Elsevier

Clinical Therapeutics

Volume 36, Issue 9, 1 September 2014, Pages 1135-1144
Clinical Therapeutics

The Impact of Heart Failure and Left Ventricular Dysfunction in Predicting Stroke, Thromboembolism, and Mortality in Atrial Fibrillation Patients: A Systematic Review

https://doi.org/10.1016/j.clinthera.2014.07.015Get rights and content

Abstract

Purpose

Atrial fibrillation (AF) is commonly associated with structural heart disease. Although heart failure (HF) has been proposed as a risk factor for stroke, the coexistence of the 2 diseases increases disproportionally the risk of thromboembolic events. Our objective was to conduct a systematic review to assess the effect of HF on the end points of stroke, systemic embolism (SE), or mortality in patients with AF.

Methods

A literature search was performed to identify studies that examined stroke/ SE in relation to AF and HF. Overall, 405 articles satisfied the preinclusion criteria.

Findings

In studies in which HF was based on a clinical diagnosis, HF independently increased stroke/SE in 5 of 13 studies, conferring 1.6- to 3.1-fold increase in risk. When HF was defined as impaired left ventricular (LV) function on echocardiography, the additive risk was evident in 4 of 6 studies, with 1.7- to 2.6-fold increase in the risk of stroke/SE. The data about HF with preserved ejection fraction were less robust, although a recent presentation with acute decompensated HF increased the risk of stroke/SE, irrespective of ejection fraction.

Implications

LV systolic impairment as identified by echocardiography is an independent risk factor for stroke/SE, although the magnitude by which it increases the risk of stroke cannot be precisely quantified. Whether a clinical diagnosis of HF is a significant risk factor remains inconclusive, although when the diagnosis is certain (recent decompensation requiring hospitalization), it does seem to be a significant risk factor irrespective of LV systolic function.

Introduction

Atrial fibrillation (AF) is a major risk factor for stroke and systemic embolism (SE).1, 2, 3 This risk is not homogeneous and depends on many additional clinical and demographic factors that, if present with AF, increase further the risk of stroke/SE.4

Even in the absence of AF, heart failure (HF) is an independent risk factor for stroke/SE,5 ranking second after AF as the underlying cause of cardioembolic strokes.6 The rate of stroke in HF trials ranges from 1.5% to 2.4% per year.6 One retrospective study of a clinical trial cohort found a 38% increase in the risk of thromboembolic events in women for every 10% decrease in ejection fraction (EF).7 Several mechanisms contribute to the increased risk of thromboembolism in patients with HF. These include blood stasis either due to a poorly functioning left ventricle or enlarged atria or due to a left ventricular (LV) aneurysm.6 Similar to AF, hemostatic abnormalities have been observed in patients with HF such as higher levels of β-thromboglobulin, thrombin-antithrombin III complexes, and D-dimers, all of which promote coagulation and are likely linked to the systemic inflammation in patients with HF.6, 8

Atrial fibrillation and HF often coexist due to common risk factors such as age, hypertension, diabetes, obesity, and structural heart disease.9 The Framingham Heart Study found that the prevalence of AF in patients with HF increased as the severity of HF increased, ranging from 5% in patients with mild HF (New York Heart Association [NYHA] class I), to up to 50% in patients with severe HF (NYHA class IV).2, 6, 9 In addition, many patients with HF may have silent AF, and occasionally paroxysms of the arrhythmia may lead to decompensation and/or thromboembolism.10

AF can lead to HF through several mechanisms.2 A reduction in cardiac output can result from the loss of atrial contraction and/or the decrease of ventricular diastolic filling time.2, 11 Alternatively, HF can cause AF.2 The increased LV filling pressure in HF can also lead to dilation and fibrosis of the atria, providing the anatomical substrate for electrical instability. Pathophysiologically, HF is associated with dysregulation of intracellular calcium and activation of various neurohormonal systems, both of which can cause AF.2 In many cases, however, it can be difficult to know whether the AF preceded HF or vice versa,2 and whether there is any difference in outcomes if one condition precedes the other.12

The objective of this systematic review is to provide an overview of published studies that have examined the effect of HF on stroke/SE risk in patients with AF.

Section snippets

Methods

A comprehensive literature search for relevant studies was performed electronically by using PubMed/Medline between January 1988 and July 2012. The following search terms were used: atrial fibrillation in combination with stroke risk, thromboembolism, heart failure, systolic dysfunction, diastolic dysfunction, left ventricular impairment, and left ventricular dysfunction.

The 405 articles retrieved by the initial search were screened for relevant titles and abstracts (Figure 1). Studies with a

HF Based on a Clinical Diagnosis

The importance of HF as a risk factor for stroke/SE in patients with AF was assessed in 13 studies14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 (Table I). Five studies found HF to have an independent significant effect on stroke risk,16, 19, 23, 24, 26 whereas 6 studies found this effect to be non-significant.14, 15, 17, 18, 20, 21 Two studies found HF to be a predictor of stroke in univariate analysis but not in multivariate analysis.22, 25 Clinically defined HF increased 1.6- to 3.1-fold

Discussion

In this systematic review, we reported that, when HF was clinically defined, it independently increased stroke/SE by 1.6- to 3.1-fold. HF defined as impaired LV function on echocardiography increased stroke/SE risk by 1.7- to 2.6-fold. With HFpEF the link to stroke/SE in AF was less clear, although a recent presentation with acute decompensated HF increased stroke/thromboembolism risk, irrespective of systolic function.

Despite our understanding of the pathophysiology, suggesting that HF would

Conclusion

LV systolic impairment identified by an echocardiogram is an independent risk factor for stroke and thromboembolism, although the magnitude by which it increases the risk of stroke cannot be precisely quantified. Whether a clinical diagnosis of HF is a significant risk factor remains inconclusive, although, when the diagnosis is certain (eg, recent decompensation requiring hospitalization), it does seem to significantly increase the risk of stroke, irrespective of LV systolic function.

Conflicts of Interest

Dr Lane has received research funding and/or honoraria for educational symposia from Boehringer-Ingelheim, Bayer Healthcare, and Bristol-Myers-Squibb/Pfizer in relation to atrial fibrillation. Professor Lip has served as a consultant for Bayer, Astellas, Merck, Astra-Zeneca, Sanofi-Aventis, Aryx, Portola, Biotronic, and Boehringer-Ingelheim and has been on the speaker bureau for Bayer, Boehringer-Ingelheim, and Sanofi-Aventis. The authors have indicated that they have no other conflicts of

Acknowledgments

Ms. Agarwal performed literature search, data collection, and wrote the first draft of the manuscript. Dr. Apostolakis interpreted the data and edited the final version of the manuscript. Drs. Lane and Lip designed and supervised the analysis and approved the final version of the manuscript. Dr. Agarwal and Dr. Apostolakis are joint first authors.

References (52)

  • R. Parkash et al.

    Atrial fibrillation in heart failure: high mortality risk even if ventricular function is preserved

    Am Heart J

    (2005)
  • A.O. Badheka et al.

    Comparison of mortality and morbidity in patients with atrial fibrillation and heart failure with preserved versus decreased left ventricular ejection fraction

    Am J Cardiol

    (2011)
  • S.M. Al-Khatib et al.

    Is rhythm control superior to rate control in patients with atrial fibrillation and congestive heart failure?

    Am J Cardiol

    (2004)
  • C.A. Sanoski

    Prevalence, pathogenesis, and impact of atrial fibrillation

    Am J Health Syst Pharm

    (2010)

  • Independent predictors of stroke in patients with atrial fibrillation: a systematic review

    Neurology

    (2007)
  • G.Y. Lip et al.

    Does heart failure confer a hypercoagulable state? Virchow’s triad revisited

    J Am Coll Cardiol

    (1999)
  • S. Kohsaka et al.

    Anticoagulation for heart failure: selecting the best therapy

    Expert Rev Cardiovasc Ther

    (2009)
  • E. Anter et al.

    Atrial fibrillation and heart failure: treatment considerations for a dual epidemic

    Circulation

    (2009)
  • G.Y. Lip et al.

    European Heart Rhythm Association. Bleeding risk assessment and management in atrial fibrillation patients. Executive Summary of a Position Document from the European Heart Rhythm Association [EHRA], endorsed by the European Society of Cardiology [ESC] Working Group on Thrombosis

    Thromb Haemost

    (2011)
  • A.M. Chamberlain et al.

    Atrial fibrillation and mortality in heart failure: a community study

    Circ Heart Fail

    (2011)
  • J.J. McMurray et al.

    ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC

    Eur J Heart Fail

    (2012)
  • P. Petersen et al.

    Risk factors for stroke in chronic atrial fibrillation

    Eur Heart J

    (1988)

  • The Stroke Prevention in Atrial Fibrillation Investigators

    Ann Intern Med

    (1992)

  • Analysis of pooled data from five randomized controlled trials

    Arch Intern Med

    (1994)

  • The SPAF III Writing Committee for the Stroke Prevention in Atrial Fibrillation Investigators

    JAMA

    (1998)

  • Echocardiographic predictors of stroke in patients with atrial fibrillation: a prospective study of 1066 patients from three clinical trials

    Arch Intern Med

    (1998)

    • Cited by (55)

    • Transcriptomics-based network medicine approach identifies metformin as a repurposable drug for atrial fibrillation

      2022, Cell Reports Medicine

    • Atrial fibrillation in chronic heart failure patients with reduced ejection fraction: The CHECK-HF registry

      2020, International Journal of Cardiology

    • Does Left Ventricular Systolic Function Matter? Treating Atrial Fibrillation in HFrEF Versus HFpEF

      2019, Cardiology Clinics
      Citation Excerpt :

      HF increases stroke and systemic embolism risk in AF via various mechanisms, with its risk being enough to justify inclusion in the most commonly used AF embolic risk score, the CHADS-VASc score. Congestive HF is assigned 1 point and as a result, therapeutic anticoagulation is recommended for any HF patient with AF (as males with a score ≥1 and females with a score ≥2 are recommended to be anticoagulated).20 Whether AF with HF-pEF or AF with HF-rEF has any individual impact on stroke risk has been assessed using several statistical methods.

    • The CHA<inf>2</inf>DS<inf>2</inf>-VASc score: Not as simple as it seems

      2018, International Journal of Cardiology
      Citation Excerpt :

      A cohort study by Sandhu et al. comparing risk of embolic events in 1103 HFrEF patients and 969 HFpEF patients with AF found that reduced ejection fraction or degree of left ventricular dysfunction did not influence risk [14]. Subsequent studies further suggest that recent presentation with acute decompensation increased stroke risk irrespective of HFrEF versus HFpEF [15]. Even in the absence of AF, patients with heart failure have an increased risk of ischemic stroke at the rate of 1.0% per year in HFpEF and 1.2% per year in HFrEF.

    • The Role of Posterior Wall Isolation in Catheter Ablation for Persistent Atrial Fibrillation and Systolic Heart Failure A Secondary Analysis of a Randomized Clinical Trial

      2023, JAMA Cardiology

    • Mechanical thrombectomy in patients with heart failure: the Italian registry of Endovascular Treatment in Acute Stroke

      2023, Neurological Sciences
    View all citing articles on Scopus
    View full text
    Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.