaemic and embolic events per se. 14 The Placement of Aortic Transcatheter Valves (PARTNER) trial has demonstrated that TAVR improved 1-year survival compared to medical therapy, but it was associated with higher rates of stroke at 30 days. 15 The PARTNER-2 trial, by randomizing 2032 intermediate surgical risk patients with severe AS to TAVR or SAVR, has shown comparable 2 years incidence rates of death from any cause and stroke, whose incidence was similar in the acute phase and in the follow-up. 15 The PARTNER-3 trial has enrolled a thousand low surgical risk AS patients to either SAVR or TAVR, resulting in significant improvement in the occurrence of post-TAVR stroke, both at 30 days and 1 year. 16 Given the above-mentioned high thromboembolic risk, anticoagulation is required during TAVR. Even if practice patterns widely vary and the current indications are mainly based on expert consensus rather than on evidence from randomized clinical trials, unfractionated heparin regimen is preferred to direct thrombin inhibitors. 17, 18 Moreover, in order to prevent celebral embolization, multiple protection devices, classified as filtering and diversion systems, have been developed and employed, but their effectiveness is still debated. 19 Interestingly, besides clinically apparent strokes, neuroimaging studies have shown that more than two-thirds of patients experience post-TAVR multiple silent ischaemic-embolic lesions, spread across both hemispheres. 20 A recent multicentre study on 3750 TAVR patients with mean age of 80 ± 8 years revealed that age, history of cerebrovascular disease, higher aortic gradient, periprocedural stroke, and the lack of anticoagulation prescription were related to augmented risk of late cerebrovascular events. 21 Controversial results emerged regarding the clinical implications and prognostic 

role of these subclinical injuries, and even their association with cognitive decline is largely debated.

Key points: unfractionated heparin should be preferred for anticoagulation during TAVR, even to reduce periprocedural cerebrovascular complications. Protection devices need to be further investigated.

Antithrombotic therapy in patients with atrial fibrillation AF constitutes the most frequent arrhythmia worldwide, and its prevalence exponentially increases with age. 22 It also represents one of the most relevant comorbidities in patients undergoing TAVR. Indeed, pre-existing AF has been documented in more than onethird of the population undergoing the percutaneous procedure, whereas new-onset AF (NOAF) occurs in about 8% of patients. 23 Stroke represents a major complication after TAVR with up to 7% of patients developing cerebral ischaemic event within the first 12 months, whilst periprocedural stroke, occurring in the first 24 h, seems to be related to prosthetic valve leaflet embolization. 24 Accordingly, recent data from registries indicate that the average time from valve replacement to stroke is 181 days, allowing to speculate that the first 6 months of higher risk corresponds to the time necessary for the complete endothelialization of the prosthetic valve. 25 However, post-procedural stroke may be also associated with comorbidities, with pre-existing rhythm disturbance and NOAF being the most relevant. More in detail, NOAF has been related to ischaemic events in the first 30 days (subacute stroke) and pre-existing AF up to 1 year (late stroke) after the procedure. 26, 27 According to other evidence, patients with stroke often develop NOAF almost immediately after TAVR 28 and it has been related to a higher risk of early stroke compared to pre-existing AF. 29 Of note, it is important to underline that NOAF occurrence is even higher after SAVR than TAVR, although constituting a side effect of both approaches. 30 Furthermore, the diagnosis of NOAF can be particularly insidious, especially in paroxysmal rhythm disturbance lasting less than 30 s, consequently, subclinical NOAF patients suffer less chance to start anticoagulant therapy than patients with pre-existing AF. 31 This clinical setting is further complicated in elderly patients, which are often asymptomatic for rhythm disturbances. Further data indicate that subclinical NOAF episodes are more common than overt NOAF after TAVR, thus suggesting that prolonged rhythm surveillance may be useful to prevent thromboembolic events. 32 Besides NOAF, preexisting AF also enhances periprocedural cardiac complications occurrence. 33 AF constitutes one of the main indication to anticoagulation therapy: the most recent ESC guidelines for the management of AF indicates oral anticoagulant (OAC) therapy for all patients with paroxysmal, persistent or permanent AF presenting a valuable thromboembolic risk assessed through CHA 2 DS 2 -VASc score (> _2 in men and > _3 in women). 34 Conditions that require the use of antiplatelet therapy are also very frequent among TAVR patients: a consistent proportion (40-70%) of the 2% of patients presenting myocardial infarction within 1year post-TAVR suffered from chronic coronary artery disease years before the valve replacement procedure, 35 thus already taking antiplatelet therapies for appropriate prevention of acute ischaemic events. 27 Similarly, in AF patients undergoing TAVR, antiplatelet therapy should also be prescribed in addition to OAC despite these Figure 1 The complexity of antithrombotic strategy after TAVR in elderly. Real-life geriatric patients suffer comorbidities and various degree of disability, which carry many issues concerning the correct choice of post-procedural optimal antithrombotic strategy. Cognitive impairment and polypharmacotherapy concur to make the balance between concomitant thromboembolic and bleeding risks even more unstable. TAVR, transcatheter aortic valve replacement.

Antithrombotic therapy in patients undergoing TAVR

therapeutic approaches exponentially increase the risk of major bleeding, which should be carefully weighed. According to ESC guidelines, empirical treatment recommendations include aspirin or thienopyridine in addition to OAC life-long in AF patients, but this therapeutic combination is not evidence-based and no clear indications are provided with regard to the timing of antiplatelet suspension. 1 In elderly patients, the evaluation of the balance between safety and efficacy is further complicated by alterations in the geriatric domains of physical performance, cognitive impairment, and social support.

The comparison between direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) has been tested in AF patients undergoing TAVR, demonstrating the non-inferiority of DOACs in terms of all-cause mortality, major and/or life-threatening bleeding and stroke. 36 Contrariwise, the worsening of renal function was more frequent with VKA compared to DOAC groups. 37 The choice of anticoagulant agents or anticoagulant/antiplatelet association after TAVR still represents a challenging problem due to the lack of robust and definitive evidence. The Global Study Comparing a Rivaroxaban-based Antithrombotic Strategy to an Antiplatelet-based Strategy After TAVR to Optimize Clinical Outcomes (GALILEO) trial has compared, in post-TAVR patients without other indications for anticoagulation, a treatment strategy with rivaroxaban at 10 mg daily plus aspirin vs. aspirin plus clopidogrel, both administered for the first 3 months postprocedure. The trial was interrupted due to increased mortality for both bleeding and thromboembolic events in the DOAC group. 38 However, it should be mentioned that the rivaroxaban-based strategy resulted more effective than an antiplatelet-based one in the prevention of subclinical leaflet-motion abnormalities. 39 Recently, the Antiplatelet Therapy for Patients Undergoing Transcatheter Aortic Valve Implantation (POPular-TAVI) trial, which included patients with an established indication for long-term oral anticoagulation, confirmed a higher incidence of bleeding events among subjects receiving oral anticoagulation plus clopidogrel than those treated with OAC alone (34.6% vs. 21 .7%). 40 Current ongoing trials are trying to better define the most correct therapeutic approach: the Edoxaban Versus standard of care and their effects on clinical outcomes in patients having undergone Transcatheter Aortic Valve Implantation in Atrial Fibrillation (ENVISAGE-TAVI) is comparing edoxaban with VKAs in terms of efficacy and safety on NOAF/pre-existing AF patients, 41 while apixaban is under investigation in the trial Oral anti-Xa anticoagulation after trans-aortic valve implantation for AS (ATLANTIS), to demonstrate the superiority of this direct anticoagulant to the current standard of care in patients post-successful TAVR. 42 This context clearly justifies the wide variations in treatment approaches among health centres, as real-world data from large registries reported that the majority of patients are not treated according to guideline recommendations, especially the elderly and frail ones. 27 It is essential to underline that real-world elderly patients sharply differ from those included in the clinical trials. Several conditions, including comorbidities, polypharmacotherapy, and various degrees of disability often represent exclusion criteria for entering in the studies, 43 despite they represent intrinsic features of the majority of outpatients and hospitals elderly patients, whose management is often determined by physician personal experience rather than by solid evidence in such heterogeneous and complex population. 44 Key points: VKA should be preferred for long-term OAC therapy in AF patients with bioprosthesis; after the third month post-valve implantation, NOAC can be used. The addiction of antiplatelet agents to OAC in AF patients is not clearly recommended. Do not underestimate the risk for asymptomatic NOAF in elderly patients.

One of the most frequent comorbidities observed in elderly patients undergoing TAVR is represented by chronic kidney disease (CKD), which seems to be inherently related to a more rapid AS progression. 45 Importantly, these two conditions share many factors involved in their pathophysiology, including advanced age, hypertension and diabetes. The alteration in bone metabolism deriving from kidney failure translates into calcification within the cardiovascular system, as also suggested by the augmented prevalence of severe AS in haemodialytic patients. Furthermore, the reduction in cardiac output due to AS results in altered kidney perfusion which in turn concurs to worsening renal function. 46, 47 The scientific literature has evaluated the clinical impact of CKD in patients undergoing TAVR, also focusing on the difficult decisionmaking process in elderly patients with several comorbidities, disability and frailty. CKD stages 3-5 patients undergoing TAVR show increased survival than those destined to pharmacological therapy, who further experience significant impairment in kidney function at 12 months. 48 Accordingly, a retrospective analysis on a cohort of Portuguese patients undergoing TAVR has demonstrated a subsequent improvement in kidney function, thus allowing to speculate on a presumable role exerted by the improvement in renal perfusion. 49 Anyhow, in a recent analysis from the Women's INternational Transcatheter Aortic Valve Implantation (WIN-TAVI) registry on 852 women undergoing TAVR, CKD emerged as being independently associated with negative outcomes, especially death, stroke, and major bleeding, with worse clinical events in the severe-CKD group than in the mild one. 50 Notably, although renal failure is often listed as exclusion criteria in randomized trials, thus resulting in limited evidence in end-stage CKD patients, recent studies suggest haemodialysis as an independent predictor of both short and long-term mortality in elderly undergoing TAVR. Indeed, periprocedural complications within 72 h occur six-fold more frequently than in the general population, 51 with 1-year mortality similar to that observed in the dialysis SAVR group, but significantly higher compared to non-dialysis patients. 52 Coagulation abnormalities represent relevant causes of morbidity and mortality in CKD, since the coagulation system is altered due to uraemic metabolism-dependent abnormalities in platelet and vessel function leading to increased risk of both bleeding and thrombosis. 53 Moreover, few data are available regarding antiplatelet and anticoagulant agents in this specific setting, especially in the older frail subjects, which makes the choice of the antithrombotic strategy in CKD/ haemodialysis patients undergoing TAVR a complex challenge. As a general consideration, it is important to underline that the most correct antiplatelet approach in CKD patients is still widely debated: clopidogrel does not always provide a satisfactory response, aspirin is often linked to impaired antiplatelet effects, ticagrelor and prasugrel cannot be recommended in advanced CKD stages. 54 Contrariwise, efficacy and safety of anticoagulants have been tested in several trials, whose indications can be summarized as follows: VKA and DOACs are almost comparable in mild to moderate CKD, with the latter preferred in stages 1-3; a grey zone is represented by the end-stage renal failure, where warfarin constitutes the only anticoagulant treatment available; heparins in the haemodialytic patients still represents a debated choice. 55 Notably, recent evidence suggested that among patients with advanced CKD, apixaban showed lower safety and comparable efficacy compared to warfarin. 56 With these premises in mind, for an optimal antithrombotic strategy in elderly CKD patients undergoing TAVR, it may be wise to consider a transitory DAPT in patients with low bleeding risk and an immediate SAPT strategy when the risk is high. Furthermore, in elderly advanced CKD patients undergoing TAVR with a concomitant indication for anticoagulant therapy, the scenario becomes even more complex and, due to the lack of specific recommendations, a personalized evaluation of the balance between haemorrhagic and thromboembolic risks becomes crucial. In this clinical setting, a careful assessment is requested to evaluate the opportunity of associating antiplatelet and anticoagulant agents. 54 Moreover, clinical practice is burdened by several other issues in older CKD patients. First, VKA displays increased bleeding risk, especially in haemodialysis patients, 57 thus even more careful dosing is required, but the elderly population is not always able to monitor international normalized ratio (INR) values, especially in the contexts of poor social support and economic difficulties. Furthermore, older IV-V CKD stages and haemodialytic patients are generally excluded from clinical trials, thus the therapeutic strategies are mostly based on data derived from small observational or pharmacokinetic studies. 58 Finally, in multimorbid elderly patients on a large number of drugs, the accurate evaluation of the impact of concomitant therapies on kidney function is requested.

Key points: in CKD, consider transitory DAPT in low bleeding risk patients and immediate SAPT strategy when the bleeding risk is high. If concomitant indication for OAC coexists, the choice between VKAs and DOACs should be carefully evaluated according to CKD stage. Elderly multimorbid patients need personalized multidisciplinary evaluations.

It is well established that ageing is related to autonomic dysfunction, and several clinical conditions very frequent in the elderly are associated with inadequate autonomic responses to physiological stressors, including diabetes, alpha synucleinopathies like Lewy body dementia, Parkinson's disease and multiple system atrophy, chronic inflammatory conditions and heart failure. 59 Despite its complex presentation, the most common symptom of autonomic dysfunction is orthostatic hypotension, occasionally causing syncope. AS also presents with exertional dyspnoea and syncope. Recent reports have underlined the importance of evaluating all possible causes of syncope in patients with AS because the concurrence of autonomic failure might jeopardize management strategies, including TAVR. 59 Moreover, markers of cardiac autonomic dysfunction are strong predictors of mortality in post-infarction and heart failure patients. Recent evidence suggests that evaluation of autonomic function in patients with AS also yields independent prognostic information. In particular, severe autonomic failure seems to be a strong predictor of mortality in both symptomatic patients with AS undergoing invasive treatment and asymptomatic patients treated conservatively. 60 In another study on patients with severe AS undergoing TAVR, deceleration capacity of heart rate, a marker of autonomic function related to vagal tone, was a strong and independent predictor of 1-year mortality. 61 Time domain indices of heart rate variability are reduced in patients with severe aortic valve disease, especially in those with a progressed clinical class of heart failure. Moreover, a further reduction of heart rate variability time domain indices was observed 1 week after uncomplicated aortic valve replacement. 62 Interestingly, few studies have demonstrated that the type of surgery might have different influence over cardiac autonomic function in patient with aortic valve disease. In a comparative study, Compostella et al. 63 have shown that while SAVR led to profound depression of cardiac autonomic parameters, TAVR did not induce any significant deterioration of heart rate variability indexes. Similarly, Retzlaff et al. 64 have demonstrated that in contrast to patients undergoing conventional open surgery, fewer alterations of heart rate variability and baroreflex sensitivity were observed in patients with TAVR. In addition, it has been shown that TAVR improves cardiac sympathetic nerve activity measured through 123 Imetaiodobenzylguanidine myocardial scintigraphy in severe aortic valve stenosis, 64 even within 2 weeks after the procedure. 65 In terms of thrombotic risk, few studies have shown that orthostatic hypotension is associated with an increase in markers of coagulability, although the mechanisms have to be elucidated. 66 In elderly patients with Parkinson's disease, the thromboembolic risk seems to be increased by a combination of factors, which include immobility in more advanced stages, chronic inflammation and increased levels of homocysteine due to treatment with L-DOPA. 67 Overall, these evidence indicate that autonomic dysfunction should be evaluated in all elderly patients with concomitant aortic valve disease to prevent concurrent complications, to predict the outcome of interventions and assess the risk of thrombotic events.

Key points: AS is related to impaired sympathetic nervous system activity, which is frequent in several age-related chronic diseases. TAVR seems to improve cardiac sympathetic nervous system dysfunction. Autonomic alteration is also related to higher thromboembolic risk, which may complicate the post-procedural management of patients undergoing TAVR.

Although it represents a contraindication to SAVR and despite TAVR may constitute the only therapeutic option to treat AS in this clinical condition, frailty has been associated with augmented risk of disability, institutionalization and mortality after TAVR. 68, 69 Physical performance impairments, very frequent in the elderly subjects, are often linked to increased risk of falls, one of the most dramatic events in this population, frequently resulting in negative outcome. Indeed, besides hip fracture, which constitutes a frequent Antithrombotic therapy in patients undergoing TAVR 5 consequence of falls in older people, fall-related major haemorrhagic events represent a feared occurrence in the elderly, especially in those assuming antithrombotic therapy. 70 Furthermore, a lot of evidence has demonstrated the impact of frequently prescribed drugs, such as antidepressants, antihypertensive (especially diuretics), and digitalis, at increasing fall risk in people aged over 65. 71,72 In this clinical setting the concomitant prescription of antithrombotic therapy almost quadruples the occurrence of intracranial haemorrhage after trauma, thus posing relevant issues regarding the safety of managing post-TAVR patients. 73 Moreover, it has been reported the favourable functional impact of rehabilitation programmes in elderly patients undergoing TAVR. 74 Mood disorders are also very frequent among elderlies, with relevant implications in terms of medical complications. In older patients undergoing surgery for AS, anxiety has been strongly associated with increased morbidity and mortality risks. 75 Similarly, patients with persisting depression suffer from a higher risk of mortality after surgery. Although the percutaneous procedure has recently demonstrated to progressively reduce depression and anxiety symptoms in elderly, compared to pre-TAVR status, 76 the antithrombotic management of patients undergoing TAVR may be complicated by the concomitant use of drugs for mood disorders, such as serotonin reuptake inhibitors, frequently associated with bleeding events and impaired haemostasis. 77 Besides being considered a typical geriatric syndrome, with relevant impact in terms of medications and stress for both patients and caregivers, 78 delirium also represents a frequent complication in older patients after TAVR. Typical risk factors are represented by advanced age, male gender, cognitive impairment, malnutrition, sleep deprivation, polytherapy, and previous documented episodes. More specifically, post-TAVR delirium seems to be more frequent in patients with acute renal failure, carotid artery stenosis and undergoing transapical approach. Delirium is related to increased risk of falls and mortality following TAVR, thus further complicating the antithrombotic management of elderly AS patients. 79 Blood disorders including anaemia, thrombocytopenia and acquired coagulative disorders are frequent among older TAVR recipients. Extensive evidence has detected an association between pre-existing anaemia, particularly common among people over 65 years, 80 and long-term mortality in elderly TAVR patients. 81 Data from the French national TAVI registry have demonstrated that the majority of patients experiences post-procedural haemoglobin drop > _2 g/dL, 82 in line with the frequent recourse to post-operative blood transfusions, that may complicate the clinical course and therapeutic management 83 and is frequently associated with increased risk of acute kidney injury. 84 Many studies have reported transitory thrombocytopenia occurring in TAVR patients, with a restoration to baseline platelet levels within a week in the vast majority of them 81 and abnormality persistence in around a third of patients. 85 Postprocedural thrombocytopenia has been linked to augmented 1-year mortality and it is frequently complicated by bleeding events. 86 Taking into account the high prevalence of blood disorders in elderly patients, the above-mentioned conflicting data on the beneficial effects of DAPT in post-TAVR patients should be urgently updated in order to provide recommendations in such specific settings.

Finally, it is worth mentioning the burden of polypharmacotherapy in very elderly patients suffering from cardiovascular diseases, particularly when the efficacy of therapeutic approaches has not been proven. 87 Key points: in elderly patients undergoing TAVR, be aware of fall risk and drug interactions that can alter haemostasis. Polypharmacotherapy, risk of delirium, and mood disorders should always be considered.

The COronaVIrus Disease-2019 (COVID-19) pandemic, caused by the novel highly pathogenic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) first identified in December 2019, is rapidly spreading worldwide, with dramatic consequences in terms of morbidity and mortality, incalculable impact on global production systems and unpredictable evolution. 88 The symptomatic presentation is variable, including mild fatigue, fever, myalgia, headache, shortness of breath, dry cough, or diarrhoea, but it has the potential to develop acute respiratory disease syndrome, systemic inflammatory response syndrome (SIRS), and multiorgan failure with a more severe presentation among elderly, probably also due to intrinsic agerelated features. 89-91 D-Dimer elevation, mild thrombocytopenia, prolongation of prothrombin time, and INR are common laboratory abnormalities, which seem to be associated with COVID-19 severity and may predispose to coagulation disorders. 92, 93 Accordingly, a relevant proportion of deaths fulfilled the disseminated intravascular coagulation criteria and elevated antiphospholipid antibodies have been described in COVID-19 patients with limb and cerebral ischaemia. 94, 95 Whether the thrombotic effect constitutes a consequence of cytokine storm that precipitates the SIRS or it is directly related to SARS-CoV2 pathogenicity remains unknown, anyhow consideration regarding antithrombotic management, even in the context of TAVR patients, may be necessary. Recently, the ESC has published the 'Guidance for the Diagnosis and Management of CV Disease during the COVID-19' also focusing on TAVR. It suggests to defer nonurgent procedures, giving priority to patients with syncope, high gradients and/or impaired systolic function and to prefer transfemoral approach in order to optimize the utilization of healthcare resources. 96 It is important to mention that some medications, such as lopinavir/ritonavir, may inhibit CYP3A4 activity thus producing potential drug interactions, and inducing physician to pay particular attention in molecules selection and dose (e.g. anticoagulants). Although remdesivir and tocilizumab also interfere with CYP3A4 activity, to date major drug-drug interactions with anticoagulants have not been reported, thus dose adjustments are not currently required.

The burden of valvular heart disease, especially AS in the elderly, is rapidly increasing and the recent developments leading to less invasive interventional strategies make it possible to tailor treatments to individual older patients. Furthermore, the management of valvular diseases in the elderly is probably one of the best examples of multidisciplinary teamwork in geriatric medicine: the ESC guidelines have established the 'Heart Team', a set of specialists (cardiologist, surgeon, anaesthetist, expert in care for the elderly, and even nonmedical figures) in which the specific skills of all components are DAPT patients were the majority and showed similar 1-year mortality risk compared to SAPT, as for stroke and MI incidence, but a significantly higher bleeding risk.

Aspirin CKD is an independent 1-year predictor of morbidity and mortality and other cardiovascular complications but did not affect the short-term results.

After Transcatheter Aortic Valve Implantation 36

Meta-analysis of five eligible studies including 2569 patients with indication to OAC, comparing DOACs to VKAs.

Primary efficacy outcomes: all-cause death, stroke events. Primary safety outcome: major and/or life-threatening bleedings.

DOACs did not provide significant difference in allcause mortality, major and/or life-threatening bleeding and stroke, compared to VKAs.

Impact of pre-and post-procedural anaemia on the incidence of acute kidney injury and 1-year mortality in patients undergoing transcatheter aortic valve implantation [from the French Aortic National CoreValve and Edwards 2 (FRANCE 2) Registry] 82 Data from 3472 patients were reported in the French national TAVI registry, divided into three groups according to post-procedural anaemia (Hb < 2 g/dL; Hb < 4 g/dL; and Hb > 4 g/dL).

Primary outcome: 1-year mortality and incidence of AKI.

Either pre-and post-procedural anaemia were correlated with AKI and 1-year mortality.

AKI, acute kidney injury; CKD, chronic kidney disease; DAPT, dual anti-platelet therapy; DOAC, direct oral anti-coagulant; Hb, haemoglobin; INR, international normalized ratio; MI, myocardial infarction; OAC, oral anti-coagulant; RCT, randomized controlled trial; SAPT, single antiplatelet therapy; TAVR, transcatheter aortic valve replacement; VKA, vitamin K antagonist.

combined in order to build a real comprehensive decision process and to choose the most appropriate treatment approach for each patient.

Nonetheless, TAVR still carries many issues concerning postprocedural optimal antithrombotic strategy to balance concomitant thromboembolic and bleeding risks. Despite the great progresses in the field obtained in the last decade, mainly related to the publications of retrospective studies and registry data, many critical points are still debated, and therefore recommendations from the guidelines do not provide sufficiently evidence-based indications ( Table 1) .

Anyhow, this field of scientific research is very active and the results of the ongoing trials will help to define the scenario more clearly. 97 The Trial to Assess the Safety and Efficacy of Prophylactic TicagrelOr With Acetylsalicylic Acid Versus CLopidogrel With Acetylsalicylic Acid in the Development of Cerebrovascular EMbolic Events During TAVI (PTOLEMAIOS, NCT02989558) is comparing DAPT with clopidogrel or ticagrelor in addition to acetylsalicylic acid on cerebrovascular events after TAVR, through transcranial Doppler ultrasound. 98 The impact of ticagrelor monotherapy, compared to clopidogrel plus acetylsalicylic acid, after TAVR is under test in the Safety Profile Evaluation of Ticagrelor Alone Compared to a Combination of Lysine Acetylsalicylate-Clopidogrel in the Context of Transcatheter Aortic Valve Implantation (TICTAVI, NCT02817789). 99 In addition to the two above-mentioned major studies that are testing the usefulness of DOACs in patients undergoing TAVR with indication to anticoagulant therapy for other clinical conditions (ATLANTIS, NCT02664649 and ENVISAGE TAVI AF, NCT02943785), anticoagulation-based strategies in patients without indication for OAC are also under investigation, after the negative results of the GALIEO trial. Indeed, the Anticoagulant Versus Dual Antiplatelet Therapy for Preventing Leaflet Thrombosis and Cerebral Embolization After Transcatheter Aortic Valve Replacement (ADAPT-TAVR, NCT03284827) trial is comparing edoxaban monotherapy vs. DAPT (aspirin and clopidogrel) on the incidence of leaflet thrombosis on cardiac CT imaging. 100 The Anticoagulation Alone Versus Anticoagulation and Aspirin Following Transcatheter Aortic Valve Interventions (AVATAR; NCT02735902) trial will assess the safety and efficacy of adding aspirin to OAC after TAVR in patients with indication for chronic anticoagulation. 101 In AF patients undergoing TAVR and with absolute or relative contraindication to OAC, a non-pharmacological approach with left atrial appendage occlusion is currently assessed in the WATCHMAN for Patients With Atrial Fibrillation Undergoing Transcatheter Aortic Valve Replacement (WATCH-TAVR; NCT03173534) and the Comparison of Left Atrial Appendage Occlusion Versus Standard Medical Therapy in Patients in AF Undergoing TAVI (TAVI/LAAO; NCT03088098) trials. 102, 103 The spread of TAVR procedures worldwide highlights the need of dedicated clinical investigations on the antithrombotic management of complex patients suffering from concomitant chronic diseases and high grades of disability and frailty. Given the difficulties to design specific studies in this population, establishment of global registers from centres with greater experience in TAVR may help to collect evidence on these subpopulations.

Elderly patients, who constitute the vast majority of people undergoing TAVR, represent a heterogeneous population, with highly variable characteristics and great vulnerability, suffering from several comorbidities and various degrees of disabilities. Since multimorbidity is often listed as an exclusion criterion in most of the research protocols, consensus documents and guidelines rarely provide ad hoc recommendations for managing complex cases, as demonstrated by the difficulties in choosing optimal antithrombotic therapy in TAVR patients when concomitant geriatric syndromes, as AF and/or CKD, occur.

In this scenario, a thorough assessment of possible ischaemic and bleeding complications and an attempt at attenuating these risks, also through behavioural measures, still remain the main challenges the physician has to face, awaiting for further evidence aiming to provide suitable indications for the complex real-life clinical practice.

ESC/EACTS Guidelines for the management of valvular heart disease

Epidemiology of aortic valve stenosis (AS) and of aortic valve incompetence (AI): is the prevalence of AS/AI similar in different parts of the world?

Medication Management of Patients Undergoing Transcatheter Aortic Valve Replacement

An Exploratory Analysis of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition and Aortic Stenosis in the FOURIER Trial

Aortic Stenosis: Epidemiology and Pathogenesis. In: Percutaneous Treatment of Left Side Cardiac Valves

How Should Very Severe Aortic Stenosis Be Defined in Asymptomatic Individuals?

Variation in post-TAVR antiplatelet therapy utilization and associated outcomes: Insights from the STS/ACC TVT Registry

Aspirin Versus Aspirin Plus Clopidogrel as Antithrombotic Treatment Following Transcatheter Aortic Valve Replacement With a Balloon-Expandable Valve

Atrial fibrillation: all the elderly go hospitalized? A minireview

Trends in outcome after transfemoral transcatheter aortic valve implantation

Risk of stroke after transcatheter aortic valve implant: The role of the new oral anticoagulants

Incidence and mechanisms of cerebral ischemia after transcatheter aortic valve implantation compared with surgical aortic valve replacement

Antithrombotic Therapy in Transcatheter Aortic Valve Replacement

Transcatheter Aortic-Valve Implantation for Aortic Stenosis in Patients Who Cannot Undergo Surgery

ACCF/AATS/SCAI/STS expert consensus document on transcatheter aortic valve replacement: Executive summary

Bivalirudin Versus Heparin Anticoagulation in Transcatheter Aortic Valve Replacement the Randomized BRAVO-3 Trial

tavr#::text=In addition to clinically apparent,ischemic embolic lesions post-TAVR.&text=These studies have shown that

Silent and apparent cerebral ischemia after percutaneous transfemoral aortic valve implantation: A diffusion-weighted magnetic resonance imaging study

Late Cerebrovascular Events Following Transcatheter Aortic Valve Replacement

Worldwide Epidemiology of Atrial Fibrillation: A Global Burden of Disease

Management, and Associated Clinical Outcomes of New-Onset Atrial Fibrillation Following Transcatheter Aortic Valve Replacement: An Analysis From the STS/ACC TVT Registry

Transcatheter Aortic Valve Thrombosis: Incidence, Predisposing Factors, and Clinical Implications

Treatment and Clinical Outcomes of Transcatheter Heart Valve Thrombosis

New-onset arrhythmias following transcatheter aortic valve implantation: A systematic review and meta-analysis

Antithrombotic therapy after transcatheter aortic valve replacement. Circulation: Cardiovascular Interventions; 12. Epub ahead of print

Predictors, incidence, and outcomes of patients undergoing transfemoral transcatheter aortic valve implantation complicated by stroke from the center-collaboration

Impact of atrial fibrillation on outcomes of patients treated by transcatheter aortic valve implantation: A systematic review and meta-analysis

Evaluation of the Incidence of New-Onset Atrial Fibrillation after Aortic Valve Replacement

Predictive Factors, and Prognostic Impact of Silent Atrial Fibrillation After Transcatheter Aortic Valve Implantation

Detection of Atrial Fibrillation and Atrial Flutter by Pacemaker Device Interrogation After Transcatheter Aortic Valve Replacement (TAVR): Implications for Management

Financial Implications and Impact of Pre-existing Atrial Fibrillation on In-Hospital Outcomes in Patients Who Underwent Transcatheter Aortic Valve Implantation (from the National Inpatient Database)

ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS

Severe aortic stenosis and coronary artery disease

Metaanalysis Comparing Direct Oral Anticoagulants Versus Vitamin K Antagonists After Transcatheter Aortic Valve Implantation

Continued Versus Interrupted Oral Anticoagulation During Transfemoral Transcatheter Aortic Valve Implantation and Impact of

Postoperative Anticoagulant Management on Outcome in Patients With Atrial Fibrillation

A controlled trial of rivaroxaban after transcatheter aortic-valve replacement

Reduced leaflet motion after transcatheter aortic-valve replacement

Anticoagulation with or without Clopidogrel after Transcatheter Aortic-Valve Implantation

EdoxabaN Versus standard of care and theIr effectS on clinical outcomes in pAtients havinG undergonE Transcatheter Aortic Valve Implantation in Atrial Fibrillation-Rationale and design of the ENVISAGE-TAVI AF trial

Oral anti-Xa anticoagulation after trans-aortic valve implantation for aortic stenosis: The randomized ATLANTIS trial

The management of combined antithrombotic therapy in patients with atrial fibrillation undergoing percutaneous coronary intervention: A particularly complex challenge, especially in the elderly

Management and Treatment of Cardiovascular Diseases in the Elderly

Chronic kidney disease and valvular heart disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference

Impact of Chronic Kidney Disease on Decision Making and Management in Transcatheter Aortic Valve Interventions

Chronic kidney disease and cardiovascular risk: Epidemiology, mechanisms, and prevention

Transcatheter aortic valve implantation versus conservative treatment in chronic kidney disease patients

Impact of transcatheter aortic valve implantation on kidney function

The impact of chronic kidney disease in women undergoing transcatheter aortic valve replacement: Analysis from the Women's INternational Transcatheter Aortic Valve Implantation (WIN-TAVI) registry. Catheter Cardiovasc Interv

Impact of Dialysis on the Prognosis of Patients Undergoing Transcatheter Aortic Valve Implantation

Transcatheter and surgical aortic valve replacement in dialysis patients: A propensity-matched comparison

Haemostasis in chronic kidney disease

Practical issues in clinical scenarios involving CKD patients requiring antithrombotic therapy in light of the 2017 ESC guideline recommendations

Anticoagulation in chronic kidney disease: from guidelines to clinical practice

Safety and efficacy of apixaban versus warfarin in patients with end-stage renal disease: Meta-analysis

Anticoagulation in chronic kidney disease patients -The practical aspects

Anti-thrombotic therapy for atrial fibrillation in patients with chronic kidney disease: Current views

Autonomic dysfunction in older people

Severe autonomic failure as a predictor of mortality in aortic valve stenosis

Deceleration capacity of heart rate predicts 1-year mortality of patients undergoing transcatheter aortic valve implantation

Factors influencing heart rate variability in patients with severe aortic valve disease

Impact of type of intervention for aortic valve replacement on heart rate variability

Preserved autonomic regulation in patients undergoing transcatheter aortic valve implantation (TAVI)-a prospective, comparative study

Early effects of transcatheter aortic valve replacement on cardiac sympathetic nervous function assessed by 123I-metaiodobenzylguanidine scintigraphy in patients with severe aortic valve stenosis

Higher levels of von Willebrand factor in patients with syncope due to orthostatic hypotension

Molecular and clinical issues about the risk of venous thromboembolism in older patients: A focus on parkinson's disease and parkinsonism

The impact of frailty on mortality after transcatheter aortic valve replacement

Predictors of poor outcomes after transcatheter aortic valve replacement results from the PARTNER (Placement of Aortic Transcatheter Valve) trial

The risk of hemorrhagic complications in hospital in-patients who fall while receiving antithrombotic therapy

US) Division of Health Promotion and Disease Prevention

Prevalence of medication-related falls in 200 consecutive elderly patients with hip fractures: a cross-sectional study

The impact of combined use of fall-risk medications and antithrombotics on injury severity and intracranial hemorrhage among older trauma patients

Long-term effect of exercise training in patients after transcatheter aortic valve implantation: Follow-up of the SPORT:TAVI randomised pilot study

Preoperative anxiety as a predictor of mortality and major morbidity in patients aged >70 years undergoing cardiac surgery

Depression and anxiety in elderly patients with severe symptomatic aortic stenosis persistently improves after transcatheter aortic valve replacement (TAVR)

Influence of antidepressants on hemostasis

Clinical practice guidelines for management of delirium in elderly

Meta-analysis of Prevalence and Risk Factors for Delirium After Transcatheter Aortic Valve Implantation

Prevalence of anemia in persons 65 years and older in the United States: Evidence for a high rate of unexplained anemia

Blood Disorders in Patients Undergoing Transcatheter Aortic Valve Replacement: A Review

Impact of pre-and post-procedural anemia on the incidence of acute kidney injury and 1-year mortality in patients undergoing transcatheter aortic valve implantation (from the French Aortic National CoreValve and Edwards 2 [FRANCE 2] Registry)

Antithrombotic therapy in TAVI

Blood transfusion and the risk of acute kidney injury after transcatheter aortic valve implantation

Predictors and clinical impact of pre-existing and acquired thrombocytopenia following transcatheter aortic valve replacement

Acquired thrombocytopenia after transcatheter aortic valve replacement: Clinical correlates and association with outcomes

Cardiovascular disease in nonagenarians: Prevalence and utilization of preventive therapies

World Health Organization W. WHO Director-General's opening remarks at the media briefing on COVID-19 -11

Clinical Characteristics of Coronavirus Disease 2019 in China

COVID-19 and the elderly: insights into pathogenesis and clinical decision-making

Elderly at time of COronaVIrus disease 2019 (COVID-19): possible role of immunosenescence and malnutrition

Diagnostic utility of clinical laboratory data determinations for patients with the severe COVID-19

COVID-19 and coagulative axis: Review of emerging aspects in a novel disease

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19

European Society of cardiology. ESC Guidance for the Diagnosis and Management of CV Disease during the COVID-19 Pandemic

Antithrombotic therapy after transcatheter aortic valve implantation

Trial to Assess the Safety and Efficacy of Prophylactic TicagrelOr With Acetylsalicylic Acid Versus CLopidogrel With Acetylsalicylic Acid in the Development of Cerebrovascular EMbolic Events During TAVI

Profile Evaluation of TICagrelor Alone Compared to a Combination of Lysine Acetylsalicylate-Clopidogrel in the Context of Transcatheter Aortic Valve Implantation (TAVI)

Anticoagulant Versus Dual Antiplatelet Therapy for Preventing Leaflet Thrombosis and Cerebral Embolization After Transcatheter Aortic Valve Replacement

Anticoagulation Alone Versus Anticoagulation and Aspirin Following Transcatheter Aortic Valve Interventions (1:1) (AVATAR)

WATCH-TAVR, WATCHMAN for Patients With Atrial Fibrillation Undergoing Transcatheter Aortic Valve Replacement

Antithrombotic therapy in patients undergoing TAVR

Dr Leonardo Bencivenga has been supported by a research grant provided by the Cardiopath PhD programme. Conflict of interest: none declared.