Atrial fibrillation (AF) has been the. Subclinical Atrial Fibrillation, Embolic Risk, and Anticoagulant Treatment

Transcription

1 MAEDICA a Journal of Clinical Medicine 2018; 13(4): Mædica - a Journal of Clinical Medicine Invited Editorial Point of View Subclinical Atrial Fibrillation, Embolic Risk, and Anticoagulant Treatment Leonida GHERASIM Honorary Member of the Romanian Academy Professor, Carol Davila University of Medicine and Pharmacy, Senior consultant, Emergency University Hospital, Bucharest, Romania Professor Leonida Gherasim, MD, PhD, is a member of the Romanian Academy. We invited him to write the editorial review for this issue. The subject how to treat the silent atrial fibrillation (that fibrillation discovered only by devices) and take the decision to anti coagulate or not is a very important clinical judgement. Professor Gherasim was the editor of several editions of the Romanian Handbook of Internal Medicine the Romanian equivalent of Harrison s, or Cecil and Loeb s Handbooks. He remains one of the most outstanding professors of internal medicine in Romania. In 2019, professor Leonida Gherasim will be 90 years old. Prof. Mircea Cinteza Chief Editor, MAEDICA J Clin Med Atrial fibrillation (AF) has been the most researched arrhythmia over the last two decades. Its presence is particularly connected to the cerebral embolic or systemic risk, the risk of heart failure (HF) development or progression as well as the risk for aggravation of associated cardiovascular (CV) conditions. Its prevalence is between 1% and 2% in the general population; it increases with age and progress of tachyarrhythmia identification methods (1). Besides the thoroughly known forms of AF (paroxysmal, persistent, permanent), the silent/subclinical atrial fibrillation has become a subject of research and studies in recent years. The basic problems of this type of short-duration, asymptomatic and repetitive AF concern its occurrence in the general population or under various cardiovascular conditions, defining the thromboembolic risk and advisability of anticoagulant treatment. The data of the problems are similar in the case of silent AF and as far as the conventional forms of AF are concerned. Article received on the 17 th of December 2018 and accepted for publication on the 20 th of December Maedica A Journal of Clinical Medicine, Volume 13, No. 4,

2 The majority of studies use the term silent or subclinical atrial fibrillation, but also the expression atrial high rate episode (AHRE) with the same meaning. AHRE is defined as atrial tachyarrhythmia episodes, with frequency > /min and minimum duration of successive beats. Out of the total number of atrial high rate episodes recorded by means of cardiac electronic devices, more than 90% are in fact silent AF episodes, being difficult to define atrial tachyarrhythmia manifestations (atrial flutter, atrial tachycardia). Silent atrial fibrillation episodes are detected and evaluated through multiple screening methods but mainly by cardiac electronic devices (pacemakers PM, cardiac resynchronization therapy devices CRT, intracardiac defibrillators ICD). In practice and in research, Holter monitoring (of variable duration), telemetry, smartphone, implantable loop recorders (externally and internally) are used. Implantable cardiac devices detect atrial fibrillation with a positive predictive value of % (2). Defining the clinical significance of silent AF (AHRE) requires the specification (evaluation) of its incidence by means of various evaluation techniques and depending on the presence of various cardiovascular conditions as well as on the term of arrhythmia burden. In major clinical studies (HOST, TRENDS, ASSERT, Healey), the incidence of silent AF established by means of implantable devices had values not much different one from another: MOST follow up 27 months, incidence 50%; TRENDS follow up 1.4 years, incidence 28%; ASSERT follow up 2.5 years, incidence 34.7%; Healey et al. incidence 53%. In the above mentioned study, the patients investigated for AHRE had one or several AF or stroke risk factors (3-6). The incidence of AHRE varies with numerous factors: type of the recording device used, screening time, the basic disease requiring follow up of tachyarrhythmia (sinus sick syndrome, atrioventricular block), presence or absence of stroke or AF history, history or presence of HF, age of investigated patients, CHADS 2 or CHA 2 DS 2 -VASc score, etc. Several studies or meta-analyses have pointed out the diversity of pathological conditions in which AHRE may occur, and, if such be the case, prediction elements for the evolution of subclinical AF. Thus, by means of the continuous Home Monitoring technique in a group of HF and cardiac resynchronization therapy patients monitored during 370 days, AHR episodes have been detected in 40% of patients. Among patients with AHRE, 2% developed thromboembolic complications within the relevant period (7). The REVEL-AF study evaluated, through ICM (implantable cardiac monitor), the incidence of AF with a duration of > six minutes, for a population with AF or AVC high risk. After 18 months, the rate of previously undiagnosed AF detection amounted to 29.3%, at an average detection time of 123 days (8). In a meta-analysis consisting of 32 trials on 5,038 stroke/transient ischemic attack TIA patients, the detection rate of new (paroxysmal) AF was 11.5% in non-selected patients and 16.9% in patients with cryptogenic considered stroke (9). In a more recent meta-analysis (2018), the prevalence of subclinical AF as evaluated by means of cardiac electronic devices has been estimated as towards 35% in patients monitored over a period of 1 to 2.5 years (2). In summary, extensive research using mainly implantable cardiac devices on patients without an AF history point to an AHRE/AF incidence of approximately 30%. The clinical significance of AHRE/AF is connected to defining two elements, namely: 1) the possible association between AHRE/AF and clinical AF, and 2) the arrhythmic burden and embolic risk. Two studies performed on 2892 patients dwelt upon the association between AHRE/AF and clinical AF: ASSERT and Ancillary MOST. During the follow-up period, patients with AHRE/subclinical AF developed clinical AF 5.7 times more frequently than those with no episodic atrial tachyarrhythmia (10). Defining the arrhythmic burden, the cut-off for the embolic risk is essential for taking a decision regarding anticoagulant prophylaxis. The arrhythmic burden, by definition, includes: the longest duration of a tachyarrhythmia episode; the total duration of AHRE/AF per one day; and the temporary association with a potential ischemic stroke/tia (11). Several important clinical studies had in view the relationship between AF/AHRE duration (the arrhythmic burden) and stroke risk. The 262 Maedica A Journal of Clinical Medicine, Volume 13, No. 4, 2018

3 AHRE/AF cut-off values as established were as follows: SOS AF AHRE five hours during one day of observation; TRENDS arrhythmic burden > 5.5 hours during one day; IMPACT arrhythmic burden > 5.5 hours; ASSERT AHRE/AF episodes > six minutes (2, 12). Although the cut-off values for the arrhythmic burden (AHRE) were relatively different, the stroke risk was > two times as to the absence of tachyarrhythmia in all clinical studies; TRENDS annual risk of 2.4%; ASSERT stroke x 2.5 vs normal; Carolink x 4 risk increase; SOS AT stroke x In recent research, the risk of stroke has been investigated with regard to short AHRE episodes (< 30 sec.). The results have not shown a direct relation between very short AHRE/AF episodes and the risk of recurrent stroke risk (13). When defining the relation between AHRE/AF and cerebral embolic risk, it is also important to establish whether there is a temporal relation between the tachyarrhythmia episodes and the ischemic neurological events. The short time (a few days) between AHRE and cerebral ischemia would be the proof of the great causal probability between tachyarrhythmia events and stroke. In the analysis of ASSERT and TRENDS studies, the temporal relation was uncertain: only for 15.4% and 22.5% of investigated patients respectively, AHRE/AF was identified within a period shorter than 30 days preceding the embolism (evaluation of PM or ICD tachyarrhythmia (14, 15). In patients with cryptogenic stroke (CRISTAL study), ICM evaluation was carried on during 365 days; the average AF detection time (asymptomatic in 79% of cases) varied between 52 and 86 days. The relation between cryptogenic stroke and silent AF is still undefined (16). Detection of AHRE/subclinical AF episodes by means of present day monitoring techniques (especially implantable cardiac devices) raises the issue of anticoagulant treatment advisability in order to prevent cerebral or systemic embolism. The answer supposes the recognition of embolic risk indicators in persons with AHRE, as resulted from clinical studies. Estimation of the embolic risk and the possible preventing anticoagulant treatment are first and foremost based on defining the characteristics of AHRE (individual evaluation). Defining the characteristics of AHRE in a particular case includes: type of atrial tachyarrhythmia, arrhythmic burden (per one day or several days), potential temporal relation between AHRE and stroke/tia. In practice, the presence of AHRE/AF is also associated with other elements that are important in increasing the embolic risk and in decision making to establish the anticoagulant treatment: AF or repeated arrhythmia events history, eventually post AF ablation; ischemic or cryptogenic stroke; a higher CHADS 2 score or CHA 2 DS 2 -VASC; case history or presence of HF; significantly higher left atrium volume. The presence of previous conditions in association with the AHRE/AF amplifies the embolic risk and the probable indication of anticoagulant treatment. Although clinic studies on AHRE/AF have proved out the increase of embolic risk under variable cut-off circumstances by at least two times, there are no well-grounded data regarding the use of anticoagulants with AHRE/AF without a previous proof of AF case history identified by conventional methods (ECG, Holter, telemetry, a.s.o.) (17). In a study limited to 445 patients with PM, AHRE/AF was detected in 53.6% of cases, with anticoagulation being used in 35.3% of these patients. Oral anticoagulant (OA) treatment was more frequently recommended for clinical AF patients (58.9%) as compared to those without clinical AF (23.7%, p < 0.01) (6). Due to the diversity of cardiovascular pathology in which AHRE/AF is detected, defining the embolic risk and OA prophylaxis advisability are based on the individual analysis of three parameters: AHRE/AF characteristics first the arrhythmic burden; AF or other atrial arrhythmias or stroke/tia case history; and CHADS 2 or CHA 2 DS 2 -VaSc score (10, 17, 18) Based on currently available data, two recent publications (2017) formulated options and recom mendations regarding the prevention with anticoagulants for AHRE/AF patients. Thus, Device detected subclinical atrial tachyarrhythmia: definition, implications, and management a European Heart Rhythm Association (EHRA) consensus document defines the conditions in which anticoagulant treatment is recommended or not depending on the arrhythmic burden and CHA 2 DS 2 -VASc (10). The recommendations are synthetic and clear: Antithrombotic therapy is not recommenda ble for any patient with CHA 2 DS 2 -VASc score 0 (B) or 1 (F), irrespective of AHRE; Maedica A Journal of Clinical Medicine, Volume 13, No. 4,

4 OA treatment is recommendable for AF burden > 5.5 hours/day and additional risk factors CHA 2 DS 2 -VASc: 2 (M) or 3 (F); for a lower AF burden, anticoagulation is possible in the presence of multiple risk factors; Administration of OA should be consi dered in case AF burden > 5.5 hours (any day) and an additional risk factor CHA 2 DS 2 -VASc of 1 (M) or 2 (F). In their recently published review, Atrial fibrillation rate episodes and stroke prevention, AJ Camm and other prominent cardiologists expose the present data regarding subclinical AHRE/AF, including the conditions in which prevention treatment with OA may be recommended (17). In the management algorithm of AHRE patients, three basic elements are to be considered towards decision-making: stroke or AF history case; arrhythmic burden; and CHA 2 DS 2 -VASc score. When analyzing patients with AHRE (detected by means of implantable devices), the presence or absence of the three aforementioned conditions allows for varied particular decisions: for patients with stroke or AF history cases who have also AHRE episodes, the standard anticoagulant treatment is recommended, because there is a high risk of embolic stroke recurrence; re-evaluation in time of the AHRE characteristics allows for the ulterior decisions (treatment duration); for patients without stroke or AF history, it is required to have the AF confirmed by means of a conventional method (Holter, telemetry, etc.), with treatment orientations depending on the presence or absence of this condition; a) the documented presence of AF leads to the recommendation of anticoagulant treatment since there is previous proof of AF or stroke/tia recurrence (conditions of great probability of stroke recurrence); and b) in the absence of proven AF and with no stroke or AF history, the recommendation of anticoagulant treatment is based on characteristics of AHRE (arrhythmic burden) > 24 hours and CHA 2 DS 2 -VASc 2 (M); 3 (F) score. For all previously mentioned situations, the periodical follow-up of tachyarrhythmia episodes allows for decisions, justified or not, with regard to continuing the anticoagulant treatment. Published results concerning the anticoagulant treatment (anti-vitamin K) used in the prevention of cerebral ischemic/systemic embolism in patients with AHRE/subclinical AF are limited and non-conclusive. At present, clinical studies with NOAC (DOAC) are being performed on large groups of AHRE patients in order to evaluate the efficiency of the said drug in the prevention of stroke/systemic embolism. In ARTESIA study, a composite end-point (stroke and systemic embolism) is aimed on administering apixaban 5 mg x 2 /day (or 2.5 mg/day) versus aspirin 81 mg/day to patients with AF and PM, ICD, CRT (19). Also, AFNET study (end-point stroke systemic embolism or cardiovascular death) investigates the efficiency of edoxaban 60 mg/day (30 mg/day) versus aspirin 100 mg/day given to patients with PM or ICD (20). The results of these studies and the newly acquired data regarding the issues of AHRE/subclinical AF will most likely ascertain whether the episodic atrial tachyarrhythmia events have an embolic risk similar to clinical AF (paroxysmal, persistent, permanent) and also similar anticoagulant prevention measures. The relatively frequent proven turning of AHRE/subclinical AF into clinical AF suggests that common elements of thrombogenesis and cardioembolic risk are present. q CONCLUSION Silent atrial fibrillation (subclinical AF), more frequently known as AHRE (atrial heart rhythm episodes), is a non-symptomatic, repetitive tachyarrhythmia of short duration (e.g., minutes), especially occurring in patients with electronic cardiac devices (PM, CRT, ICD). Its average incidence is of approximately 30%, varying with arrhythmia screening methods and cardiovascular condition of the explored patients. The clinical significance of AHRE refers to three conditions: arrhythmic burdens for a certain period of time, cerebral/systemic embolic risk, and the possibility of its turning into cli nical AF. The practical problems in cases of subclinical AF concern the advisability of anticoagulant treatment to prevent cardiac embolism. The individual decision to prescribe OA takes into consideration the arrhythmic burden, the CHA 2 DS 2 -VASc score and the AF or stroke/tia history, cryptogenic stroke included. 264 Maedica A Journal of Clinical Medicine, Volume 13, No. 4, 2018

5 According to present day opinions, prophylactic treatment with OA is recommended to patients with AHRE and stroke/tia history and patients without known history but having AHRE-cut off five hours during one day and CHA 2 DS 2 -VASc 2 (M) and 3 (F). Anticoagulation is not justified for patients with a CHA 2 DS 2 -VASc score of 0 (M) or (F), irrespective of the existence of AHRE. q References 1. Kirchhof P, Benussi S, Kotecha D, et al ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37: org/ /eurheartj/ehw Mahajan R, Perera T, Elliott AD, et al. Subclinical device-detected atrial fibrillation and stroke risk: a systemic review and meta-analysis. Euro Heart J 2018;19: Glotzer TV, Hellkamp AT, Zimmerman J, et al on behalf of the Most Investigators. Atrial high episodes detected by pacemaker diagnostics predict death and stroke: report of the Atrial Diagnostics Ancillary Study of the Mode Selection Trial. Circulation 2003;107: Glotzer TV, Daoud EG, Wyse DE, et al. The relationship between daily atrial tachyarritmia burden from implantable device diagnostic and stroke risk: the TRENDS study. Circ Arrhythm Electrophysiol 2009;2: Healey JS, Connolly SJ, Gold MR, et al on behalf of the ASSERT Investigators. Subclinical atrial fibrillation and risk of stroke. N Engl J Med 2012;366: Healey JS, Martin JL, Duncan A, et al. Pacemaker detected atrial fibrillation in patients with pacemakers: prevalence, prediction and current use of atrial anticoagulation. Can J Cardiol 2013;29: Shanmugan N, Boerdlein A, Proff J, et al. Detection of atrial high-rate events by continuous Home Monitoring: Clinical significance in the heart failure cardiac resynchronization therapy population. Europace 2012;14: Reiffel JA, Verma A, Kowey PR, et al. for the REVEAL AF Investigators. Incidence of previously undiagnosed atrial fibrillation using insertable cardiac monitors in a High-Risk Population the REVEAL AF Study. JAMA Cardiol 2017;919: Kishore A. Vail A, Magid A, et al. Detection of atrial fibrillation after ischemic stroke and transient attack: a systemic review and meta-analysis. Stroke 2014;45: Gorenek B, Bax J, Bariani G, et al. Device-detected subclinical atrial tahyarrhythmias: definition, implications and management. An European Heart Rhythm Association consensus document. Europace 2017;19: Chen Lin Y. Atrial fibrillation burden: moving beyond Atrial Fibrillation as a binary entity. Circulation 2018;137:e623 e Bariani G, GlotzerTV, Santini M, et al. Device-detected atrial fibrillation and risk for stroke: an analysis of > patients from the SOS AF project (Stroke prevention Strategies based on Atrial Fibrillation information from implanted devices). Eur Heart J 2011;35: Sposato LH, Cipriano LL, Riccio PM, et al. Very short paroxysms account for more than half of the cases of atrial fibrillation detected after stroke and TIA: a systemic review and meta-analysis. Int J Stroke 2015;10: Brambatti M, Connolly SJ, Gold MR, et al. on behalf of the ASSERT Investigators. Improved relationship between subclinical atrial fibrillation and embolic events. Circulation 2014, 129: Daoud EG, Glotzer TV, Wyse DE, et al. on behalf of the TRENDS Investigators. Temporal relationship of atrial tachyarrthythmias cerebral atrial events and systemic emboli based on stored device data: a subgroup analysis of TRENDS. Heart Rhythm 2011;8: Ringawala SM, Tomson TT, Passman RS. Cardiac monitoring for atrial fibrillation in cryptogenic stroke. Card Clin 2016;36: Camm JA, Simantirakis E, Goethe A, et al. Atrial high rate episodes and stroke prevention. Europace 2017;19: Bariani G, Botto GL, Padeletti I, et al. Improving stroke risk stratification using CHADS2 and CHA2DS2-VASc risk scores in patients with paroxysmal atrial fibrillation by continuous arrhythmia burden monitoring. Stroke 2011;42: Population Health Research Institute. Apixaban for the Reduction of Thrombo-Embolism in Patients with Device-Detected sub-clinical Atrial Fibrillation (ARTESI). govjet/show/study/ncto/ (Ian 2016). 20. German Atrial Fibrillation Network. Non-vitamin K antagonist Oral Anticoagulants in Patients with Atrial High Rate Episodes (NOAC). gov/ct2 (show) Ntco /Ian Maedica A Journal of Clinical Medicine, Volume 13, No. 4,