Risk of stroke in chronic heart failure patients with preserved ejection fraction, but without atrial fibrillation: analysis of the CHARM-Preserved and I-Preserve trials

Aims The incidence and predictors of stroke in patients with heart failure and preserved ejection fraction (HF-PEF), but without atrial fibrillation (AF), are unknown. We described the incidence of stroke in HF-PEF patients with and without AF and predictors of stroke in those without AF. Methods and results We pooled data from the CHARM-Preserved and I-Preserve trials. Using Cox regression, we derived a model for stroke in patients without AF in this cohort and compared its performance with a published model in heart failure patients with reduced ejection fraction (HF-REF)—predictive variables: age, body mass index, New York Heart Association class, history of stroke, and insulin-treated diabetes. The two stroke models were compared and Kaplan–Meier curves for stroke estimated. The risk model was validated in a third HF-PEF trial. Of the 6701 patients, 4676 did not have AF. Stroke occurred in 124 (6.1%) with AF and in 171 (3.7%) without AF (rates 1.80 and 1.00 per 100 patient-years, respectively). There was no difference in performance of the stroke model derived in the HF-PEF cohort and the published HF-REF model (c-index 0.71, 95% confidence interval 0.57–0.84 vs. 0.73, 0.59–0.85, respectively) as the predictive variables overlapped. The model performed well in the validation cohort (0.86, 0.62–0.99). The rate of stroke in patients in the upper third of risk approximated to that in patients with AF (1.60 and 1.80 per 100 patient-years, respectively). Conclusions A small number of clinical variables identify a subset of patients with HF-PEF, but without AF, at elevated risk of stroke.

[1]  J. McMurray,et al.  Risk of Stroke in Chronic Heart Failure Patients Without Atrial Fibrillation: Analysis of the Controlled Rosuvastatin in Multinational Trial Heart Failure (CORONA) and the Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza Cardiaca-Heart Failure (GISSI-HF) Trials , 2015, Circulation.

[2]  M. Pfeffer,et al.  Relationship Between Degree of Left Ventricular Dysfunction, Symptom Status, and Risk of Embolic Events in Patients With Atrial Fibrillation and Heart Failure , 2015, Stroke.

[3]  Sanjiv J Shah,et al.  Spironolactone for heart failure with preserved ejection fraction. , 2014, The New England journal of medicine.

[4]  C. Iadecola,et al.  Hypertension: A Harbinger of Stroke and Dementia , 2013, Hypertension.

[5]  V. Wadley,et al.  Identifying a high stroke risk subgroup in individuals with heart failure. , 2013, Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association.

[6]  Karl Swedberg,et al.  Predicting survival in heart failure: a risk score based on 39 372 patients from 30 studies. , 2013, European heart journal.

[7]  J. McMurray,et al.  What have we learned about patients with heart failure and preserved ejection fraction from DIG-PEF, CHARM-preserved, and I-PRESERVE? , 2012, Journal of the American College of Cardiology.

[8]  Shunichi Homma,et al.  Warfarin and aspirin in patients with heart failure and sinus rhythm. , 2012, The New England journal of medicine.

[9]  D. Atar,et al.  Apixaban versus warfarin in patients with atrial fibrillation. , 2011, The New England journal of medicine.

[10]  R. Troughton,et al.  Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. , 2011, The New England journal of medicine.

[11]  S. Yusuf,et al.  Dabigatran versus warfarin in patients with atrial fibrillation. , 2009, The New England journal of medicine.

[12]  C. Wanner,et al.  Reverse Epidemiology in Systolic and Nonsystolic Heart Failure: Cumulative Prognostic Benefit of Classical Cardiovascular Risk Factors , 2009, Circulation. Heart failure.

[13]  Ewout W. Steyerberg,et al.  Prognostic Models With Competing Risks: Methods and Application to Coronary Risk Prediction , 2009, Epidemiology.

[14]  C. O'connor,et al.  Randomized Trial of Warfarin, Aspirin, and Clopidogrel in Patients With Chronic Heart Failure: The Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) Trial , 2009, Circulation.

[15]  John G F Cleland,et al.  Predictors of fatal and non‐fatal outcomes in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA): incremental value of apolipoprotein A‐1, high‐sensitivity C‐reactive peptide and N‐terminal pro B‐type natriuretic peptide , 2009, European journal of heart failure.

[16]  S. Forman,et al.  Fitting Cox Model Using PROC PHREG and Beyond in SAS , 2009 .

[17]  Susan Anderson,et al.  Irbesartan in patients with heart failure and preserved ejection fraction. , 2008, The New England journal of medicine.

[18]  Li-sheng Liu,et al.  Treatment of hypertension in patients 80 years of age or older. , 2008, The New England journal of medicine.

[19]  George A. Johnson,et al.  Risk of Thromboembolism in Heart Failure: An Analysis From the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) , 2007, Circulation.

[20]  V. Roger,et al.  Trends in prevalence and outcome of heart failure with preserved ejection fraction. , 2006, The New England journal of medicine.

[21]  P. Toutouzas,et al.  Efficacy of antithrombotic therapy in chronic heart failure: The HELAS study , 2006, European journal of heart failure.

[22]  Salim Yusuf,et al.  Predictors of mortality and morbidity in patients with chronic heart failure. , 2006, European heart journal.

[23]  R. McKelvie,et al.  The irbesartan in heart failure with preserved systolic function (I-PRESERVE) trial: rationale and design. , 2005, Journal of cardiac failure.

[24]  M. Redfield,et al.  Epidemiology of diastolic heart failure. , 2005, Progress in cardiovascular diseases.

[25]  M. Pencina,et al.  Overall C as a measure of discrimination in survival analysis: model specific population value and confidence interval estimation , 2004, Statistics in medicine.

[26]  P A Poole-Wilson,et al.  The Warfarin/Aspirin Study in Heart failure (WASH): a randomized trial comparing antithrombotic strategies for patients with heart failure. , 2004, American heart journal.

[27]  J. Laragh,et al.  Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial , 2004, The Lancet.

[28]  Kamyar Kalantar-Zadeh,et al.  Reverse epidemiology of conventional cardiovascular risk factors in patients with chronic heart failure. , 2004, Journal of the American College of Cardiology.

[29]  K. Swedberg,et al.  Heart failure with preserved left ventricular systolic function; epidemiology, clinical characteristics, and prognosis. , 2004, Journal of the American College of Cardiology.

[30]  Karl Swedberg,et al.  Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial , 2003, The Lancet.

[31]  C. Reid,et al.  A comparison of outcomes with angiotensin-converting--enzyme inhibitors and diuretics for hypertension in the elderly. , 2003, The New England journal of medicine.

[32]  B. Davis,et al.  Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). , 2002, JAMA.

[33]  M. Nieminen,et al.  For Personal Use. Only Reproduce with Permission from the Lancet Publishing Group , 2022 .

[34]  M. Pfeffer,et al.  Candesartan in heart failure--assessment of reduction in mortality and morbidity (CHARM): rationale and design. Charm-Programme Investigators. , 1999, Journal of cardiac failure.

[35]  Robert Gray,et al.  A Proportional Hazards Model for the Subdistribution of a Competing Risk , 1999 .

[36]  M. Domanski,et al.  Ejection fraction and risk of thromboembolic events in patients with systolic dysfunction and sinus rhythm: evidence for gender differences in the studies of left ventricular dysfunction trials. , 1997, Journal of the American College of Cardiology.

[37]  F. Harrell,et al.  Prognostic/Clinical Prediction Models: Multivariable Prognostic Models: Issues in Developing Models, Evaluating Assumptions and Adequacy, and Measuring and Reducing Errors , 2005 .

[38]  C. Iadecola,et al.  A Harbinger of Stroke and Dementia , 2022 .