Dapagliflozin to Prevent Atrial Fibrillation Recurrence After Transcatheter Pulmonary Venous Isolation.

Dapagliflozin to Prevent Atrial Fibrillation Recurrence After Transcatheter Pulmonary Venous Isolation.

Dapagliflozin to Prevent Atrial Fibrillation Recurrence After Transcatheter Pulmonary Venous Isolation.

2nd Department of Cardiology, "Attikon" University Hospital, National and Kapodistrian University of Athens

Transcatheter left atrial antral ablation, aiming at complete electrical isolation of the pulmonary veins (PVI), has become mainstay in atrial fibrillation (AF) treatment. This approach has been proved superior to medical rhytmh control strategy in maintaining sinus rhythm. Moreover PVI has been associated with significant survival benefit in patients with heart failure and reduced left ventricular ejection fraction. Nevertheless, despite progress in the field of catheter ablation, recurrence rates remain high. Inhibitors of type 2 sodium- glucose co-transporter (SGLT2i) is a relatively recent addition to the array of anti-diabetic agents, becoming part of everyday clinical practice. However, although SGLT2i were first used solely as antidiabetics because of their glycosuric effect, further research demonstrated that these drugs may independently reduce cardiovascular events, especially in patients with heart failure, a benefit that was consistent among diabetic and non-diabetic patients. Moreover, pleiotropic effects have been observed, including a reno-protective action. These findings suggest that SGLT2i mechanisms of action extend beyond the obvious increase in urinary sodium and glucose excretion. Various studies propose that these drugs promote favourable metabolic changes in myocardial energetics, while they also inhibit inflamation and sympathetic activation, resulting in restriction of induced fibrosis and structural remodeling, which are key elements in atrial fibrillation generation and maintenance. These findings suggest that the use of SGLT2i could offer antiarrhythmic benefit by reducing and/or reversing structural and electrical remodeling, leading to the assumption that use of theese drugs could reduce recurrences after transcatheter AF ablation.

Atrial Fibrillation Recurrent, Pulmonary Venous Isolation, Catheter Ablation, Sodium-glucose Co-transporter 2 Inhibitors

dapagliflozin, Sodium-glucose co-transporter 2 inhibitors, Atrial Fibrillation, recurrence, catheter ablation, SGLT2 inhibitors

AF/AT are defined as any episodes of AF or atrial flutter or other re-entrant atrial tachycardia recorded either on surface ECG or on Holter monitoring and lasting for at least 30 s. All episodes will be reviewed by two independent electrophysiologists, who will be blinded as to patient identity and randomization.The first 3 months after the ablation procedure will be regarded as a blanking period.

Any episode of hypoglycemia defined as serum glucose 60< mg/dl associated with symptoms of hypoglycemia.

Any episode of metabolic acidosis (pH<7.3) with decreased serum bicarbonate (<18mEq/ml) and increased anion gap (>10) and increased serum glucose (>250mg/dl) and positive urine dipstick test for ketones.

Inclusion Criteria: Age>18 years Atrial Fibrillation (paroxysmal or sustained); Written informed consent; Glomerular Filtration Rate (GFR) >45 ml/min/1.73m2 (Cockroft-Gault equation) Exclusion Criteria: Hypertrophic cardiomyopathy (Left ventricular wall thickness ≥15mm, not explained by abnormal pressure/volume conditions); Severe mitral valve stenosis (as defined in European Guidelines); Active malignancy; Participation in other intervention studies; Pregnancy or willing of pregnancy during the follow up period Guideline Class I or equivalent indication for treatment with a SGLT2 inhibitor *Eligible patients randomized in the active comparator arm will be also included in a prospective observational registry study regarding the role of SGLT2 inhibitors in post-ablation AF recurrence.

2nd Department of Cardiology, National and Kapodistrian University of Athens, Faculty of Medicine, Athens, Greece

2nd Department of Cardiology, National and Kapodistrian University of Athens, Faculty of Medicine, Athens, Greece.

Haissaguerre M, Jais P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, Le Mouroux A, Le Metayer P, Clementy J. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med. 1998 Sep 3;339(10):659-66. doi: 10.1056/NEJM199809033391003.

Asad ZUA, Yousif A, Khan MS, Al-Khatib SM, Stavrakis S. Catheter Ablation Versus Medical Therapy for Atrial Fibrillation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Circ Arrhythm Electrophysiol. 2019 Sep;12(9):e007414. doi: 10.1161/CIRCEP.119.007414. Epub 2019 Aug 21.

Packer DL, Mark DB, Robb RA, Monahan KH, Bahnson TD, Poole JE, Noseworthy PA, Rosenberg YD, Jeffries N, Mitchell LB, Flaker GC, Pokushalov E, Romanov A, Bunch TJ, Noelker G, Ardashev A, Revishvili A, Wilber DJ, Cappato R, Kuck KH, Hindricks G, Davies DW, Kowey PR, Naccarelli GV, Reiffel JA, Piccini JP, Silverstein AP, Al-Khalidi HR, Lee KL; CABANA Investigators. Effect of Catheter Ablation vs Antiarrhythmic Drug Therapy on Mortality, Stroke, Bleeding, and Cardiac Arrest Among Patients With Atrial Fibrillation: The CABANA Randomized Clinical Trial. JAMA. 2019 Apr 2;321(13):1261-1274. doi: 10.1001/jama.2019.0693.

Ganesan AN, Shipp NJ, Brooks AG, Kuklik P, Lau DH, Lim HS, Sullivan T, Roberts-Thomson KC, Sanders P. Long-term outcomes of catheter ablation of atrial fibrillation: a systematic review and meta-analysis. J Am Heart Assoc. 2013 Mar 18;2(2):e004549. doi: 10.1161/JAHA.112.004549.

Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. doi: 10.1056/NEJMoa1504720. Epub 2015 Sep 17.

Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Zelniker TA, Kuder JF, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Ruff CT, Gause-Nilsson IAM, Fredriksson M, Johansson PA, Langkilde AM, Sabatine MS; DECLARE-TIMI 58 Investigators. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019 Jan 24;380(4):347-357. doi: 10.1056/NEJMoa1812389. Epub 2018 Nov 10.

Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR; CANVAS Program Collaborative Group. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017 Aug 17;377(7):644-657. doi: 10.1056/NEJMoa1611925. Epub 2017 Jun 12.

McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Belohlavek J, Bohm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukat A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O'Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjostrand M, Langkilde AM; DAPA-HF Trial Committees and Investigators. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019 Nov 21;381(21):1995-2008. doi: 10.1056/NEJMoa1911303. Epub 2019 Sep 19.

Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, Verma S, Tsutsui H, Brueckmann M, Jamal W, Kimura K, Schnee J, Zeller C, Cotton D, Bocchi E, Bohm M, Choi DJ, Chopra V, Chuquiure E, Giannetti N, Janssens S, Zhang J, Gonzalez Juanatey JR, Kaul S, Brunner-La Rocca HP, Merkely B, Nicholls SJ, Perrone S, Pina I, Ponikowski P, Sattar N, Senni M, Seronde MF, Spinar J, Squire I, Taddei S, Wanner C, Zannad F; EMPEROR-Reduced Trial Investigators. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020 Oct 8;383(15):1413-1424. doi: 10.1056/NEJMoa2022190. Epub 2020 Aug 28.

Zannad F, Ferreira JP, Pocock SJ, Anker SD, Butler J, Filippatos G, Brueckmann M, Ofstad AP, Pfarr E, Jamal W, Packer M. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet. 2020 Sep 19;396(10254):819-829. doi: 10.1016/S0140-6736(20)31824-9. Epub 2020 Aug 30.

Heerspink HJL, Stefansson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, Mann JFE, McMurray JJV, Lindberg M, Rossing P, Sjostrom CD, Toto RD, Langkilde AM, Wheeler DC; DAPA-CKD Trial Committees and Investigators. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020 Oct 8;383(15):1436-1446. doi: 10.1056/NEJMoa2024816. Epub 2020 Sep 24.

Lopaschuk GD, Verma S. Mechanisms of Cardiovascular Benefits of Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors: A State-of-the-Art Review. JACC Basic Transl Sci. 2020 Jun 22;5(6):632-644. doi: 10.1016/j.jacbts.2020.02.004. eCollection 2020 Jun.

Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia. 2018 Oct;61(10):2108-2117. doi: 10.1007/s00125-018-4670-7. Epub 2018 Aug 22.

Andreadou I, Efentakis P, Balafas E, Togliatto G, Davos CH, Varela A, Dimitriou CA, Nikolaou PE, Maratou E, Lambadiari V, Ikonomidis I, Kostomitsopoulos N, Brizzi MF, Dimitriadis G, Iliodromitis EK. Empagliflozin Limits Myocardial Infarction in Vivo and Cell Death in Vitro: Role of STAT3, Mitochondria, and Redox Aspects. Front Physiol. 2017 Dec 19;8:1077. doi: 10.3389/fphys.2017.01077. eCollection 2017.

Wan N, Rahman A, Hitomi H, Nishiyama A. The Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Sympathetic Nervous Activity. Front Endocrinol (Lausanne). 2018 Jul 26;9:421. doi: 10.3389/fendo.2018.00421. eCollection 2018.

Maejima Y. SGLT2 Inhibitors Play a Salutary Role in Heart Failure via Modulation of the Mitochondrial Function. Front Cardiovasc Med. 2020 Jan 8;6:186. doi: 10.3389/fcvm.2019.00186. eCollection 2019.

Li WJ, Chen XQ, Xu LL, Li YQ, Luo BH. SGLT2 inhibitors and atrial fibrillation in type 2 diabetes: a systematic review with meta-analysis of 16 randomized controlled trials. Cardiovasc Diabetol. 2020 Aug 26;19(1):130. doi: 10.1186/s12933-020-01105-5.