Female "Paradox" in Atrial Fibrillation-Role of Left Truncation Due to Competing Risks

Overview

Journal Life (Basel)

Specialty Biology

Date 2023 May 27

PMID 37240777

Authors

Tomoki Nakamizo

Munechika Misumi

Tetsuya Takahashi

Satoshi Kurisu

Masayasu Matsumoto

Akira Tsujino

Affiliations

Soon will be listed here.

Abstract

Female sex in patients with atrial fibrillation (AF) is a controversial and paradoxical risk factor for stroke-controversial because it increases the risk of stroke only among older women of some ethnicities and paradoxical because it appears to contradict male predominance in cardiovascular diseases. However, the underlying mechanism remains unclear. We conducted simulations to examine the hypothesis that this sex difference is generated non-causally through left truncation due to competing risks (CR) such as coronary artery diseases, which occur more frequently among men than among women and share common unobserved causes with stroke. We modeled the hazards of stroke and CR with correlated heterogeneous risk. We assumed that some people died of CR before AF diagnosis and calculated the hazard ratio of female sex in the left-truncated AF population. In this situation, female sex became a risk factor for stroke in the absence of causal roles. The hazard ratio was attenuated in young populations without left truncation and in populations with low CR and high stroke incidence, which is consistent with real-world observations. This study demonstrated that spurious risk factors can be identified through left truncation due to correlated CR. Female sex in patients with AF may be a paradoxical risk factor for stroke.

References

Nielsen P, Skjoth F, Overvad T, Larsen T, Lip G . Female Sex Is a Risk Modifier Rather Than a Risk Factor for Stroke in Atrial Fibrillation: Should We Use a CHADS-VA Score Rather Than CHADS-VASc?. Circulation. 2018; 137(8):832-840. DOI: 10.1161/CIRCULATIONAHA.117.029081. View

Chan Y, Wu L, Chang S, Lee H, Liu J, See L . Young Male Patients with Atrial Fibrillation and CHA2DS2-VASc Score of 1 May Not Need Anticoagulants: A Nationwide Population-Based Study. PLoS One. 2016; 11(3):e0151485. PMC: 4795759. DOI: 10.1371/journal.pone.0151485. View

Kim T, Yang P, Uhm J, Kim J, Pak H, Lee M . CHADS-VASc Score (Congestive Heart Failure, Hypertension, Age ≥75 [Doubled], Diabetes Mellitus, Prior Stroke or Transient Ischemic Attack [Doubled], Vascular Disease, Age 65-74, Female) for Stroke in Asian Patients With Atrial Fibrillation: A Korean.... Stroke. 2017; 48(6):1524-1530. DOI: 10.1161/STROKEAHA.117.016926. View

Lin L, Lee C, Yu C, Tsai C, Lai L, Hwang J . Risk factors and incidence of ischemic stroke in Taiwanese with nonvalvular atrial fibrillation-- a nation wide database analysis. Atherosclerosis. 2011; 217(1):292-5. DOI: 10.1016/j.atherosclerosis.2011.03.033. View

Schooling C, Jones H . Clarifying questions about "risk factors": predictors versus explanation. Emerg Themes Epidemiol. 2018; 15:10. PMC: 6083579. DOI: 10.1186/s12982-018-0080-z. View

Hernandez-Diaz S, Schisterman E, Hernan M . The birth weight "paradox" uncovered?. Am J Epidemiol. 2006; 164(11):1115-20. DOI: 10.1093/aje/kwj275. View

Li Y, Yatsuya H, Tanaka S, Iso H, Okayama A, Tsuji I . Estimation of 10-Year Risk of Death from Coronary Heart Disease, Stroke, and Cardiovascular Disease in a Pooled Analysis of Japanese Cohorts: EPOCH-JAPAN. J Atheroscler Thromb. 2020; 28(8):816-825. PMC: 8326173. DOI: 10.5551/jat.58958. View

Nakamizo T, Yamamoto M, Johkura K . Changes in stroke risk by freedom-from-stroke time in simulated populations with atrial fibrillation: Freedom-from-event effect when event itself is a risk factor. PLoS One. 2018; 13(3):e0194307. PMC: 5847231. DOI: 10.1371/journal.pone.0194307. View

Vincent L, Leedy D, Masri S, Cheng R . Cardiovascular Disease and Cancer: Is There Increasing Overlap?. Curr Oncol Rep. 2019; 21(6):47. DOI: 10.1007/s11912-019-0796-0. View

10.

Rothwell P, Coull A, Silver L, Fairhead J, Giles M, Lovelock C . Population-based study of event-rate, incidence, case fatality, and mortality for all acute vascular events in all arterial territories (Oxford Vascular Study). Lancet. 2005; 366(9499):1773-83. DOI: 10.1016/S0140-6736(05)67702-1. View

11.

DAgostino Sr R, Grundy S, Sullivan L, Wilson P . Validation of the Framingham coronary heart disease prediction scores: results of a multiple ethnic groups investigation. JAMA. 2001; 286(2):180-7. DOI: 10.1001/jama.286.2.180. View

12.

Tomita H, Okumura K, Inoue H, Atarashi H, Yamashita T, Origasa H . Validation of Risk Scoring System Excluding Female Sex From CHA2DS2-VASc in Japanese Patients With Nonvalvular Atrial Fibrillation – Subanalysis of the J-RHYTHM Registry. Circ J. 2015; 79(8):1719-26. DOI: 10.1253/circj.CJ-15-0095. View

13.

Chao T, Huang Y, Liu C, Chen S, Wang K, Lin Y . Acute myocardial infarction in patients with atrial fibrillation with a CHA2DS2-VASc score of 0 or 1: a nationwide cohort study. Heart Rhythm. 2014; 11(11):1941-7. DOI: 10.1016/j.hrthm.2014.08.003. View

14.

Siu C, Lip G, Lam K, Tse H . Risk of stroke and intracranial hemorrhage in 9727 Chinese with atrial fibrillation in Hong Kong. Heart Rhythm. 2014; 11(8):1401-8. DOI: 10.1016/j.hrthm.2014.04.021. View

15.

Xiong S, Yin S, Deng W, Zhao Y, Li W, Wang P . Impact of liver fibrosis score on the incidence of stroke: A cohort study. Liver Int. 2022; 42(10):2175-2185. DOI: 10.1111/liv.15359. View

16.

Friberg L, Benson L, Rosenqvist M, Lip G . Assessment of female sex as a risk factor in atrial fibrillation in Sweden: nationwide retrospective cohort study. BMJ. 2012; 344:e3522. PMC: 3365143. DOI: 10.1136/bmj.e3522. View

17.

Renoux C, Coulombe J, Suissa S . Revisiting sex differences in outcomes in non-valvular atrial fibrillation: a population-based cohort study. Eur Heart J. 2017; 38(19):1473-1479. DOI: 10.1093/eurheartj/ehw613. View

18.

Christensen D, Strange J, Phelps M, Schjerning A, Sehested T, Gerds T . Age- and sex-specific trends in the incidence of myocardial infarction in Denmark, 2005 to 2021. Atherosclerosis. 2022; 346:63-67. DOI: 10.1016/j.atherosclerosis.2022.03.003. View

19.

Wagstaff A, Overvad T, Lip G, Lane D . Is female sex a risk factor for stroke and thromboembolism in patients with atrial fibrillation? A systematic review and meta-analysis. QJM. 2014; 107(12):955-67. DOI: 10.1093/qjmed/hcu054. View

20.

Mosca L, Barrett-Connor E, Wenger N . Sex/gender differences in cardiovascular disease prevention: what a difference a decade makes. Circulation. 2011; 124(19):2145-54. PMC: 3362050. DOI: 10.1161/CIRCULATIONAHA.110.968792. View