How much atrial fibrillation causes symptoms of heart failure?

ORIGINAL PAPER How much atrial fibrillation causes symptoms of heart failure? M. Guglin, R. Chen Linked Comment: Lip. Int J Clin Pract 2014; 68: 408 9. SUMMARY Introduction: Patients with atrial fibrillation (AF) are more symptomatic than patients with sinus rhythm. However, it is unknown what per cent of time spent in AF is associated with symptoms. Methods: We used a limited access dataset from the Atrial Fibrillation Follow-up Investigation of Rhythm Management trial. Patients had their current rhythm and New York Heart Association (NYHA) class recorded at baseline and at every follow-up visit. The ratio of number of visits when patients were in AF to the total number of visits was used as a surrogate measure of AF burden. The median number of visits was 12 per patient. We grouped patients labelled as class 0 and I by NYHA as having no symptoms and NYHA II or III as having symptoms. Furthermore, we calculated mortality and the prevalence of symptoms depending on the per cent of visits when they had AF. Results: Of 4060 patients enrolled in the trial, 74 had no follow-up visits and were excluded; the remaining 3986 patients were analysed. Patients who had no or little AF throughout the study (0 20%) had the lowest prevalence of symptoms. Prevalence of symptoms increased with greater per cent of time spent in AF. Specifically, symptoms became more prevalent when AF burden reached 20 40%. Mortality was similar regardless of proportion of visits when patients were in AF. Conclusions: Higher AF burden is associated with higher prevalence of symptoms. The increment became significant when patients were in AF at 20 40% of visits. What s known Atrial fibrillation (AF) is associated with more symptoms and poorer exercise tolerance than sinus rhythm. Many symptoms of AF are related to heart failure (HF). What s new It is unknown how much time does the patient need to be in AF to start experiencing symptoms of HF. We demonstrated, for the first time, that symptomatic deterioration in AF starts with 20 40% of time spent in AF. University of South Florida, Tampa, FL, USA Correspondence to: Maya Guglin, University of South Florida, Tampa, FL, USA Tel.: +1 248 346 3507 Fax: +1 813 259 0669 Email: mguglin@gmail.com Disclosure We do not have any conflicts of interest. Introduction Studying the data from the Atrial Fibrillation Followup Investigation of Rhythm Management (AFFIRM) trial, Chung et al. (1) clearly demonstrated that presence of AF was associated with worse functional class, regardless of the treatment arm. In our previous study, we found that symptomatic heart failure (HF) was more common in the rate control than in the rhythm control arm. Unlike prior analyses, we pooled patients without HF symptoms (NYHA, New York Heart Association 0 and I) and with symptomatic HF (NYHA II and III), and based the comparison on the number of follow-up visits when patients current rhythm and NYHA functional class were recorded (2). New York Heart Association includes dyspnoea, fatigue and palpitations, graded by the amount of physical activity producing them. In the context of AF, these symptoms may manifest HF, but not necessarily, because symptoms may be experienced because of AF itself. It remains unknown whether the total amount of time spent in AF is associated with worse symptoms, and if it is, then the question remains, of how much time spent in AF results in more severe symptoms. Our objective was to compare the prevalence of symptoms defined as NYHA II/III depending on the per cent of time spent in AF. Methods We used a limited access dataset from the AFFIRM trial provided by the National Heart, Lung and Blood Institute. This study enrolled 4060 patients with AF who required long-term therapy and who were 65 years of age or older or who had other risk factors for stroke or death (3). Patients current rhythm and NYHA functional class were recorded at baseline and at every follow-up visit. The ratio of number of visits when patients were in AF to the total number of visits (including baseline) was used as a surrogate measure of AF burden. Patients were divided into five groups based on the ratio of visits. doi: 10.1111/ijcp.12262 453

454 Atrial fibrillation and heart failure they appeared to be in AF to the total number of visits: 0 20%, 21 40%, 41 60%, 61 80% and 81 100%. Treatment arm (rate control or rhythm control) was not taken into account. In the trial, patients were classified by the investigators as NYHA functional class 0, I, II and III. There were no patients in NYHA class IV. Because the difference between NYHA 0 and NYHA I is not clear, we grouped patients labelled as class 0 and I by NYHA as having no symptoms and NYHA II or III as having symptoms. For each patient, per cent of follow-up visits when they were in AF ( AF burden ) was calculated. We compared the baseline characteristics of patients based on the per cent of visits they had AF. Symptoms defined as being in NYHA II III class, general mortality, cardiovascular mortality and non-cardiovascular mortality were compared depending on AF burden. Outcomes were adjusted for the baseline differences in the multivariate analysis with linear regression. As over 70% of patients did not have symptoms on any of the follow-up visits, the event of having symptoms was assumed to follow a Poisson distribution. To check the five AF burden categories, a generalised mixed linear model was applied. All statistics was conducted using SAS (version 9.2; SAS, Cary, NC, USA). Results Of 4060 patients enrolled in the trial, 74 had no follow-up visits and were excluded; therefore, a dataset of the remaining 3986 patients was analysed. Mean age was 69.5 8.1 years, and 60.8% were male. Throughout the study, the median number of visits per patient was 12 (range 2 18). The per cent of visits when the patients were in AF was as following: 1871 (46.9%) patients had no or little AF throughout the study (0 20% of visits), 476 (11.9%) had AF on 21 40% of visits, 343 (8.6%) had AF on 41 60% of visits, 346 (8.7%) had AF on 61 80% of visits and 950 (23.8%) had AF on more than 80% of visits. Baseline characteristics of these five groups are detailed in Table 1. The groups differed in gender, diastolic blood pressure which was lower in patients with lowest prevalence of AF, and, as expected, in prevalence of history of HF. Patients who had no or little AF throughout the study (0 20% of visits) had the lowest prevalence of symptoms (7.7%). This group was used as a reference for the other groups with higher prevalence of AF. All groups of patients with greater AF burden had significantly higher prevalence of symptoms (Tables 2 and 3). Thus, 10% of patients who were in AF on 21 40% of follow-up visits had NYHA II III symptoms (odds ratio 1.3, 95% confidence intervals 0.04 0.52, p = 0.02). This number further increased in those who presented in AF at 40 60% of visits (12.7%, odds ratio 1.75, 95% confidence intervals 0.33 0.79, p < 0.0001). Maximal prevalence of symptoms was observed in patients with an AF burden 61 80% (13.7%, odds ratio 1.9, 95% confidence intervals 0.41 0.87, p < 0.001). Prevalence of NYHA Table 1 Baseline characteristics of patients based on the per cent of visits they were in AF Percentage of visits when patients were in AF Overall 0 20% 21 40% 41 60% 61 80% 81 100% p-value 3986 1871 (46.9%) 476 (11.9%) 343 (8.6%) 346 (8.7%) 950 (23.8%) Continuous variables, mean SD Age 69.5 8.1 69.5 8.1 69.5 7.8 69.4 8.4 68.7 8.3 69.7 8.0 0.3844 Systolic blood pressure (mmhg) 134.8 18.9 135.2 19.3 133.1 18.4 134.2 18.2 134.2 18.2 135.2 18.7 0.2025 Diastolic blood pressure (mmhg) 76.4 10 70.0 13.4 74.3 14.8 74.3 14.9 73.6 14.6 76.6 14.1 < 0.0001 Body mass index (kg/m 2 ) 28.9 6.0 28.7 5.9 28.9 5.8 28.9 6.6 29.7 56.1 29.1 56.0 0.1821 Categorical variables, n (%) Gender: male 2423 (60.8) 57.2% 65.8% 56.9% 63.9% 65.6% < 0.0001 History of coronary artery disease 1522 (32.8) 38.1% 40.3% 39.1% 43.4% 35.2% 0.0701 History of congestive heart failure 913 (22.9) 20.5% 24.0% 27.1% 26.3% 24.4% 0.009 History of diabetes 798 (20.0) 20.2% 20.0% 20.4% 25.1% 17.7% 0.0615 History of hypertension 2830 (71.0) 71.5% 68.9% 72.0% 69.7% 71.2% 0.7839 History of myocardial infarction 692 (17.4) 17.2% 18.3% 16.3% 19.1% 17.0% 0.8466 History of stroke 527 (13.2) 12.9% 13.5% 13.4% 15.0% 13.0% 0.8759 Smoking 11.8% 13.7% 15.2% 11.3% 11.4% 0.2967 Rhythm at time of randomisation Atrial fibrillation or flutter 1748 27.7% 55.0% 46.7% 47.0% 76.4% < 0.0001 Sinus 2057 72.3% 45.0% 53.3% 53.0% 23.6%

Atrial fibrillation and heart failure 455 Table 2 Prevalence of symptoms and mortality depending on AF burden AF burden 0 20% 21 40% 41 60% 61 80% 81 100% Total n of patients 1871 476 343 346 950 Symptomatic HF (NYHA II-III), n (%) 144 (7.7) 48 (10.1)* 43 (12.7)* 46 (13.7)* 106 (11.2)* Cardiovascular death, n (%) 124 (6.6) 37 (7.1) 29 (8.5) 22 (6.4) 88 (9.3) Non-cardiac, n (%) 142 (7.6) 34 (7.1) 23 (6.7) 21 (6.1) 53 (5.6) Unknown reason of death, n (%) 15 (0.8) 6 (1.3) 5 (1.5) 7 (2) 15 (1.6) Any death, n (%) 281 (15) 77 (16.2) 57 (16.6) 50 (14.5) 156 (16.4) Symptomatic NYHA classes were significantly more prevalent in the subgroups with higher AF burden, Mortality was not different. AF, atrial fibrillation; HF, heart failure; NYHA, New York Heart Association. *Difference from 0% to 20% group is statistically significant. For details, see Table 3. Table 3 Comparison of prevalence of symptoms between the groups with different prevalence of AF AF burden (%) Odds ratio Standard error Wald 95% Confidence limits p 0 20 Reference 21-40 1.32 0.12 0.04 0.52 0.0227 41 60 1.75 0.12 0.33 0.79 < 0.0001 61 80 1.90 0.12 0.41 0.87 < 0.0001 81 100 1.49 0.09 0.22 0.58 < 0.0001 AF, atrial fibrillation. II III symptoms in patients with AF burden of 41 60% and in those who spent almost all of the time in AF (81 100%) was similar (12.7% and 11.2%, respectively). There was no difference in cardiac, non-cardiac or total mortality depending on per cent of visits when the patients were in AF (Table 2). In multivariate analysis, with gender, diastolic blood pressure and history of HF entered into the model, per cent of visits when patients were in AF was strongly associated with NYHA II/III symptoms (p < 0.0001). Discussion In this retrospective analysis of the AFFIRM limited access dataset, we demonstrated that the least amount of time spent in AF (0 20%) was associated with the most favourable profile in terms of symptoms. Patients who appeared to be in AF on more than 20% of follow-up visits had an increasingly higher prevalence of NYHA II III symptoms. The maximal prevalence of symptoms was observed in patients who spent 61 80% of time in AF. Their risk of having symptoms was almost double (odds ratio 1.9) compared with the lowest risk group. Furthermore, prevalence of NYHA II III symptoms was somewhat lower in those who remained in AF almost all time (81 100%). For this group, the risk of having symptoms was 11.2%, or 1.5 times higher than in those with minimal AF burden group. Because the patients in the AFFIRM trial did not have implantable devices which would accurately record the amount of time spent in AF (true AF burden), we used per cent of visits when patients appeared to be in AF as a surrogate. The number of visits per patients in the AFFIRM trial was quite high, with the median of 12. Fully realising the crudeness of such estimate, we still think it is logical to assume that if somebody had documented AF at 8 of 12 visits, their AF burden was higher than in those who only had AF at the baseline and sinus rhythm at each subsequent visit. The argument about advantages and disadvantages of being in AF is ongoing. It was addressed in two large randomised controlled clinical trials AFFIRM (3) and RACE (4) and multiple publications thereafter. As was demonstrated in both trials, AF is not associated with greater morbidity or mortality than is sinus rhythm. To our knowledge, stratification of these data by AF burden was never conducted before. In this study, cardiac, non-cardiac or total mortality

456 Atrial fibrillation and heart failure was the same regardless of the amount of time patients spent in AF. The Atrial Fibrillation and Congestive Heart Failure trial, which specifically addressed the question on AF in patients with HF secondary to left ventricular systolic dysfunction, also showed that a routine strategy of rhythm control does not reduce the cardiovascular mortality more than a rate control strategy (5). The question about functional status, or symptoms, is more controversial. According to a subanalysis of the AFFIRM, functional status was similar in patients with different degrees of left ventricular systolic dysfunction, whether they were randomised into a rate control or rhythm control arm (6). In addition, in the RACE trial, rate control was not inferior to rhythm control in mild to moderate HF; however, the conclusion was made that, if sinus rhythm could be maintained, outcomes might improve (7). When patients of the AFFIRM were analysed by their actual rhythm, rather than by their arm, it appeared that functional status was better when they were in sinus rhythm, regardless of the treatment strategy as well as of the time elapsing from the beginning of the study, but the amount of AF needed to produce symptoms was not estimated (1). In our prior study (2), we demonstrated for the first time that, in the AFFIRM trial, symptomatic HF was more common in the rate control than in the rhythm control arm. HF was not an inclusion criterion to the AFFIRM trial and was present in a minority of patients. In fact, 90% of all individuals enrolled in the trial had NYHA class 0 or I symptoms. To overcome this limitation, we pooled patients without HF symptoms (NYHA 0 and I) and those with symptomatic HF (NYHA II and III). In an analysis based on actual rhythm, we also found that NYHA functional status was best in patients who were in stable sinus rhythm, was somewhat worse if they were consistently in AF, and much worse if they switched between rhythm control and rate control strategies. Furthermore, patients had fewer symptoms and required fewer medications, such as angiotensin converting enzyme inhibitors and diuretics, when they were in sinus rhythm compared with AF (2). There are many data available regarding the disadvantages of being in AF. For example, AF is associated with an increased total and HF mortality (8) and with a 2.5 times higher likelihood of being in NYHA class III IV vs. I II, even after adjustment for age, left ventricular ejection fraction and aetiology of HF. In additionally, patients with similar functional class and left ventricular ejection fraction have higher BNP (9), shorter 6-min walking distance, poorer quality of life, more severe diastolic dysfunction and more frequent hospitalisations for HF if they also had AF (10). Conversely, being in a normal sinus rhythm was linked to improved survival in the DIAMOND study (11). In an on-treatment analysis of the AFFIRM study, sinus rhythm was also associated with mortality reduction (12). Restoration and maintenance of sinus rhythm for 3 months resulted in improved systolic function (13) and long-term prognosis (14). Similar effects of sinus rhythm on left ventricular ejection fraction and decrease in left atrial size was observed in a subanalysis of the RACE trial (15). When patients with persistent AF and chronic symptomatic HF were randomised to rhythm or rate control, 1 year later, left ventricular systolic function and NT-proBNP levels were better in the rhythm control arm (16). Despite the above observations, the question of quantity of AF translating into worse functional status or symptoms on exertion has not previously been investigated. Intuitively, it seems that more AF would result in worse symptoms; this was true on a comparison of AF burden of 0 20%, 21 40%, 41 60% and 61 80%. The prevalence of symptomatic classes of HF, NYHA II and III, increased from 7.7% to 10.1%, 12.7% and 13.7%, respectively. However, in the group with the highest AF burden, 81 100%, there was a decrease in prevalence of symptomatic HF to 11.2%. In our prior analysis of the AFFIRM, we found something very similar. Specifically, the highest NYHA functional class was not found among patients with stable AF but in patients who changed treatment arms back and forth several times. It appears that stable chronic AF may be better tolerated than is intermittent AF with some amount of time spent in sinus rhythm. Although the number of follow-up visits when the patients were in AF is a crude surrogate for AF burden, NYHA class is a surrogate for symptoms. Exertional dyspnoea or fatigue are quite non-specific and can be a manifestation of HF or AF per se. History of HF was less prevalent in patients with the lowest AF burden, but as the tools, used to establish such a history, were not specified, this finding is very difficult to interpret. Patients in this category could have been less symptomatic before the study because of lower prevalence of HF or because of lower AF burden. Limitations We only analysed the data available from the limited access dataset of the AFFIRM and did not have access to the complete study data. In addition, this was a retrospective analysis of the main trial;

Atrial fibrillation and heart failure 457 therefore, the results should be interpreted with caution. Per cent of clinic visits, when patients were in AF, was used as a surrogate of AF burden. Throughout the text, when we say that AF burden was, for example, 40%, it only means that when the patient came to follow-up visit they were in AF 40% of the visits. Because none of the patients were under continuous monitoring, it is impossible to say what rhythm they were in between the visits. Conclusions Higher AF burden is associated with higher prevalence of symptoms. This increment becomes significant at the level of AF burden of 21 40% and increases progressively until it reached a level of 61 80%. Patients in chronic AF, with a burden 81 100%, demonstrated fewer symptoms than those with less prevalent AF. Acknowledgement The Atrial Fibrillation Follow-up Investigation of Rhythm Management is conducted and supported by the NHLBI in collaboration with the AFFIRM Study Investigators. This manuscript was prepared using a limited access dataset obtained from the NHLBI and does not necessarily reflect the opinions or views of the AFFIRM or the NHLBI. Authorship Maya Guglin study hypothesis, study design, IRB submission, obtaining an agreement with NHLBI, initial statistics, drafting and editing the manuscript. Ren Chen data analysis. Maya Guglin had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. References 1 Chung MK, Shemanski L, Sherman DG et al. Functional status in rate- versus rhythm-control strategies for atrial fibrillation: results of the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Functional Status Substudy. J Am Coll Cardiol 2005; 46: 1891 9. 2 Guglin M, Chen R, Curtis AB. Sinus rhythm is associated with fewer heart failure symptoms: insights from the AFFIRM trial. Heart Rhythm 2010; 7: 596 601. 3 Wyse DG, Waldo AL, DiMarco JP et al. 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