The impact of atrial fibrillation and long-term oral anticoagulant use on all-cause and cardiovascular mortality: A 12-year evaluation of the prospective Brazilian Study of Stroke Mortality and Morbidity

Abstract

Background

Atrial fibrillation is a predictor of poor prognosis after stroke.

Aims

To evaluate atrial fibrillation and all-cause and cardiovascular mortality in a stroke cohort with low socioeconomic status, taking into consideration oral anticoagulant use during 12-year follow-up.

Methods

All-cause mortality was analyzed by Kaplan–Meier survival curve and Cox regression models to estimate hazard ratios and 95% confidence intervals (95% CI). For specific mortality causes, cumulative incidence functions were computed. A logit link function was used to calculate odds ratios (OR) with 95% CIs. Full models were adjusted by age, sex, oral anticoagulant use (as a time-dependent variable) and cardiovascular risk factors.

Results

Of 1121 ischemic stroke participants, 17.8% had atrial fibrillation. Overall, 654 deaths (58.3%) were observed. Survival rate was lower (median days, interquartile range-IQR) among those with atrial fibrillation (531, IQR: 46–2039) vs. non-atrial fibrillation (1808, IQR: 334–3301), p-log rank < 0.0001). Over 12-year follow-up, previous atrial fibrillation was associated with increased mortality: all-cause (multivariable hazard ratios, 1.82; 95% CI: 1.43–2.31) and cardiovascular mortality (multivariable OR, 2.07; 95% CI: 1.36–3.14), but not stroke mortality. In the same multivariable models, oral anticoagulant use was inversely associated with all-cause mortality (oral anticoagulant time-dependent effect: multivariable hazard ratios, 0.47; 95% CI: 0.30–0.50, p = 0.002) and stroke mortality (oral anticoagulant time-dependent effect ≥ 6 months: multivariable OR, 0.09; 95% CI: 0.01–0.65, p-value = 0.02), but not cardiovascular mortality.

Conclusions

Among individuals with low socioeconomic status, atrial fibrillation was an independent predictor of poor survival, increasing all-cause and cardiovascular mortality risk. Long-term oral anticoagulant use was associated with a markedly reduced risk of all-cause and stroke mortality.

Keywords

Stroke epidemiology stroke in developing countries stroke prevention

Get full access to this article

View all access options for this article.

References

Feigin

Forouzanfar

Krishnamurthi

, et al. Global and regional burden of stroke during 1990-2010: findings from the Global Burden of Disease Study 2010. Lancet 2014; 383: 245–254.

Andrew

Kilkenny

Harris

Price

Cadilhac

. Outcomes for people with atrial fibrillation in an Australian national audit of stroke care. Int J Stroke 2014; 9: 270–277.

Lamassa

Di Carlo

Pracucci

, et al. Characteristics, outcome, and care of stroke associated with atrial fibrillation in Europe: data from a multicenter multinational hospital-based registry (The European Community Stroke Project). Stroke 2001; 32: 392–398.

Marini

De Santis

Sacco

, et al. Contribution of atrial fibrillation to incidence and outcome of ischemic stroke: results from a population-based study. Stroke 2005; 36: 1115–1119.

Lin

Hao

, et al. Characteristics, treatment and outcome of ischemic stroke with atrial fibrillation in a Chinese hospital-based stroke study. Cerebrovasc Dis 2011; 31: 419–426.

Healey

Oldgren

Ezekowitz

, et al. RE-LY Atrial Fibrillation Registry and Cohort Study investigators. Occurrence of death and stroke in patients in 47 countries 1 year after presenting with atrial fibrillation: a cohort study. Lancet 2016; 388: 1161–1169.

Mozaffarian

Benjamin

, et al. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation 2015; 131: e29–e322.

Benjamin

Wolf

D'Agostino

Silbershatz

Kannel

Levy

. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998; 98: 946–952.

Schnabel

Yin

Gona

, et al. 50 Year trends in atrial fibrillation prevalence, incidence, risk factors, and mortality in the Framingham Heart Study: A Cohort Study. Lancet 2015; 386: 154–162.

10.

Link

Giugliano

Ruff

, et al. ENGAGE AF-TIMI 48 investigators. Stroke and mortality risk in patients with various patterns of atrial fibrillation: results from the ENGAGE AF-TIMI 48 Trial (effective anticoagulation with Factor Xa next generation in atrial fibrillation-thrombolysis in myocardial infarction 48). Circ Arrhythm Electrophysiol 2017; 10: e004267.

11.

Rivera-Caravaca

Roldán

Esteve-Pastor

, et al. Cessation of oral anticoagulation is an important risk factor for stroke and mortality in atrial fibrillation patients. Thromb Haemost 2017; 117: 1448–1454.

12.

Baturova

Lindgren

Carlson

Shubik

Bertil Olsson

Platonov

. Non-permanent atrial fibrillation and oral anticoagulant therapy are related to survival during 10 years after first-ever ischemic stroke. Int J Cardiol 2017; 1: 232: 134–139.

13.

Arnao

Agnelli

Paciaroni

. Direct oral anticoagulants in the secondary prevention of stroke and transient ischemic attack in patients with atrial fibrillation. Intern Emerg Med 2015; 10: 555–560.

14.

Castro

HHG

Alencar

Benseñor

Lotufo

Goulart

. Multimorbidities Are Associated to Lower Survival in Ischaemic Stroke: results from a Brazilian Stroke Cohort (EMMA Study). Cerebrovasc Dis 2017; 44: 232–239.

15.

Abreu

Goulart

Birck

Benseñor

. Stroke at baseline of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil): a cross-sectional analysis. Sao Paulo Med J 2018; 136: 398–406.

16.

Chin

Sakinah

Aryati

Hassan

. Prevalence, risk factors and secondary prevention of stroke recurrence in eight countries from south, east and southeast Asia: a scoping review. Med J Malaysia 2018; 73: 90–99.

17.

Smith

Xuereb

Pattison

Lip

Lane

. TRial of an Educational intervention on patients' knowledge of atrial fibrillation and Anticoagulant therapy, INR control, and outcome of Treatment with warfarin (TREAT). BMC Cardiovasc Disord 2010; 10: 21.

18.

Heneghan

Garcia-Alamino

Spencer

, et al. Self-monitoring and self-management of oral anticoagulation. Cochrane Database Syst Rev 2016; 7: CD003839.

19.

World Health Organization. WHO STEPS stroke manual: the WHO STEPwise approach to stroke surveillance/noncommunicable diseases and mental health. World Health Organization, http://www.who.int/chp/steps/stroke/manual/en/index.html (2006, accessed 12 June 2010).

20.

Lotufo

Benseñor

. Improving WHO STEPS Stroke in Brazil. Lancet Neurol 2007; 6: 387–388.

21.

Goulart

Bustos

Abe

, et al. A stepwise approach to stroke surveillance in Brazil: the EMMA (Estudo de Mortalidade e Morbidade do Acidente Vascular Cerebral) study. Int J Stroke 2010; 5: 284–289.

22.

Kaplan

Meier

. Nonparametric Estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.

23.

Cox

. Regression model and life tables. Series B (Methodological). J Royal Stat Soc 1972; 34: 187–220.

24.

Gray

. A class of k-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 1988; 16: 1141–1154.

25.

Klein

Andersen

. Regression modeling of competing risks data based on pseudovalues of the cumulative incidence function. Biometrics 2005; 61: 223–229.

26.

Klein

Gerster

Andersen

Tarima

Perme

. SAS and R functions to compute pseudo-values for censored data regression. Comput Meth Programs Biomed 2008; 89: 289–300.

27.

Graw

Gerds

Schumacher

. On pseudo-values for regression analysis in competing risks models. Lifetime Data Anal 2009; 15: 241–255.

28.

Fornari

Calderaro

Nassar

, et al. Misuse of antithrombotic therapy in atrial fibrillation patients: frequent, pervasive and persistent. J Thromb Thrombolysis 2007; 23: 65–71.

29.

Clarkesmith DE, Lip GYH and Lane DA. Patients' experiences of atrial fibrillation and non-vitamin K antagonist oral anticoagulants (NOACs), and their educational needs: a qualitative study. Thromb Res 2017; 153: 19–27.

30.

Pritchett

Clarke

Jolly

, et al. Clinicians’ views and experiences of prescribing oral anticoagulants for stroke prevention in atrial fibrillation: a qualitative meta-synthesis. PLoS One 2020; 15: e0232484.

31.

de Moraes

ERFL

Cirenza

Lopes

Carvalho

Guimaraes

Rodrigues

AAE

de Paola

AAV

. Prevalence of atrial fibrillation and stroke risk assessment based on telemedicine screening tools in a primary healthcare setting. Eur J Intern Med 2019; 67: 36–41.

32.

Brant

LCC

Nascimento

Passos

VMA

, et al. Variations and particularities in cardiovascular disease mortality in Brazil and Brazilian states in 1990 and 2015: estimates from the Global Burden of Disease. Rev Bras Epidemiol 2017; 20: 116–128.

33.

Suissa

. Immortal time bias in pharmacoepidemiology. Am J Epidemiol 2008; 167: 492–99.

34.

Lévesque

Hanley

Kezouh

Suissa

. Problem of immortal time bias in cohort studies: example using statins for preventing progression of diabetes. BMJ 2010; 340: b5087.