Atrial fibrillation (AF) in the presence of heart failure (HF) is associated with poor outcomes including a high-risk of stroke and other thromboembolic events. Identifying patients without AF who are at high-risk of developing this arrhythmia has important clinical implications.
To develop a risk score to identify HF patients at high risk of developing AF.
The COMMANDER-HF trial enrolled 5022 patients with HF and a LVEF ≤ 40%, history of coronary artery disease, and absence of AF at baseline (confirmed with an electrocardiogram). Patients were randomized to either rivaroxaban (2.5 mg bid) or placebo. New-onset AF was confirmed by the investigator at study visits.
241 (4.8%) patients developed AF during the follow-up (median 21 months). Older age (≥ 65 years), LVEF < 35%, history of PCI or CABG, White race, SBP < 110 mmHg, and higher BMI (≥ 25 kg/m2) were independently associated with risk of new-onset AF, whereas the use of DAPT was associated with a lower risk of new-onset AF. We then built a risk score from these variables (with good accuracy C-index = 0.71) and calibration across observed and predicted tertiles of risk. New-onset AF events rates increased steeply by increasing tertiles of the risk-score. Compared to tertile 1, the risk of new-onset AF was 2.5-fold higher in tertile 2, and 6.3-fold higher in tertile 3. Rivaroxaban had no effect in reducing new-onset AF. In time-updated models, new-onset AF was associated with a higher risk of subsequent all-cause death: HR (95%CI) 1.38 (1.11–1.73).
A well-calibrated risk-score identified patients at risk of new-onset AF in the COMMANDER-HF trial. Patients who developed AF had a higher risk of subsequent death.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Ferreira JP, Girerd N, Alshalash S, Konstam MA, Zannad F (2016) Antithrombotic therapy in heart failure patients with and without atrial fibrillation: update and future challenges. Eur Heart J.
Marrouche NF, Brachmann J, Andresen D, Siebels J, Boersma L, Jordaens L, Merkely B, Pokushalov E, Sanders P, Proff J, Schunkert H, Christ H, Vogt J, Bänsch D (2018) Catheter ablation for atrial fibrillation with heart failure. N Engl J Med 378(5):417–427
Dörr M, Nohturfft V, Brasier N, Bosshard E, Djurdjevic A, Gross S, Raichle CJ, Rhinisperger M, Stöckli R, Eckstein J (2019) The Watch AF trial: SmartWATCHes for detection of atrial fibrillation. JACC Clin Electrophysiol 5(2):199–208
Perez MV, Mahaffey KW, Hedlin H, Rumsfeld JS, Garcia A, Ferris T, Balasubramanian V, Russo AM, Rajmane A, Cheung L, Hung G, Lee J, Kowey P, Talati N, Nag D, Gummidipundi SE, Beatty A, Hills MT, Desai S, Granger CB, Desai M, Turakhia MP (2019) Large-scale assessment of a smartwatch to identify atrial fibrillation. N Engl J Med 381(20):1909–1917
Attia ZI, Noseworthy PA, Lopez-Jimenez F, Asirvatham SJ, Deshmukh AJ, Gersh BJ, Carter RE, Yao X, Rabinstein AA, Erickson BJ, Kapa S, Friedman PA (2019) An artificial intelligence-enabled ECG algorithm for the identification of patients with atrial fibrillation during sinus rhythm: a retrospective analysis of outcome prediction. Lancet 394(10201):861–867
Zannad F, Greenberg B, Cleland JG, Gheorghiade M, van Veldhuisen DJ, Mehra MR, Anker SD, Byra WM, Fu M, Mills RM (2015) Rationale and design of a randomized, double-blind, event-driven, multicentre study comparing the efficacy and safety of oral rivaroxaban with placebo for reducing the risk of death, myocardial infarction or stroke in subjects with heart failure and significant coronary artery disease following an exacerbation of heart failure: the COMMANDER HF trial. Eur J Heart Fail 17(7):735–742
Zannad F, Anker SD, Byra WM, Cleland JGF, Fu M, Gheorghiade M, Lam CSP, Mehra MR, Neaton JD, Nessel CC, Spiro TE, van Veldhuisen DJ, Greenberg B (2018) Rivaroxaban in patients with heart failure, sinus rhythm, and coronary disease. N Engl J Med.
Mehra MR, Vaduganathan M, Fu M, Ferreira JP, Anker SD, Cleland JGF, Lam CSP, van Veldhuisen DJ, Byra WM, Spiro TE, Deng H, Zannad F, Greenberg B (2019) A comprehensive analysis of the effects of rivaroxaban on stroke or transient ischaemic attack in patients with heart failure, coronary artery disease, and sinus rhythm: the COMMANDER HF trial. Eur Heart J 40(44):3593–3602
Greenberg B, Neaton JD, Anker SD, Byra WM, Cleland JGF, Deng H, Fu M, La Police DA, Lam CSP, Mehra MR, Nessel CC, Spiro TE, van Veldhuisen DJ, Vanden Boom CM, Zannad F (2019) Association of rivaroxaban with thromboembolic events in patients with heart failure, coronary disease, and sinus rhythm: a post hoc analysis of the COMMANDER HF trial. JAMA Cardiol 4(6):515–523
Cunningham JW, Ferreira JP, Deng H, Anker SD, Byra WM, Cleland JGF, Gheorghiade M, Lam CSP, La Police D, Mehra MR, Neaton JD, Spiro TE, van Veldhuisen DJ, Greenberg B, Zannad F (2020) Natriuretic peptide-based inclusion criteria in a heart failure clinical trial: insights from COMMANDER HF. JACC Heart Fail.
Jp F, Rj G (1999) A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 94:496–509
Collier TJ, Pocock SJ, McMurray JJ, Zannad F, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pitt B (2013) The impact of eplerenone at different levels of risk in patients with systolic heart failure and mild symptoms: insight from a novel risk score for prognosis derived from the EMPHASIS-HF trial. Eur Heart J 34(36):2823–2829
Abdul-Rahim AH, Perez AC, Fulton RL, Jhund PS, Latini R, Tognoni G, Wikstrand J, Kjekshus J, Lip GY, Maggioni AP, Tavazzi L, Lees KR, McMurray JJ (2015) 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. Circulation 131(17):1486–1494
Borissoff JI, Spronk HM, Heeneman S, ten Cate H (2009) Is thrombin a key player in the ‘coagulation-atherogenesis’ maze? Cardiovasc Res 82(3):392–403
Abdul-Rahim AH, Perez AC, MacIsaac RL, Jhund PS, Claggett BL, Carson PE, Komajda M, McKelvie RS, Zile MR, Swedberg K, Yusuf S, Pfeffer MA, Solomon SD, Lip GYH, Lees KR, McMurray JJV (2017) 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. Eur Heart J 38(10):742–750
Ferreira JP, Girerd N, Gregson J, Latar I, Sharma A, Pfeffer MA, McMurray JJV, Abdul-Rahim AH, Pitt B, Dickstein K, Rossignol P, Zannad F (2018) Stroke risk in patients with reduced ejection fraction after myocardial infarction without atrial fibrillation. J Am Coll Cardiol 71(7):727–735
Cleland JG, Findlay I, Jafri S, Sutton G, Falk R, Bulpitt C, Prentice C, Ford I, Trainer A, Poole-Wilson PA (2004) The Warfarin/Aspirin Study in Heart failure (WASH): a randomized trial comparing antithrombotic strategies for patients with heart failure. Am Heart J 148(1):157–164
Cokkinos DV, Haralabopoulos GC, Kostis JB, Toutouzas PK (2006) Efficacy of antithrombotic therapy in chronic heart failure: the HELAS study. Eur J Heart Fail 8(4):428–432
Massie BM, Collins JF, Ammon SE, Armstrong PW, Cleland JG, Ezekowitz M, Jafri SM, Krol WF, O’Connor CM, Schulman KA, Teo K, Warren SR (2009) Randomized trial of warfarin, aspirin, and clopidogrel in patients with chronic heart failure: the warfarin and antiplatelet therapy in chronic heart failure (WATCH) trial. Circulation 119(12):1616–1624
Homma S, Thompson JL, Pullicino PM, Levin B, Freudenberger RS, Teerlink JR, Ammon SE, Graham S, Sacco RL, Mann DL, Mohr JP, Massie BM, Labovitz AJ, Anker SD, Lok DJ, Ponikowski P, Estol CJ, Lip GY, Di Tullio MR, Sanford AR, Mejia V, Gabriel AP, del Valle ML, Buchsbaum R (2012) Warfarin and aspirin in patients with heart failure and sinus rhythm. N Engl J Med 366(20):1859–1869
Ferreira JP, Lam CSP, Anker SD, Mehra MR, van Veldhuisen DJ, Byra WM, La Police DA, Cleland JGF, Greenberg B, Zannad F (2020) Plasma D-dimer concentrations predicting stroke risk and rivaroxaban benefit in patients with heart failure and sinus rhythm: an analysis from the COMMANDER-HF trial. Eur J Heart Fail.
Belkin MN, Soria CE, Waldo AL, Borleffs CJW, Hayes DL, Tung R, Singh JP, Upadhyay GA (2018) Incidence and clinical significance of new-onset device-detected atrial tachyarrhythmia: a meta-analysis. Circ Arrhythm Electrophysiol 11(3):e005393
Degrauwe S, Pilgrim T, Aminian A, Noble S, Meier P, Iglesias JF (2017) Dual antiplatelet therapy for secondary prevention of coronary artery disease. Open Heart 4(2):e000651
Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, Cutlip DE, Steg PG, Normand SL, Braunwald E, Wiviott SD, Cohen DJ, Holmes DR, Krucoff MW, Hermiller J, Dauerman HL, Simon DI, Kandzar IE, Garratt KN, Lee DP, Pow TK, Ver Lee P, Rinaldi MJ, Massaro JM (2014) Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 371(23):2155–2166
Bhatia GS, Lip GY (2004) Atrial fibrillation post-myocardial infarction: frequency, consequences, and management. Curr Heart Fail Rep 1(4):149–155
Lau DH, Nattel S, Kalman JM, Sanders P (2017) Modifiable risk factors and atrial fibrillation. Circulation 136(6):583–596
Alonso A, Krijthe BP, Aspelund T, Stepas KA, Pencina MJ, Moser CB, Sinner MF, Sotoodehnia N, Fontes JD, Janssens AC, Kronmal RA, Magnani JW, Witteman JC, Chamberlain AM, Lubitz SA, Schnabel RB, Agarwal SK, McManus DD, Ellinor PT, Larson MG, Burke GL, Launer LJ, Hofman A, Levy D, Gottdiener JS, Kääb S, Couper D, Harris TB, Soliman EZ, Stricker BH, Gudnason V, Heckbert SR, Benjamin EJ (2013) Simple risk model predicts incidence of atrial fibrillation in a racially and geographically diverse population: the CHARGE-AF consortium. J Am Heart Assoc 2(2):e000102
Ferreira JP, Duarte K, Pfeffer MA, McMurray JJV, Pitt B, Dickstein K, Zannad F, Rossignol P (2018) Association between mean systolic and diastolic blood pressure throughout the follow-up and cardiovascular events in acute myocardial infarction patients with systolic dysfunction and/or heart failure: an analysis from the high-risk myocardial infarction database initiative. Eur J Heart Fail 20(2):323–331
Schmitt J, Duray G, Gersh BJ, Hohnloser SH (2009) Atrial fibrillation in acute myocardial infarction: a systematic review of the incidence, clinical features and prognostic implications. Eur Heart J 30(9):1038–1045
Lau CP, Gbadebo TD, Connolly SJ, Van Gelder IC, Capucci A, Gold MR, Israel CW, Morillo CA, Siu CW, Abe H, Carlson M, Tse HF, Hohnloser SH, Healey JS (2013) Ethnic differences in atrial fibrillation identified using implanted cardiac devices. J Cardiovasc Electrophysiol 24(4):381–387
Alonso A, Agarwal SK, Soliman EZ, Ambrose M, Chamberlain AM, Prineas RJ, Folsom AR (2009) Incidence of atrial fibrillation in whites and African-Americans: the atherosclerosis risk in communities (ARIC) study. Am Heart J 158(1):111–117
Ferreira JP, Cleland JGF, Lam CSP, van Veldhuisen DJ, Byra WM, La Police DA, Anker SD, Mehra MR, Leroy C, Eschwege V, Toussaint-Hacquard M, Rossignol P, Greenberg B, Zannad F (2021) Impact of geographic region on the COMMANDER-HF trial. JACC Heart Fail 9(3):201–211
Jamaly S, Carlsson L, Peltonen M, Jacobson P, Sjöström L, Karason K (2016) Bariatric surgery and the risk of new-onset atrial fibrillation in swedish obese subjects. J Am Coll Cardiol 68(23):2497–2504
Stienen S, Ferreira JP, Girerd N, Duarte K, Lamiral Z, McMurray JJV, Pitt B, Dickstein K, Zannad F, Rossignol P (2019) Mean BMI, visit-to-visit BMI variability and BMI changes during follow-up in patients with acute myocardial infarction with systolic dysfunction and/or heart failure: insights from the high-risk myocardial Infarction Initiative. Clin Res Cardiol 108(11):1215–1225
Padwal R, McAlister FA, McMurray JJ, Cowie MR, Rich M, Pocock S, Swedberg K, Maggioni A, Gamble G, Ariti C, Earle N, Whalley G, Poppe KK, Doughty RN, Bayes-Genis A (2014) The obesity paradox in heart failure patients with preserved versus reduced ejection fraction: a meta-analysis of individual patient data. Int J Obes (Lond) 38(8):1110–1114
Oreopoulos A, Padwal R, Kalantar-Zadeh K, Fonarow GC, Norris CM, McAlister FA (2008) Body mass index and mortality in heart failure: a meta-analysis. Am Heart J USA 156:13–22
Spronk HM, De Jong AM, Verheule S, De Boer HC, Maass AH, Lau DH, Rienstra M, van Hunnik A, Kuiper M, Lumeij S, Zeemering S, Linz D, Kamphuisen PW, Ten Cate H, Crijns HJ, Van Gelder IC, van Zonneveld AJ, Schotten U (2017) Hypercoagulability causes atrial fibrosis and promotes atrial fibrillation. Eur Heart J 38(1):38–50
JF and FZ are supported by the RHU Fight-HF, a public grant overseen by the French National Research Agency (ANR) as part of the second “Investissements d’Avenir” program (reference: ANR-15-RHUS-0004), and by the French PIA project “Lorraine Université d’Excellence” (reference: ANR-15-IDEX-04-LUE).
The COMMANDER-HF trial was supported by Janssen Research and Development.
Conflicts of interest
The authors report no conflicts of interest regarding the content of this manuscript.
Below is the link to the electronic supplementary material.
About this article
Cite this article
Ferreira, J.P., Cleland, J.G., Lam, C.S.P. et al. New-onset atrial fibrillation in patients with worsening heart failure and coronary artery disease: an analysis from the COMMANDER-HF trial. Clin Res Cardiol (2021). https://doi.org/10.1007/s00392-021-01891-2
- New-onset atrial fibrillation
- Heart failure