key: cord-0842353-tn63urou
authors: Harb, Serge C; Wang, Tom Kai Ming; Nemer, David; Wu, Yuping; Cho, Leslie; Menon, Venu; Wazni, Osama; Cremer, Paul C; Jaber, Wael
title: CHA(2)DS(2)-VASc score stratifies mortality risk in patients with and without atrial fibrillation
date: 2021-11-23
journal: Open Heart
DOI: 10.1136/openhrt-2021-001794
sha: c56d159307754dfd151ee1d326b1bdf90b0ecb97
doc_id: 842353
cord_uid: tn63urou

OBJECTIVES: The CHA(2)DS(2)-VASc score is the preferred risk model for anticoagulation decision-making in atrial fibrillation (AF) patients. Recent studies have found this score to have prognostic value in other cardiovascular diseases. We assessed the relationships between CHA(2)DS(2)-VASc score and long-term mortality in adults referred for stress testing, METHODS: 165 184 consecutive patients from January 1991 to December 2014 from a prospective registry were studied, with CHA(2)DS(2)-VASc score calculated for all patients, and AF and anticoagulation status were recorded. The primary endpoint was all-cause mortality. RESULTS: In this cohort, 12 450 (7.5%) patients had AF and mean CHA(2)DS(2)-VASc score was 2.2±1.2. There were 22 152 (18.4%) deaths during mean follow-up of 6.1±4.8 years. In multivariable analysis, CHA(2)DS(2)-VASc score, presence of AF and anticoagulation use, along with end-stage renal failure and smoking were all independently associated with mortality with HRs (95% CIs) of 1.23 (1.21 to 1.25), 1.18 (1.10 to 1.27) and 1.50 (1.40 to 1.60), respectively. Higher CHA(2)DS(2)-VASc score was incrementally associated with worse survival both in patients with and without AF (log-rank p<0.001). Anticoagulation use was associated with reduced survival in non-AF patients with alternative anticoagulation indications at all CHA(2)DS(2)-VASc score categories, and AF patients with lower CHA(2)DS(2)-VASc score 0–2, but was protective in AF patients with higher CHA(2)DS(2)-VASc score 4–9. CONCLUSION: Incrementally higher CHA2DS2-VASc score, a simple clinical tool, is associated with mortality in patients regardless of presence of AF and anticoagulation status. Anticoagulation use was associated with worse survival in non-AF patients and AF patients with low CHA(2)DS(2)-VASc scores, but was protective in AF patients with high CHA(2)DS(2)-VASc scores.

The CHA 2 DS 2 -VASc score is the most widely used and guideline-recommended model for estimating thromboembolic risk and deciding on anticoagulation therapy in atrial fibrillation (AF) patients. [1] [2] [3] A number of contemporary studies have reported the CHA 2 DS 2 -VASc score to be associated with adverse clinical outcomes in a variety of cardiovascular diseases beyond AF, such as heart failure, acute coronary syndrome, hypertension, cerebrovascular disease, peripheral arterial disease and even non-cardiovascular disease like chronic obstructive pulmonary disease and COVID-19 infection. [4] [5] [6] [7] [8] [9] [10] Whether the CHA 2 DS 2 -VASc score stratify mortality risk in both patients with AF and without AF (non-AF), regardless of the number of co-morbidities, is not well established, but important to investigate given recent interests in clinical electronic medical records (EMR) embedded calculator based risk prediction in general populations. Patients undergoing stress tests are a relatively low-risk cohort compared with those with established cardiovascular disease, and are often referred for risk stratification.

What is already known about this subject? ► CHA2DS2-VASc score is an establishing thromboembolism risk model in atrial fibrillation (AF) patients, however, its prognostic utility in the other general and low-risk populations are less well established.

What does this study add?

► In this large cohort study of 165 184 patients referred for stress tests, the CHA 2 DS 2 -VASc score, along with presence of AF, anticoagulation use and reduced metabolic equivalent of task were independently associated with mortality during follow-up. Whereas CHA 2 DS 2 -VASc score was associated with worse prognosis regardless of AF status, anticoagulation was associated with reduced survival in all non-AF patients and AF patients with low CHA 2 DS 2 -VASc score, but was protective in AF patients with higher CHA 2 DS 2 -VASc score.

How might this impact on clinical practice? ► CHA2DS2-VASc is a simple score that adequately stratifies mortality risk, and can be embedded as a calculator in electronic medical records for widespread use in adults regardless of AF status. This study aimed to evaluate the prognostic utility of CHA 2 DS 2 -VASc score in a large prospective stress testing registry of patients from a tertiary referral centre and its interactions with AF and anticoagulation status. Figure 1 illustrates anticoagulation prescription in the cohort by AF status and CHA 2 DS 2 -VASc score. Anticoagulation use increased with the CHA 2 DS 2 -VASc score category in AF and non-AF patients (p<0.001 for trend in both). In AF patients however, utilisation of anticoagulation in CHA 2 DS 2 -VASc score 3 or higher was only 56%-63%, while in CHA 2 DS 2 -VASc score 0-1 category it was 36%.

Survival by CHA 2 DS 2 -VASc score, AF and anticoagulation status During mean follow-up of 6.1±4.8 years for the cohort, there were 22 152 (13.4%) deaths. Figure 2 (and Central illustration) displays survival by CHA 2 DS 2 -VASc score for the total cohort, non-AF and AF subgroups. Increasing CHA 2 DS 2 -VASc score was associated with reduced survival in all three cohorts (log-rank p<0.001). In addition, for all CHA 2 DS 2 -VASc score categories, AF patients had higher mortality during follow-up than non-AF patients. Figure 3 shows the survival curves of AF and anticoagulation status for each CHA 2 DS 2 -VASc score category. Patients without AF and no anticoagulation use had consistently the best prognosis at all CHA 2 DS 2 -VASc score categories. Patients without AF but with anticoagulation use had the worst prognosis in CHA 2 DS 2 -VASc score 0-1 and 2, but were similar to AF patients at higher CHA 2 DS 2 -VASc scores. In patients with AF, anticoagulation use and survival differed depending on the in CHA 2 DS 2 -VASc score category. Anticoagulation use was associated with increased mortality during follow-up in AF patients at CHA 2 DS 2 -VASc score 0-1 and 2, no difference in CHA 2 DS 2 -VASc score 3, but lower mortality especially later on during follow-up at CHA 2 DS 2 -VASc score of 4 and 5-9.

Multivariable analysis for long-term mortality Results of multivariable analysis for all-cause mortality during follow-up are listed in table 2 in all patients, AF patients only and non-AF patients only. Increasing CHA 2 DS 2 -VASc score was independently associated with long term mortality in all three groups of patients, with adjusted HR (95% CI) of 1.23 (1.21 to 1.25) for the all Figure 4 shows the adjusted hazards ratios for mortality during follow-up by CHA 2 DS 2 -VASc score category in all patients, non-AF and AF patients. There is a markedly increase in risk of death as CHA 2 DS 2 -VASc score increased in adjusted analyses whether AF was present or not.

In this prospective cohort of 165 184 adults with a small proportion having AF (7.5%) and on anticoagulation (8.4%) overall, there were important findings:

(1) Increasing CHA 2 DS 2 -VASc score was associated with higher mortality during follow-up in both univariable and multivariable analysis, and in both AF and non-AF patients, (2) AF itself was also independently associated with worse survival, (3) Furthermore, anticoagulation use in the overall cohort was also associated with mortality during follow-up, and this was true in CHA 2 DS 2 -VASc score categories of non-AF patients but only the lower CHA 2 DS 2 -VASc score categories 0-3 in AF patients and (4) Other factors adjusting for CHA 2 DS 2 -VASc score associated with reduced survival were identified, including smoking history, end-stage renal disease, aspirin use and reduced METs achieved during stress test. Current guidelines continue to advocate using the CHA 2 DS 2 -VASc score to decide on anticoagulation in AF patients for stroke prevention. [1] [2] [3] Other recent studies have also demonstrated the prognostic value of CHA 2 DS 2 -VASc score in various cardiovascular and noncardiovascular diseases, for clinical outcomes beyond stroke such as death, major adverse cardiovascular events, heart failure hospitalisations and cardiac hospitalisations. [4] [5] [6] [7] [8] [9] [10] Most of the patients in these studies have established cardiovascular diseases, are hospitalised and/ or undergoing cardiovascular procedures, whereas our study differs with having a large proportion of patients who are stable outpatients. Even so, the CHA 2 DS 2 -VASc score was an important risk prognosticator in our lower risk population, and this comes as no surprise given that most of the CHA 2 DS 2 -VASc components are known cardiovascular risk factors. Importantly, the CHA 2 DS 2 -VASc score which was traditionally used for stroke (and to lesser extent mortality) risk stratification and anticoagulation guidance in AF patients was shown in our large 'all comers' cohort of stress testing patients to be an elegant tool for long term mortality risk stratification. Furthermore, the prognostic value of CHA 2 DS 2 -VASc score was present in both AF and non-AF patients.

Given that the CHA 2 DS 2 -VASc score is simple and based solely on clinical history and no laboratory or imaging parameters compared with existing Framingham-based cardiovascular risk calculators, ACC/AHA ASCVD risk estimator or SCORE (all of which require either a blood test, an imaging test, or a geographical European location), CHA 2 DS 2 -VASc score may provide a simpler clinical alternative for mortality risk stratification. [12] [13] [14] One parameter of the CHA 2 DS 2 -VASc score that is not a known predictor of mortality is female sex. Indeed, there was a recent change in AF guidelines to using a genderbased threshold, where anticoagulation is not recommended for scores of 0 in men and 0 or 1 in women, can be considered for scores of 1 in men and 2 in women, and recommended with scores of 2 or more in men and 3 or more in women. Removing the female sex parameter may improve the prognostic utility of this score for death as well. CHA 2 DS 2 -VASc can be simply imbedded in any EMR to generate a risk for stroke based on published data, 1 or total mortality risk in patients with or without AF based on the data from this cohort. We believe that this simple yet informative tool can be used by healthcare providers, administrators and most importantly patients to assess treatment strategies, health economics and healthcare/ treatment decision making, respectively.

Another important observation is the association of AF with mortality during follow-up in our population, Cardiac risk factors and prevention which reiterates results from prior studies. [15] [16] [17] AF is well known to be associated with multiple adverse cardiovascular outcomes especially stroke and heart failure, which partly explains the impact on prognosis. 2 3 18 19 Other reasons include adverse events of the therapies used to mitigate the consequences of AF such as bleeding risk associated with anticoagulation and antiarrhythmics. The association between AF and mortality in our cohort persisted after adjusting for the clinical CHA 2 DS 2 -VASc score and anticoagulation, so other mechanisms are at play. AF ablation has been shown to improve cardiovascular outcomes in selected patients meeting inclusion criteria of recent randomised trials, including as initial therapy or with concurrent heart failure. [20] [21] [22] Our findings again highlight the importance of optimal management of AF including risk factor modification, medical therapy and interventions where indicated, and ongoing research necessary to further reduce the mortality risk gap between AF and the general population. 2 3 Our findings also show that AF is a risk marker associated with other unadjusted co-morbidities (such as obesity, sleep apnoea, sedentary life style, untreated hypertension and valvular disease), and potentially contributes to a higher risk of death rather than just an innocent bystander.

Our findings pertaining to anticoagulation status is also interesting. In patients without AF, those taking anticoagulants have worse survival than those without, and this is related to the other underlying medical conditions warranting anticoagulation such as prosthetic heart valves, venous thromboembolism and thrombophilia. In AF patients, the association between anticoagulation use and death is more complex, whereby anticoagulation use had higher mortality during follow-up in lower CHA 2 DS 2 -VASc scores (0-2), and lower mortality CHA 2 DS 2 -VASc at higher scores (4 or more). Our findings are despite the well-established role of thromboembolic stroke prevention of anticoagulants in AF compared with placebo or aspirin, and suggest that the absolute risk reduction of stroke is only greater enough to lead to mortality reduction at higher CHA 2 DS 2 -VASc score. [23] [24] [25] Also, other comorbidities and events that are not adjusted for in our multivariable analysis may increase the risk of death in those on anticoagulation whether AF is present or not, such as malignancy and bleeding. Indeed, most anticoagulation trials did not show significant reduction in mortality, except the very original warfarin versus placebo in AF study, along with apixaban versus warfarin. 25 26 Aspirin use increasing the risk of death is likely related to both the presence of cardiovascular disease and additional Cardiac risk factors and prevention bleeding risk, including when taken together with anticoagulants. 27 28 On the other hand, statin use was associated with improved prognosis, likely related to a substantial proportion of patients having elevated risk of or established cardiovascular diseases. 12 Other factors identified including end-stage renal failure, smoking history and lower METS at time of test are also known to signal poor survival. 11 

This study has some expected limitations. It is a singlecentre observational registry but reflects real-world experience, data were prospectively collected, and is the largest stress testing registry in the literature. The stress testing cohort is not equivalent to the general healthy population to allow direct generalisability, but is of lower risk than established cardiovascular disease cohorts in the literature using the CHA 2 DS 2 -VASc score, and the next step would be testing the score in a general population. The time spanning the study is another limitation given the changes in cardiovascular risk factor burden, definitions of cardiovascular risk factors and diseases, and therapies during the study period. AF diagnosis relied on clinical records without routine monitoring, and AF variables during follow-up such as antiarrhythmic therapy, ablations, and incident AF were not available to us for evaluation. The type of anticoagulation was not available for analysis which have changed substantially over the study period, and their use were based on at the time of stress test, so subsequent use and adherence during follow-up were also not studied. The cause of death data were not available, and other outcomes beyond all-cause mortality such as stroke, myocardial infarction and bleeding were not assessed.

In conclusion, the CHA 2 DS 2 -VASc score was independently associated all-cause mortality during follow-up in this large registry of adult patients undergoing stress tests. This was true in both patients with and without AF, and also whether patients were taking anticoagulation medications or not. AF patients also had lower survival than non-AF patients at the same CHA 2 DS 2 -VASc score category. Anticoagulation use was associated with lower survival in non-AF patients and AF patients with low CHA 2 DS 2 -VASc scores 0-2, but protective in AF patients with high CHA 2 DS 2 -VASc scores 4-9. Overall, the CHA 2 DS 2 -VASc score can be embedded in EMR as a simple clinical tool to assess long term mortality risk in adults regardless of AF status.

Twitter Serge C Harb @SergeHarbMD and Tom Kai Ming Wang @TomKMWang

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Contributors SCH, TKMW, DN, PCC and WJ were involved in the planning and conduct of the study, and YW assisted with statistical analyses. SCH, TKMW and WJ were involved in the writing of the manuscript, and all authors were involved in the critical revision of the manuscript and approved the submission. WJ is responsible for the overall study content as guarantor.Competing interests None declared.Patient consent for publication Not applicable.Ethics approval Institutional review board approval was obtained prior to the commencement of the study (IRB 15-596), and patient consent was waived.Provenance and peer review Not commissioned; externally peer reviewed.Data availability statement All data relevant to the study are included in the article or uploaded as online supplemental information.Open access This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http:// creativecommons. org/ licenses/ by-nc/ 4. 0/.

Serge C Harb http:// orcid. org/ 0000-0002-7442-4928 Tom Kai Ming Wang http:// orcid. org/ 0000-0001-5570-9402