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[email protected] Current Drug Targets, 2017, 18, 000-000
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REVIEW ARTICLE
Stroke Risk Stratification Schemes in Atrial Fibrillation in the Era of NonVitamin K Anticoagulants: Misleading and Obsolete, At Least for the “Low-Risk” Patients? Antonis S. Manolis*, Theodora A. Manolis, Antonis A. Manolis and Helen Melita Third Department of Cardiology, Athens University School of Medicine, and Onassis Cardiac Surgery Center, Athens, Greece
ARTICLE HISTORY Received: June 25, 2016 Revised: August 24, 2016 Accepted: August 30, 2016 DOI: 10.2174/138945011766616090511 1822
Abstract: The thromboembolic risk of atrial fibrillation (AF) is significantly mitigated by oral anticoagulation (OAC) therapy, albeit at an increasing bleeding risk. The general principle is that the expected protective benefit of OAC must not exceed the potential harm conferred by possible bleeding. Over the recent years, the CHA2DS2-VASc score has been proven to be superior to other scores in identifying ‘low risk’ AF patients. However, even this latest score does not incorporate all possible risk factors causing a high thromboembolic risk, while the individual components of the CHA2DS2-VASc score do not seem to carry equal thromboembolic risk. Thus, the quest for more reliable risk stratification schemes and identification of “truly low-risk” patients has been continued. A variety of clinical, echocardiographic, genetic and biochemical or coagulation parameters can also predict adverse thromboembolic events. Nevertheless, the addition or adoption of more complex schemes may defeat the purpose of simplicity and practicality, demanding more extensive and costly assessments to decide on a relatively simple question, that of the need for anticoagulation. In the era of non-vitamin K oral anticoagulants (NOACs), this may not be necessary any more, and a simple recommendation of dispensing OAC therapy almost to every patient afflicted by AF may prove to be a more practical and a ubiquitous approach, as long as safety is ensured by these newer agents. In this article, data concerning the risk stratification schemes and particularly the CHA2DS2-VASc score of 1 and 0, are critically reviewed and a practical algorithm is proposed for all and more specifically for the “low-risk” patients.
Keywords: Anticoagulation, vitamin K anticoagulants, bleeding, non-vitamin K anticoagulants, risk stratification schemes, CHA2DS2-VASc score, lone atrial fibrillation. INTRODUCTION Atrial fibrillation (AF) confers a high risk of thromboembolism, particularly stroke, which is significantly mitigated by oral anticoagulation (OAC) therapy, albeit at an increasing bleeding risk [1]. The general principle is that the expected protective benefit of anticoagulation in lowering the thromboembolic risk must not exceed the potential harm conferred by possible bleeding [2]. Indeed, in a Medicare patient population, a continued, steady decline in ischemic stroke rates between 1992 and 2007 in patients with prevalent AF was reported in parallel to increasing warfarin use (26.7% in 1992; 63.1% in 2007), while the hemorrhagic stroke rate remained constant at nearly 2 per 1000 patientyears throughout the study period [3]. In a large Danish cohort study comprising 132,373 patients with non-valvular AF and assessing both the thromboembolic and bleeding risk, there was increased risk of bleeding but the net clinical benefit was clearly positive, in favour of warfarin, the classical *Address correspondence to this author at the Athens University School of Medicine, Athens, Greece; Tel/Fax: +30-213-2088470 / +30-213-2088676; E-mail:
[email protected] 1389-4501/17 $58.00+.00
vitamin K antagonist (VKA), in patients with increased risk of stroke/thromboembolism; furthermore, the study confirmed the efficacy of VKA and no effect of aspirin treatment on the thromboembolic risk [4]. Earlier on, an attempt was made to identify clinical risk factors for stroke in patients with non-valvular AF [5, 6]. In 1994, an analysis of pooled data from 5 early randomized studies evaluating VKAs in AF patients identified age >65 years, history of hypertension, previous transient ischemic attack (TIA) or stroke, and diabetes as stroke predictive risk factors [5]. Patients younger than 65 years who had none of the other predictive factors (constituting 15% of the population) had an annual rate of stroke of 1%. Initially, the CHADS2 (defined as congestive heart failure, hypertension, age ≥75 years, type 2 diabetes mellitus, previous stroke [doubled]) score was devised and heavily promoted as a popular scoring system for over 10 years because of its simplicity in identifying “high-risk” patients [7]. However, its discriminatory power for low-risk AF patients who may not require OAC was very poor, as the annual stroke rate was still around 2% for patients with a CHADS2 score of 0, suggesting that the CHADS2 score was inadequate and mislead© 2017 Bentham Science Publishers
2 Current Drug Targets, 2017, Vol. 18, No. 5
ing in identifying truly low-risk patients; indeed, among patients with a low-risk CHADS2 (score = 0), the stroke rate could be as high as 3.2-4.5%/year when substratified by the CHA2DS2-VASc score [8, 9]. Thus, the CHA2DS2-VASc score was introduced and has been proven to be superior to the CHADS2 score in identifying “low risk” AF patients [911]. In this new score, the number of risk factors was expanded to include the following additional factors, such as age 65-74 years, presence of vascular disease and female gender, and the increased allotment of 2 points (vs 1 point in CHADS2) for age >75 years. Nevertheless, the quest for more reliable risk stratification schemes and identification of “truly low-risk” patients has not ceased since the introduction and wider acceptance of the CHA2DS2-VASc score, the main reason being that even this latest score does not incorporate all possible risk factors causing a high thromboembolic risk, [12-14] while the individual components of the CHA2DS2-VASc score do not seem to carry equal thromboembolic risk [15]. Factors such as renal dysfunction, obesity, obstructive sleep apnea, tobacco and ethanol use, ethnicity, genetics, echocardiographic (e.g. left atrial size, left atrial appendage-LAA morphology, etc) and biochemical or coagulation parameters (e.g. troponin I, B-type natriuretic peptide, C-reactive protein, von Willebrand factor, D-dimer, etc) can also predict adverse thromboembolic events [13, 14, 16-19]. However, in the long run, the addition or adoption of more complex schemes may defeat the purpose of simplicity and practicality, demanding more extensive and costly assessments to decide on a relatively simple question, that of the need for anticoagulation. In the era of non-vitamin K oral anticoagulants (NOACs),[20] this may not be necessary any more, and a simple recommendation of dispensing OAC therapy to every patient afflicted by AF may prove to be a more practical and ubiquitous approach, as long as safety is ensured by these newer agents (NOACs: dabigatran, rivaroxaban, apixaban, endoxaban). CHA2DS2-VASc SCORE The CHA2DS2-VASc score (congestive heart failure; hypertension; age ≥75 years [doubled]; diabetes; previous stroke, transient ischemic attack, or thromboembolism [doubled]; vascular disease; age 65 to 75 years; and sex category) was introduced in 2009 [21] and is currently the recommended tool as a refined risk score for estimating the risk for thromboembolism in non-valvular AF patients and determining the need for OAC therapy. Adoption of this risk score by the revised 2012 ESC and the revised 2014 ACC/AHA guideline and partial adoption by the 2014 Canadian guideline appears to have substantially increased the proportion of patients recommended for OAC, with near-universal indication for patients older than 65 years [22-25]. Even the most recent 2016 ESC guidelines are heavily relying on this risk score [26]. As there is usually great confusion whether the risk of a female patient assigned a CHA2DS2-VASc score of 1 when aged 65 years or most patients who have a CHADS2 score > 1; they consider that women with vascular disease do not qualify for OAC therapy unless they are aged > 65 or have an additional CHADS2 risk factor [24]. Latest (2014) guidelines by NICE recommend anticoagulation for men with a CHA2DS2VASc score of >1 (https://www.nice.org.uk/guidance/ cg180). This recommendation change was prompted by ample evidence from studies showing a high annual stroke risk in AF patients with a CHA2DS2-VASc score of 1 and no OAC treatment, ranging from 0.5% to 6.6%/year (Table 1) [11, 15, 29, 30]. CHA2DS2-VASc >1 IN MEN / >2 IN WOMEN Thus, OAC is now recommended for more AF patients by the new guidelines by including men with a CHA2DS2VASc score of >1, and practically every patient of either gender older than 65 years. According to the ORBIT AF Registry, two-thirds of patients with AF who were previously not recommended for OAC are newly recommended under the 2014 American guidelines [25]. Post-hoc analysis of a cohort derived from merged datasets of SPORTIF III and V trials indicated that among 1,097 patients of non-valvular AF with only one additional stroke risk factor (i.e. CHA2DS2-VASc= 1 in males or 2 in females), the rates of major adverse events (stroke/systemic thromboembolic event, mortality) were high, despite being anticoagulated [31]. Time in therapeutic range (TTR) in warfarin-treated patients was inversely associated with the occurrence of both stroke/systemic thromboembolic event and all-cause death. Among 2,177 (24%) of 8,962 AF patients having zero or one additional stroke risk factor, ie, CHA2DS2-VASc score = 1 in men, 2 in women (53% were prescribed OAC), over a mean follow-up of 2.7 years, OAC use was independently associated with an improved prognosis for stroke/systemic thromboembolism/death) (adjusted hazard ratio-HR, 0.59; P = 0.007) [32]. According to a meta-analysis of 6 reports enrolling a total of 2594 patients with AF, a high CHA2DS2-VASc score was
Dispensing with the Risk Stratification Schemes in AF?
Table 1.
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3
Thromboembolic event rates in AF patients with CHA2DS2-VASc score of 1.
Study
Patients/Group (n/N)
Gender
Annual Event Rate
OAC
NOAC
Poli 2011 [42]
35/662
Both
0.8%
√
--
Olesen 2011 [4]
15,866/132,372
Both
1.6%
-- / √
--
Olesen 2011 [11]
8,203/73,538
Both
2.01%
--
--
Friberg 2012 [43]
6770/90,706
Both
0.6% †
-- / √
--
Singer 2013 [44]
NR/10,927
Both
0.55%
--
--
Huang 2014 [29]
358/9,727
Both
6.6%
--
--
Chao 2014 [36]
19,325/186,570
Both
1.72%
--
--
Lip 2014 [45]
12,756/72,452
Both
2.94%
--
--
Chao 2015 [15]
12,935/186,570
Male
2.75%
--
--
van den Ham 2015 [46]
6,544/60,594
Both
0.78%
--
--
Abumuaileq 2015 [18]
95/1,065
Both
1.05%
√
--
Lip 2015 [47]
NR/22,582
Male
4.32%
--
--
Lip 2015 [30]
18,287/39,400
Both
1.55% *
--/√
--
Friberg 2015 [48]
12,298/140,420
Both
0.5-0.9%‡
--
--
Chao 2016 [9]
19,325/186,570
Both
2.11%
--
--
Aspberg 2016 [77]
15,694/152,153
Both
0.7%
--
--
Proietti 2016 [31]
1,097/7,329
Both**
1.4% ***
-- / √
--
Chan 2016 [49]
27,521/190,210
Both
1.98%
--
--
AF = atrial fibrillation; NOAC = non-vitamin oral anticoagulant; OAC = oral anticoagulant; NR = not reported 1.3% for those who were anticoagulated † 0.3% for those who were anticoagulated ‡ ischemic stroke rate for women 0.1-0.2% / event rate of 1.3% in men for TIA, pulmonary embolism, arterial embolism, and all strokes (ischemic or hemorrhagic) * 1.06% for those who were anticoagulated ** CHA2DS2-VASc= 1 in males, or 2 in females *** 0.9% for those who were anticoagulated.
independently associated with the presence of left atrial thrombus/spontaneous echocardiographic contrast in patients with non-valvular AF [33]. This pooled analysis demonstrated a statistically significant 70% increase in detection of thrombus or echo contrast with higher CHA2DS2-VASc score to lower CHA2DS2-VASc score in the random effects model (OR, 1.70; P = 0.006); only patients with a CHA2DS2-VASc score of 0 were free of left atrial thrombus. The CHA2DS2-VASc score is also predictive of thromboembolism in conjunction with cardioversion [34]. Among 22,874 AF patients undergoing electrical cardioversion, 10,722 with and 12,152 without OAC pre-treatment, those with low stroke risk (CHA2DS2-VASc 0–1) did not suffer from any thromboembolic complications within 30 days after cardioversion. However, cardioversion without prior anticoagulation was not safe for patients with risk factors for thromboembolism (CHA2DS2-VASc score >1 point). Among patients with medium and high thromboembolic risk, there were fewer thromboembolic complications among those using OAC prior to cardioversion. After adjustment for risk factors included in CHA2DS2-VASc, the odds ratio
(OR) for thromboembolic complications within 30 days after cardioversion was 2.54 (p < 0.001) for patients without anticoagulation, compared to patients with anticoagulation. Among 8981 patients (mean age, 65 years; 42% male) admitted to the hospital with a diagnosis of AF, over a mean follow-up of 46 months, the CHA2DS2-VASc score was an independent prognostic marker of poor outcomes following hospitalization [35]. Specifically, mortality rates of patients with CHA2DS2-VASc scores of 0, 1, and ≥2 were 23.2, 42.3, and 54% for total population, and 21.5, 41.4, and 54.2% for those without rheumatic heart disease respectively. By multivariate analysis, a high CHA2DS2-VASc score and the presence of chronic kidney disease were among the worst prognostic factors. Compared to CHA2DS2-VASc 0, a CHA2DS2-VASc 1 had a hazard ratio of 1.33 and a CHA2DS2-VASc of 2 a hazard ratio of 1.50 for death after AF hospitalization [35]. CHA2DS2-VASc 0-1 A CHA2DS2-VASc score of 0 has been considered to predict a truly low incidence of stroke, with an annual
4 Current Drug Targets, 2017, Vol. 18, No. 5
Manolis et al.
ischemic stroke rate of approximately 1% [36]. More specifically, a CHA2DS2-VASc score of 0 identified a cohort at low, albeit non-negligible, risk with annual event rates at 1-, 5-, 10-, and 15-year follow-up examinations of 1.06, 1.00, 1.09, and 1.15 per 100 person-years, respectively [36]. Other studies have also shown low, but non-zero, stroke risk with a CHA2DS2-VASc score of 0 (Table 2). A nationwide Danish cohort study validating the CHA2DS2-VASc score indicated that among 73,538 patients with non-valvular AF, the rate of thromboembolism per 100 person-years was 0.78 in patients at "low risk" (score = 0) at one year's follow-up [11]. In another study comprising 39,400 patients discharged with incident nonvalvular AF with 0 or 1 CHA2DS2-VASc risk factor (23,572 not treated, 5,353 placed on aspirin, and 10,475 on warfarin), stroke event rates for untreated low-risk patients with a CHA2DS2-VASc score of 0 (male) or 1 (female) were 0.49 per 100 person-years at 1 year and 0.47 per 100 person-years at full follow-up (mean 5.9 years) [30].
additional risk factors who though have a CHA2DS2-VASc score of 1 (solely attributable to female gender) [38]. Although the former group appear to be of truly low risk, the latter group may be of much higher stroke risk. CHA2DS2-VASc 1 IN WOMEN Although there is universal agreement that AF women over 65 years (CHA2DS2-VASc score 2) with no additional risk factors have a higher risk than their male counterparts (CHA2DS2-VASc score 1), [39] there is dispute whether younger ( 2-fold higher risk of stroke (hazard ratio of 2.3) compared with 190 patients with CHA2DS2-VASc score of 0.
The problem with the newer CHA2DS2-VASc score, as was with its predecessor, relates to the fact that it was validated in different patient populations, leading to markedly different estimated stroke risks [37]. Nevertheless, as mentioned, the data indicate that CHA2DS2-VASc score better stratifies AF patients who are truly low-risk (score of 0 for male or 1 for female) who should not be offered anticoagulation as the risks outweigh the benefits. However, these data emanate mostly or exclusively from studies utilizing VKAs (Tables 1 & 2) [32]. Some data indicate that the strategy for thromboprophylaxis may need to be different for male AF patients with no additional risk factors (CHA2DS2-VASc score 0) from the one needed for female patients with no Table 2.
A higher risk of stroke and mortality over a median of ~15 years has also been confirmed for 1011 women (2.9%) who developed AF among 34,722 women aged > 45 years participating in the Women’s Health Study who were free of AF and cardiovascular disease at baseline [40]. Women who developed AF compared with those who did not, had higher incidence rates of all-cause mortality per 1000 person-years
Thromboembolic event rates in AF patients with CHA2DS2-VASc score of 0. Study
Patients/Group (n/N)
Gender
Annual Event Rate
OAC
NOAC
Poli 2011 [42]
12/662
Male
0%
√
--
Olesen 2011 [11]
6,369/73,538
Male
0.78%
--
--
Friberg 2012 [43]
5,538/90,706
Male
0.2%
-- / √
--
Taillandier 2012 [55]
616/8,962
Male
0.69%
-- / √
--
Singer 2013 [44]
NR/10,927
Male
0.04%
--
--
Huang 2014 [29]
190/9,727
Male
2.4%
--
--
Chao 2014 [36]
9,416/186,570
Male
1.06%
--
--
Lip 2014 [45]
20,851/72,452
Male
1.13%
--
--
van den Ham 2015 [46]
4000/60,594
Male
0.38%
--
--
Abumuaileq 2015 [18]
67/1,065
Male
0%
√
--
Lip 2015 [47]
NR/22,582
Male
1.13%
--
--
Lip 2015 [30]
12,685/39,400
Male
0.49-0.88%
--/√
--
Chao 2016 [9]
9,416/186,570
Male
1.15%
--
--
Aspberg 2016 [77]
12,266/152,153
Male
0.4%
--
--
Chan 2016 [49]
27,521/190,210
Male
1.18%
--
--
Dispensing with the Risk Stratification Schemes in AF?
(10.8 vs 3.1), cardiovascular (4.3 vs 0.57) and noncardiovascular mortality (6.5 vs 2.5). In multivariable models, hazard ratios (HRs) of new-onset AF for all-cause, cardiovascular, and noncardiovascular mortality were 2.14, 4.18, and 1.66, respectively. Adjustment for nonfatal cardiovascular events potentially leading to death attenuated these risks, but incident AF remained associated with all mortality components (all-cause: HR, 1.70; cardiovascular: HR, 2.57; and noncardiovascular: HR, 1.42). Among women with paroxysmal AF (n=656), the increase in mortality risk was limited to cardiovascular causes (HR, 2.94), raising the possibility that individuals with paroxysmal AF may have a lower mortality risk than those with other AF patterns (persistent or permanent). Thus, newly identified AF in apparently healthy women, initially free of any risk factor, portends a worrisome prognosis and should be treated aggressively with OAC therapy which is known to reduce stroke and mortality risk, as there is no reliable way to apriori identify those who will not subsequently develop cardiovascular risk factors and will thus continue remaining at low risk. Somewhat contrasting findings came from a Swedish cohort study of 100,802 patients with AF followed-up for a median 1.2 years. Women with AF had a moderately increased risk of stroke compared with men (6.2% vs 4.2% per year; hazard ratio 1.47, P65 YEARS BUT 65 years with no other risk factor [4, 8, 22, 24, 51] (www.nice.org.uk/ guidance/cg180). Of course, this also holds true for women aged > 65 years, who by definition have a CHA2DS2-VASc score of 2. The risk of thromboembolism increases with increasing age > 65 years, [52] rising approximately 1.5-fold per decade [53]. The issue of the need for OAC therapy remains controversial for women with AF aged or = 65 years of age with well-preserved left ventricular systolic function. Am J Cardiol 2005; 96(6): 832-6. Laukkanen JA, Kurl S, Eranen J, Huttunen M, Salonen JT. Left atrium size and the risk of cardiovascular death in middle-aged men. Arch Intern Med 2005; 165(15): 1788-93. Di Biase L, Santangeli P, Anselmino M, et al. Does the left atrial appendage morphology correlate with the risk of stroke in patients with atrial fibrillation? Results from a multicenter study. J Am Coll Cardiol 2012; 60(6): 531-8. Friberg L, Hammar N, Rosenqvist M. Stroke in paroxysmal atrial fibrillation: report from the Stockholm Cohort of Atrial Fibrillation. Eur Heart J 2010; 31(8): 967-75. Inoue H, Atarashi H, Okumura K, Yamashita T, Kumagai N, Origasa H. Thromboembolic events in paroxysmal vs. permanent nonvalvular atrial fibrillation. Subanalysis of the J-RHYTHM Registry. Circ J 2014; 78(10): 2388-93. Lip GY, Frison L, Grind M. Stroke event rates in anticoagulated patients with paroxysmal atrial fibrillation. J Intern Med 2008; 264(1): 50-61. Al-Khatib SM, Thomas L, Wallentin L, et al. Outcomes of apixaban vs. warfarin by type and duration of atrial fibrillation: results from the ARISTOTLE trial. Eur Heart J 2013; 34(31): 2464-71. Chen LY, Agarwal SK, Norby FL, et al. Persistent but not Paroxysmal Atrial Fibrillation Is Independently Associated With Lower Cognitive Function: ARIC Study. J Am Coll Cardiol 2016; 67(11): 1379-80. Vidal-Perez R, Otero-Ravina F, Lado-Lopez M, et al. The change in the atrial fibrillation type as a prognosis marker in a community study: long-term data from AFBAR (Atrial Fibrillation in the BARbanza) study. Int J Cardiol 2013; 168(3): 2146-52. Walters TE, Nisbet A, Morris GM, et al. Progression of atrial remodeling in patients with high-burden atrial fibrillation: Implications for early ablative intervention. Heart Rhythm 2016; 13(2): 331-9. Anter E. Paroxysmal atrial fibrillation: A window of opportunity to modify disease progression. Heart Rhythm 2016; 13(2): 340-1.
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