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Cognitive Impairment Associated With Atrial Fibrillation: A Meta-analysis

Shadi Kalantarian, MD, MPH; Theodore A. Stern, MD; Moussa Mansour, MD; and Jeremy N. Ruskin, MD
[+] Article and Author Information

From the Cardiac Arrhythmia Service and the Institute for Heart, Vascular, and Stroke Care at Massachusetts General Hospital, Boston, Massachusetts.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, the National Center for Research Resources, or the National Institutes of Health.

Acknowledgment: The authors thank Jose Sarmiento, MD, MPH, from Harvard School of Public Health; Kasra Moazzami, MD, MPH, from Massachusetts General Hospital, who did duplicate data extraction; Hang Lee, PhD, and Brian Healy, PhD, from Harvard Catalyst, who provided biostatistical consultation; Susan Landry, who edited a draft of this manuscript; Julie Goodman, PhD, and Donald Halstead, BA, from Harvard School of Public Health, for their help and support. They also thank the following persons who provided them with additional data from their published studies: Jared Bunch, MD; Alessandra Marengoni, MD; Yan-Jiang Wang, MD, PhD; Sascha Dublin, MD, PhD; and Ruth Peters, MD.

Grant Support: By the Deane Institute for Integrative Research in Atrial Fibrillation and Stroke at Massachusetts General Hospital. This work was conducted with support from Harvard Catalyst and the Harvard Clinical and Translational Science Center (National Institutes of Health Award UL1 RR 025758 and financial contributions from Harvard University and its affiliated academic health care centers).

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-1971.

Requests for Single Reprints: Jeremy N. Ruskin, MD, Cardiac Arrhythmia Service, Massachusetts General Hospital, 55 Fruit Street, GRB 109, Boston, MA 02114; e-mail, jruskin@partners.org.

Current Author Addresses: Dr. Kalantarian: Cardiac Arrhythmia Service, Massachusetts General Hospital, 55 Fruit Street, Jackson 1302, Boston, MA 02114.

Dr. Stern: Psychiatry Associates-Inpatient Consult, 55 Fruit Street, WRN 605, Boston, MA 02114-2696.

Drs. Mansour and Ruskin: Cardiac Arrhythmia Service, Massachusetts General Hospital, 55 Fruit Street, GRB 109, Boston, MA 02114.

Author Contributions: Conception and design: S. Kalantarian, T.A. Stern, J.N. Ruskin.

Analysis and interpretation of the data: S. Kalantarian, J.N. Ruskin.

Drafting of the article: S. Kalantarian, T.A. Stern, J.N. Ruskin.

Critical revision of the article for important intellectual content: S. Kalantarian, T.A. Stern, M. Mansour, J.N. Ruskin.

Final approval of the article: T.A. Stern, J.N. Ruskin.

Statistical expertise: S. Kalantarian.

Administrative, technical, or logistic support: J.N. Ruskin.

Collection and assembly of data: S. Kalantarian.


Ann Intern Med. 2013;158(5_Part_1):338-346. doi:10.7326/0003-4819-158-5-201303050-00007
Text Size: A A A

Background: Atrial fibrillation (AF) has been linked with an increased risk for cognitive impairment and dementia.

Purpose: To complete a meta-analysis of studies examining the association between AF and cognitive impairment.

Data Sources: Search of MEDLINE, PsycINFO, Cochrane Library, CINAHL, and EMBASE databases and hand search of article references.

Study Selection: Prospective and nonprospective studies reporting adjusted risk estimates for the association between AF and cognitive impairment.

Data Extraction: Two abstracters independently extracted data on study characteristics, risk estimates, methods of AF and outcome ascertainment, and methodological quality.

Data Synthesis: Twenty-one studies were included in the meta-analysis. Atrial fibrillation was significantly associated with a higher risk for cognitive impairment in patients with first-ever or recurrent stroke (relative risk [RR], 2.70 [95% CI, 1.82 to 4.00]) and in a broader population including patients with or without a history of stroke (RR, 1.40 [CI, 1.19 to 1.64]). The association in the latter group remained significant independent proof of clinical stroke history (RR, 1.34 [CI, 1.13 to 1.58]). However, there was significant heterogeneity among studies of the broader population (I2 = 69.4%). Limiting the analysis to prospective studies yielded similar results (RR, 1.36 [CI, 1.12 to 1.65]). Restricting the analysis to studies of dementia eliminated the significant heterogeneity (P = 0.137) but did not alter the pooled estimate substantially (RR, 1.38 [CI, 1.22 to 1.56]).

Limitations: There is an inherent bias because of confounding variables in observational studies. There was significant heterogeneity among included studies.

Conclusion: Evidence suggests that AF is associated with a higher risk for cognitive impairment and dementia, with or without a history of clinical stroke. Further studies are required to elucidate the association between AF and subtypes of dementia as well as the cause of cognitive impairment.

Primary Funding Source: Deane Institute for Integrative Research in Atrial Fibrillation and Stroke at the Massachusetts General Hospital.

Figures

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Appendix Figure 1.

Summary of evidence search and selection.

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Figure 1.

Meta-analysis of 14 studies evaluating the association between AF and cognitive impairment in patients with or without history of stroke.

Diamonds represent the pooled risk estimates. All studies were multivariate-adjusted, with the exception of Jozwiak and colleagues (30) and Tilvis and colleagues (33), which had minimal adjustment (including at least adjustment for age). History of stroke was included as a covariate for Bilato and colleagues (32), Peters and coworkers (16), Bunch and colleagues (11), and Marzona and coworkers (36). AF = atrial fibrillation; CVA = cerebrovascular accident; NR = not reported.

* Weights are from random-effects analysis. Percentages may not sum to 100 due to rounding.

† Patients with history of stroke were excluded in a subgroup analysis.

‡ Patients with no focal neurologic deficits (e.g., previous strokes, head injuries, head neurosurgery, tumors of the central nervous system) were only considered for this meta-analysis.

§ Conversion from normal cognition to dementia.

¶ Conversion from mild cognitive impairment to dementia.

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Figure 2.

Separating dementia outcomes from cognitive impairment.

Diamonds represent the pooled risk estimates. AF = atrial fibrillation; NR = not reported.

* Weights are from random-effects analysis. Percentages may not sum to 100 due to rounding.

† Patients with dementia were excluded.

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Appendix Figure 2.

Meta-analysis of the association between AF and cognitive impairment or decline.

Cognitive impairment was defined as a Mini-Mental State Examination score ≤24; cognitive decline was defined as a ≥3-point decrease in the Mini-Mental State Examination score. Diamonds represent the pooled risk estimates. AF = atrial fibrillation; NR = not reported.

* Weights are from random-effects analysis. Percentages may not sum to 100 due to rounding.

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Figure 3.

The association between AF and cognitive impairment independent of stroke history.

Diamonds represent the pooled risk estimates. All studies were multivariate-adjusted, with the exception of Jozwiak and colleagues (30), which had minimal adjustment (including at least adjustment for age). History of stroke was included as a covariate for Bilato and colleagues (32), Peters and coworkers (16), and Bunch and colleagues (11). AF = atrial fibrillation; CVA = cerebrovascular accident; NR = not reported.

* Weights are from random-effects analysis. Percentages may not sum to 100 due to rounding.

† Patients with history of stroke were excluded in a subgroup analysis.

‡ Patients with no focal neurologic deficits (e.g., previous strokes, head injuries, head neurosurgery, tumors of the central nervous system) were only considered for this meta-analysis.

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Figure 4.

Meta-analysis of 7 studies evaluating the association between AF and cognitive impairment after stroke in patients with recurrent or first-ever stroke.

Diamonds represent the pooled risk estimates. AF = atrial fibrillation; NR = not reported.

* Weights are from random-effects analysis. Percentages may not sum to 100 due to rounding.

† 5 additional patients developed AF (2 were diagnosed with dementia after stroke) during follow-up.

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Appendix Figure 3.

Funnel plot for assessment of publication bias among the 14 studies evaluating patients with or without history of stroke.

RR = relative risk.

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Tables

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Comments

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Atrial Fibrellation, Dementia and Cognitive Impairment
Posted on March 11, 2013
David A Nardone, MD
Portland VAMC
Conflict of Interest: None Declared

In the meta-analysis by Kalantarian et al, the authors conclude that atrial fibrillation (AF) predicts cognitive impairment and dementia; and they recommend further study to clarify any association of AF with dementia by subtype (1). I agree, but suggest an equal focus on assessing any difference in the risk of cognitive decline according to AF sub-types --- paroxysmal, persistent, and permanent.

Several studies support the value of AF categorization. Patients with sub-clinical AF of longer duration may have a higher incidence of stroke (2).  AF burden (<= 5 minutes per day, >5 minutes but <24 hours per day, and >= 24 hours per day) may strengthen CHADS models for predicting the risk of thrombo-embolism (3). Patients with AF may have lower brain volume than those without AF. This association appears to be stronger for those with persistent and permanent AF (4). Short term outcomes in patients with persistent AF and acute cerebral infarction may be worse than those with paroxysmal AF and infarction (5).

Considering the high prevalence of AF, stroke, and dementia, and their cause and effect relationships pathophysiologically, categorizing subtypes for both AF and dementia could have profound impact on assessing the risk of complications, the benefits and risks of therapy, as well as long-term planning for affected patients and their caregivers. If categorizing is clinically appropriate for dementia, why not for AF?

1. Kalantarian S, Stern TA, Mansour M, Ruskin JN. Cognitive Impairment Associated With Atrial Fibrillation: A Meta-analysis. Ann Intern Med. 5 March 2013;158(5_Part_1):338-346.

2. Healey JS, Connolly SJ, Gold MR, Israel CW, Van Gelder IC, Capucci A, Lau CP, Fain E, Yang S, Bailleul C, Morillo CA, Carlson M, Themeles E, Kaufman ES, Hohnlosser SH. Sub-clinical Atrial Fibrillation and Risk of Stroke. N Engl J Med 2012; 366: 120-129.

3. Boriani G. Botto GL. Padeletti L. Santini M. Capucci A. Gulizia M. Ricci R. Biffi M. De Santo T. Corbucci G. Lip GY. Italian AT-500 Registry Investigators. Improving stroke risk stratification using the CHADS2 and CHA2DS2-VASc risk scores in patients with paroxysmal atrial fibrillation by continuous arrhythmia burden monitoring. Stroke. 42(6):1768-70, 2011 Jun.

4. Stefansdottir H, Arnar DO, Aspelund T, Sigurdsson S, Jonsdottir MK, Hjaltason H, Launer LJ, Gudnason V. Atrial Fibrillation is Associated With Reduced Brain Volume and Cognitive Function Independent of Cerebral Infarcts. Stroke. 2013 Feb 26. [Epub ahead of print]

5. Naess H, Waje-Andreassen U, Thomassen L. Persistent atrial fibrillation is associated with worse prognosis than paroxysmal atrial fibrillation in acute cerebral infarction. ISRN Cardiol. 2012;2012:650915.

 

Author's Response
Posted on April 10, 2013
Shadi Kalantarian, MD, MPH, Jeremy N. Ruskin, MD
Massachusetts General Hospital
Conflict of Interest: None Declared

We appreciate Dr. Nardone’s comments and agree with his suggestions. These are very important observations which we attempted to address and investigate during the data extraction. However, sufficient data was not available to allow for any meaningful analysis of cognitive impairment risk by AF subtypes. Fourteen studies reported the association between atrial fibrillation (AF) and cognitive impairment in a broad population [1], but only two [2,3] reported the type of AF. One [3] reported AF type as chronic, and one [2] reported AF type as either paroxysmal or chronic. However, none of the included studies reported separate risk estimates by AF subtype.  In a letter to the editor, Rozzini et al [4] reported the risk of cognitive impairment by AF subtype in a population of elderly patients above 70 years of age with no history of cerebrovascular events. This nonprospective study evaluated three groups of patients:  214 patients with sinus rhythm, 13 patients with paroxysmal AF defined as at least one AF episode lasting less than 48 hours and 42 patients with chronic AF defined as AF of more than 6 months duration. There was a significant association between chronic AF and the risk of cognitive impairment while no significant association was observed for paroxysmal AF (multivariate adjusted odds ratio [OR], 3.2 [95% CI, 1.5 to 6.6] vs. OR, 1.2 [CI, 0.3 to 4.8], respectively). While this study supports Dr. Nardone’s proposition, it is important to note that the accuracy of the methods used to differentiate between subtypes of AF in this study is unclear. In conclusion, there is a paucity of evidence assessing the risk of cognitive impairment by AF type and burden. Future studies should distinguish between AF subtypes and estimate AF burden when reporting the association between AF and cognitive impairment.

 

  1. Kalantarian S, Stern TA, Mansour M, Ruskin JN. Cognitive Impairment Associated With Atrial Fibrillation: A Meta-analysis. Ann Intern Med. 2013 Mar 5;158(5 Pt 1):338-46. doi: 10.7326/0003-4819-158-5-201303050-00007.[PMID: 23460057]
  2. Elias MF, Sullivan LM, Elias PK, Vasan RS, D’Agostino RB Sr, Seshadri S, et al. Atrial fibrillation is associated with lower cognitive performance in the Framingham offspring men. J Stroke Cerebrovasc Dis. 2006;15:214-22. [PMID: 17904078]
  3. Marengoni A, Qiu C, Winblad B, Fratiglioni L. Atrial fibrillation, stroke and dementia in the very old: a population-based study. Neurobiol Aging. 2011; 32:1336-7. [PMID: 19732992]
  4. Rozzini R, Sabatini T, Trabucchi M. Chronic atrial fibrillation and low cognitive function. Stroke. 1999 Jan;30(1):190-1. [PMID: 9880414]

Shadi Kalantarian MD, MPH

Jeremy N. Ruskin, MD

 

 

 

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