Association between Statin use and the risk of atrial fibrillation in community-dwelling older people in Shanghai, China：a propensity score-matched study

doi:10.21203/rs.3.rs-4354297/v1

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Association between Statin use and the risk of atrial fibrillation in community-dwelling older people in Shanghai, China：a propensity score-matched study

https://doi.org/10.21203/rs.3.rs-4354297/v1

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Objective: Whether statins prevent atrial fibrillation remains unclear. In particular, the data on the elderly are limited. Thus we investigated the association between statin use and the risk of atrial fibrillation (AF) in community-dwelling older people in Shanghai ,China.

Methods: This registry-based cohort study was conducted in one community in Shanghai. Participants without history of AF were enrolled in this study, then new-onset of AF was recorded and evaluated in the followed three years. Poisson generalized linear models were conducted to examine the association between statin therapy and the incidence of AF. All analysis were performed with both conventional adjustment and propensity score matching methods. Univariate and multivariate regression analysis were performed to evaluate the risk factor of AF in community-dwelling older people

Results: In the cohort of 5675 participants (43.5% men; median age, 68.0 years), 456 (8.0%) were treated with stains. Two propensity score-matched cohorts of 453 participants (with or without statin treatment) were analyzed, in respectively. Statin use did not reduce the proportion of atrial fibrillation incidence, with hazard ratios (HRs) and 95% confidence intervals (CIs) of 0.982(0.948 to 1.018) (p＞0.05) in the unmatched cohort and 0.833 (0.459 to 1.512) (p＞0.05) in the matched cohort. The result of multivariate regression analysis showed that age, systolic blood pressure (SBP), BMI, Serum creatinine (Scr), total cholesterol (TC),were the independent risk factors of the new onset of AF.

Conclusion: Older age, SBP, BMI, Scr, TC, were independent predictors of AF onset. However, statin use was not associated with a decreased risk of atrial fibrillation incidence of AF in the elderly.

atrial fibrillation

statins

community-dwelling older people

Atrial fibrillation (AF) is the most common arrhythmia in adults and its prevalence is increasing rapidly. A nationwide survey of adults in China about AF prevalence showed that AF prevalence was 1.8%, but it varied according to the geographical regions[1] .AF is associated with increased cardiovascular morbidity and mortality, with stroke being an important and potentially devastating complication[2]. Available drug therapy for atrial fibrillation has major limitations, such as low blood pressure, bradycardia, cardiac arrest[2] Hence, there is growing interest among researchers in seeking improved therapeutic approaches regarding AF. Statins as the newly upstream drug, the effects in AF is associated with the multiple mechanisms[3] [4]. Such as, statins can improve vascular endothelial function in order to alleviate atrial tissue ischemia reducing the incidence of AF, statins can remodel the electrical and modulate inflammation [5, 6].Although some studies have shown the existence of protective effect, the role of statins in the primary prevention of atrial fibrillation remains controversial [7, 8]. The study population and research methods may be the reasons for the different results.

As far as we know, the study concerning statin effects of AF in the elderly are few, and the result of the studies remain debate. The primary aim of the study was to determine whether statin use could reduce new-onset AF in elder patients. Second, we assessed predictors of new-onset AF of the elderly in dwell-community.

Study Design and Participants

Data of this study were obtained from the Physical Examination System of Community Health Service Center. Free medical physical examination services are provided annually to community-dwelling people aged ≥ 60 years in Shanghai, China. We obtained the electronic medical records of health examinations from the Physical Examination System in 2018,2019,2020,2021. Given the focus of this study, we assembled a cohort, with participants who being not with AF in 2018 eligible for the baseline study and has no history of AF before. Follow-up was conducted in 2019, 2020, 2021 and new-onset AF during follow-up was recorded. New-onset AF adjudicated by a standard 12-lead electrocardiogram at a core laboratory reading center. Therefore, using the physical examination data from 2018 to 2021, we analyzed the relationship of satin prescription with new-onset in both stain users and nonusers. Then we explore the risk factors of new-onset AF in the elder people. All procedures were performed in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Shanghai Pudong Hospital, Fudan University. Written consent was obtained from each participant after they had been informed of the objectives, benefits, medical items, and confidentiality of personal information.

Participants were eligible for the study if they (1)were ≥ 60 years old, (2) had a Shanghai household registration or were resident in this community for more than three years,(3)without AF or AF history and (4)had complete baseline data in 2018 and 12-lead electrocardiogram at a core laboratory reading center in 2019,2020,2021.Exclusion criteria included (1) with AF in 2018 and a history of AF,(2) incomplete baseline data provided in 2018,(3)presence of severe mental illness, cognitive impairment or malignant tumors in 2018, and (4) incomplete 12-lead electrocardiogram at a core laboratory reading center provided in 2019,2020,2021(Fig. 1)

Data Collection and Outcome Measures

For each patient, comprehensive data were extracted from electronic medical records. Medical records included participant demographics (age and sex), body mass index (BMI), waist-to-hip ratio(WHR), systolic blood pressure (SBP) and diastolic blood pressure (DBP), history of smoking and drinking. We also collected information on participant clinical data ( including the prescription of angina-ten, sin-converting-enzyme inhibitor/angiotensin receptor blockers[ACEIs/ARBs]), calcium channel blockers[CCBs], beta-blocker, diuretics, and antidiabetic drugs, and medical history of hypertension and diabetes mellitus) and laboratory data (including glycated hemoglobin [HbA1c], fasting plasma glucose[FPG], total cholesterol [TC], triglyceride [TG], high-density lipoprotein [HDL], low-density lipoprotein [LDL], aspartate transaminase [AST], alanine transaminase [ALT],blood urea nitrogen[BUN],total bilirubin[TBIL],uric acid [UA] and serum creatinine [Scr] ), Neutrophil percentage(N%), Lymphocyte percentage(L%).

New-onset AF was defined as 12-lead electrocardiogram test manifested with AF in the follow up year and had no history of AF.

Statistical analysis

To reduce potential confounding and selection bias, we use the propensity score-matching method. propensity scores were calculated through a logistic regression model, with statin users versus nonusers as the dependent variable and covariates measured at baseline as independent variables(Table 1). Matched pairs were obtained using a greedy nearest-neighbor matching algorithm(1:1 ratio, without replacement ) and with a caliper width equal to 0.2 of the SD of the logit of the propensity score. A standardized difference of less than 0.1 was used to indicate a negligible difference in covariates between the groups.

Poisson generalized linear models were conducted to explore the association between statin use and new-onset AF rates. Univariate binary logistic regression analysis(P<0.1 was considered as significant) and multivariate logistic regression analysis (P<0.05 was considered as significant)were performed to test the predictor of the new-onset of the community dwelling older people. Statistical analysis was performed by SPSS (NY, USA).

New-on set of AF and effect of statin treatment

The study cohort comprised 5675 older Chinese people. Their median age was 67(64, 71) years old, and 2467 (34%) were men. Statins were prescribed to 8.03% (456 of 5675) of the participants. Compared with the nonstatin use group, the statin use group had a higher prevalence of female participants, ARB/ACEI drugs, Beta-blockers drugs, Diuretic drugs, CCBs drugs, higher rate of drinking history, higher levels of AST, LDL-c, TC, median age and had a lower rate of smoking history, the antidiabetic drugs, lower level of FPG. Two propensity score-matched cohorts of 453 participants were defined according to statin use and analyzed. After propensity score matching, no significant differences in baseline characteristics were found between statin and nonstatin groups (Table 1). Participants were followed up for 3 years. The incidences of new-onset AF for one, two, and three times were 3.7% (17of 456), 1.1% (5 of 456), an 0.9% (3of 456) in the unmatched cohort for statin users, and 4.3% (223 of 5675), 1.4% (74of 5675), and 0.9% (45 of 5675) for nonusers (p = 0.73) (Fig. 2A).

After propensity score matching, the incidences were 3.5% (16 of 453), 1.5% (7 of 453), and 0.9% (4 of 453) for non-statin users and 3.5% (16of 453), 1.1% (5 of 453), and 0.7% (3of 453) for statin-users (p = 0.698) (Fig. 2B). Poisson generalized linear analyses showed that statin use was not significantly associated with a decreased risk of new-onset AF, with hazard ratios (HRs) and 95% confidence intervals (CIs) of 0.982(0.948 to 1.018) (p>0.05) after adjustment for the covariates in the unmatched cohort and 0.833(0.459to 1.512) (p>0.05) in the matched cohort (Table 2)

Other predictors of new-onset AF

To identify the most important factors associated with new-onset AF of the community old people, we made Univariate and Multivariate regression analysis to explore the risk factor of AF in community-dwelling older people. Univariate analysis result showed that sex, age, SBP, BMI, WHR, Scr, HbA1c were significantly different between the AF group and non-AF group. Sex, age, SBP, BMI, Scr, TC were the independent risk factors for the AF of old people

The role of statin in atrial fibrillation is controversial. Differences in the study population and methodology, as well as the number of years of follow-up, may have contributed to the different results of the studies.

In the present study, we used both a conventional adjustment method and propensity score-matching method to evaluate the association between statin prescription and new-onset AF in community-dwelling older people. This study has shown that statin use was not associated with a decreased risk of new-onset AF with HRs (95% CIs) of 0.982(0.948 to 1.018)(p>0.05) in the unmatched cohort and 0.833(0.459 to 1.512) (p>0.05) in the matched cohort. Our study result was consistent with a meta-analysis by Fauchier et al. of nine RCTs, statin therapy had no beneficial effect on primary prevention of AF (OR: 1.00, 95% CI: 0.86–1.15)[9]. And the result of a retrospective study including individuals between 70 and 82 years of age with a history of established vascular disease also showed pravastatin had no effect on primary prevention of AF [10]. Perioperative statin therapy did not prevent postoperative atrial fibrillation in patients undergoing elective cardiac surgery. Acute kidney injury was more common with rosuvastatin[11].Statins have been shown to reduce the incidence of postoperative atrial fibrillation in perioperative cardiac patients in previous studies [12] [13], and meta-analyses have shown that statin use in electrically cardioverted patients also reduces the recurrence of atrial fibrillation [14]. Statins can reduce the risk of atrial fibrillation in patients with chronic kidney disease[15], they are effective in reducing new-onset atrial fibrillation in people with a first myocardial infarction[16], and high-dose atorvastatin is effective in preventing new-onset atrial fibrillation in patients with a previous stroke[17]. Previous studies have shown that the type of statin dose and duration of statin application may also be important in determining whether statins are effective. Overall, the effectiveness of statins in treating and preventing the onset of disease is controversial. In the present study, it might be showed that the treatment period was not enough to show any benefit. However, Fig. 1 demonstrates that during and at the end of 3 years, there was a very similar incidence of AF in the matched and unmatched groups, with no suggestion of a trend in favor of either group that might have continued significance in a longer study of the old people. Our study does not indicate whether the type and dose of statin will have an effect on whether the incidence of atrial fibrillation in older people in the community.

In addition, we analysed the risk factors for new onset of AF in the elderly and showed that age, gender, systolic blood pressure, BMI, blood creatinine, and total cholesterol were independent risk factors for new onset of AF in the elderly. As we all know, age and gender are the risk factors for the AF [2], cohort study meta-analysis showed that BMI also associated with the incidence of AF, Study shows significant correlation between obesity and the development of atrial fibrillation[18] [19] [20]. In our study, we found that blood creatinine is the independent risk factor of AF in the elderly, Some studies suggest that reduced kidney function is a risk factor for atrial fibrillation[21].

At the same time, there are some limitations of the study. First, we could not conclude whether the association depended on the type of statin, the dose, or the duration of treatment, so more research is needed to clarify the type of statin in future studies to confirm the association of statins with new-onset atrial fibrillation in community-dwelling elderly populations. Second, this was a retrospective observational study, which is not a perfect substitute for a randomized trial. Finally, our results were obtained from one community in Shanghai and are therefore insufficient to generalize to China as a whole. Therefore, further validation of studies involving other regions would better reflect the results of a nationwide population.

The results of this study suggest that statin use was not associated with a decreased risk of new-onset AF in community-dwelling older people in Shanghai, China. Further randomized controlled studies are needed to confirm the AF efficacy of statins among community-dwelling older people.

atrial fibrillation

Scr

serum creatinine

BMI

body mass index

WHR

waist-to-hip ratio

SBP

systolic blood pressure

DBP

diastolic blood pressure

ACEIs/ARBs

angiotensin converting-enzyme inhibitors/angiotensin receptor blockers

CCBs

calcium channel blockers

HbA1c

glycated hemoglobin

FPG

fasting plasma glucose

total cholesterol

triglycerides

HDL

high-density lipoprotein

LDL

low density lipoprotein

AST

aspartate transaminase

ALT

alanine transaminase

BUN

blood urea nitrogen

TBIL

total bilirubin

uric acid

hazard ratio

confidence interval

HMG-CoA

hydroxymethylglutaryl-CoA.

Data Sharing Statement

All the data supporting the study findings are within the manuscript. Addition detailed information and raw data are Available from the corresponding author on reasonable request.

Ethics Approval and Informed Consent

The study was performed in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Shanghai Pudong Hospital, Fudan University. Written consent was obtained from each participant after they had been informed of the objectives, benefits, medical items, and confidentiality of personal information.

Funding

No funding

Acknowledgments

We thank all participants for their dedication to the study.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Conflicts

The authors report no conflicts of interest in this work.

Du X, Guo L, Xia S, Du J, Anderson C, Arima H, Huffman M, Yuan Y, Zheng Y, Wu S et al: Atrial fibrillation prevalence, awareness and management in a nationwide survey of adults in China. Heart 2021, 107(7):535-541.
Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomstroem-Lundqvist C, Boriani G, Castella M, Dan G-A, Dilaveris PE et al: 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). European Heart Journal 2021, 42(5):373-498.
Harada M, Van Wagoner DR, Nattel S: Role of Inflammation in Atrial Fibrillation Pathophysiology and Management. Circulation Journal 2015, 79(3):495-502.
Oesterle A, Laufs U, Liao JK: Pleiotropic Effects of Statins on the Cardiovascular System. Circulation Research 2017, 120(1):229-243.
Pinho-Gomes AC, Reilly S, Brandes RP, Casadei B: Targeting Inflammation and Oxidative Stress in Atrial Fibrillation: Role of 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibition with Statins. Antioxidants & Redox Signaling 2014, 20(8):1268-1285.
Laszlo R, Menzel KA, Bentz K, Schreiner B, Kettering K, Eick C, Schreieck J: Atorvastatin treatment affects atrial ion currents and their tachycardia-induced remodeling in rabbits. Life Sciences 2010, 87(15-16):507-513.
Bang CN, Greve AM, Boman K, Egstrup K, Gohlke-Baerwolf C, Kober L, Nienaber CA, Ray S, Rossebo AB, Wachtell K: Effect of lipid lowering on new-onset atrial fibrillation in patients with asymptomatic aortic stenosis: The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. American Heart Journal 2012, 163(4):690-696.
Haywood LJ, Ford CE, Crow RS, Davis BR, Massie BM, Einhorn PT, Williard A: Atrial Fibrillation at Baseline and During Follow-Up in ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial). Journal of the American College of Cardiology 2009, 54(22):2023-2031.
Fauchier L, Clementy N, Babuty D: Statin therapy and atrial fibrillation: systematic review and updated meta-analysis of published randomized controlled trials. Current Opinion in Cardiology 2013, 28(1):7-18.
Macfarlane PW, Murray H, Sattar N, Stott DJ, Ford I, Buckley B, Jukema JW, Westendorp RGJ, Shepherd J: The incidence and risk factors for new onset atrial fibrillation in the PROSPER study. Europace 2011, 13(5):634-639.
Zheng Z, Jayaram R, Jiang L, Emberson J, Zhao Y, Li Q, Du J, Guarguagli S, Hill M, Chen Z et al: Perioperative Rosuvastatin in Cardiac Surgery. New England Journal of Medicine 2016, 374(18):1744-1753.
Goh SL, Yap KH, Chua KC, Chao VTT: Does preoperative statin therapy prevent postoperative atrial fibrillation in patients undergoing cardiac surgery? Interactive Cardiovascular and Thoracic Surgery 2015, 20(3):422-428.
Patti G, Bennett R, Seshasai SRK, Cannon CP, Cavallari I, Chello M, Nusca A, Mega S, Caorsi C, Spadaccio C et al: Statin pretreatment and risk of in-hospital atrial fibrillation among patients undergoing cardiac surgery: a collaborative meta-analysis of 11 randomized controlled trials. Europace 2015, 17(6):855-863.
Yan P, Dong P, Li Z, Cheng J: Statin Therapy Decreased the Recurrence Frequency of Atrial Fibrillation after Electrical Cardioversion: A Meta-Analysis. Medical Science Monitor 2014, 20:2753-2758.
Chang C-H, Lee Y-C, Tsai C-T, Chang S-N, Chung Y-H, Lin M-S, Lin J-W, Lai M-S: Continuation of statin therapy and a decreased risk of atrial fibrillation/flutter in patients with and without chronic kidney disease. Atherosclerosis 2014, 232(1):224-230.
Bang CN, Gislason GH, Greve AM, Torp-Pedersen C, Kober L, Wachtell K: Statins reduce new-onset atrial fibrillation in a first-time myocardial infarction population: a nationwide propensity score-matched study. European Journal of Preventive Cardiology 2014, 21(3):330-338.
Schwartz GG, Chaitman BR, Goldberger JJ, Messig M: High-dose atorvastatin and risk of atrial fibrillation in patients with prior stroke or transient ischemic attack: Analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. American Heart Journal 2011, 161(5):993-999.
Middeldorp ME, Kamsani SH, Sanders P: Obesity and atrial fibrillation: Prevalence, pathogenesis, and prognosis. Progress in Cardiovascular Diseases 2023, 78:34-42.
Limpitikul WB, Das S: Obesity-Related Atrial Fibrillation: Cardiac Manifestation of a Systemic Disease. Journal of Cardiovascular Development and Disease 2023, 10(8).
Shu H, Cheng J, Li N, Zhang Z, Nie J, Peng Y, Wang Y, Wang DW, Zhou N: Obesity and atrial fibrillation: a narrative review from arrhythmogenic mechanisms to clinical significance. Cardiovascular Diabetology 2023, 22(1).
Laukkanen JA, Zaccardi F, Karppi J, Ronkainen K, Kurl S: Reduced kidney function is a risk factor for atrial fibrillation. Nephrology 2016, 21(8):717-720.

Tables 1 to 4 are available in the Supplementary Files section

No competing interests reported.

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Association between Statin use and the risk of atrial fibrillation in community-dwelling older people in Shanghai, China：a propensity score-matched study

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