Heart Failure with Reduced Ejection Fraction: Don't Wait, Ablate!

Cardiac arrhythmia ablation was first performed in 1981 by Dr. Scheinman in a patient with atrial fibrillation and multiple comorbidities that prohibited the then usual treatment of surgical ablation via sternotomy and cardiotomy.1 After intense research, the treatment of atrial fibrillation moved on to radiofrequency ablation of the pulmonary veins and shifted away from nodal techniques in this patient population.1 Over more than four decades, these giant leaps in treatment technology have dramatically reduced the need for sternotomy and other highly invasive techniques and revolutionized the treatment of atrial fibrillation. In recent years, the treatment of atrial fibrillation using ablation strategies has again seen an expansion in use to the heart failure population. As perioperative physicians, anesthesiologists must be cognizant of the nuances of the expanded use of this technology to the high-risk heart failure population. Recently, in their manuscript “Catheter Ablation in End-Stage Heart Failure with Atrial Fibrillation” (CASTLE HTx), Sohns et al demonstrated an impressive mortality benefit with the application of catheter based atrial fibrillation ablation in patients with atrial fibrillation and left ventricular ejection fraction (LVEF) ≤ 35%.2 In this investigation, the authors randomized patients with reduced LVEF and symptomatic atrial fibrillation (persistent or paroxysmal) to catheter ablation (pulmonary vein isolation +/- other) and goal-directed medical therapy (GDMT), or GDMT alone. After enrolling 97 patients per arm, and following an 18-month median follow-up period, the study was halted due to significant outcome differences between the groups, with a dramatic reduction in mortality (6% vs 20%, hazard ratio 0.29, intention-to-treat analysis) noted for the ablation group. Alone, this would be a remarkable finding, but it must also be noted that there was significant crossover of patients from the GDMT to the ablation arm. This raises the possibility that the true differences in outcomes between GDMT and ablation may be even more pronounced. This work has the potential to significantly alter the routine management of this patient population, and it stands to reason that anesthesiologists will increasingly encounter this complex group in the electrophysiology lab. The findings of CASTLE-HTx raise important questions about which specific populations and demographics may benefit most from catheter ablation and which require special attention to optimize outcomes. As always, the devil is in the details, and care must be taken when interpreting and applying the findings. Upon review of the supplemental data from CASTLE HTx, a few interesting results emerge. First, the demonstrated mortality and outcome differences are far more robust in patients with higher baseline LVEF in the range of 25-35% (HR 0.13 CI 0.04-0.45), when compared with <25% (HR 0.49, CI 0.17-1.41).2 Although underpowered to demonstrate outcome differences with this level of stratification, the confidence interval for patients with LVEF <25 suggests that there may not be as much benefit to the intervention in this group. Similarly, though there were trends towards significance, the study was underpowered to demonstrate outcome differences in women (HR 0.33, CI 0.07-1.50), patients ≥65 years of age (HR 0.41, CI 0.16-1.04) and patients with paroxysmal atrial fibrillation (HR 0.50, CI 0.17-1.48). 2 As with many other invasive interventions, there may be a tipping point where benefits do not justify procedural risks. In Castle-HTx, the authors publish very low rates of procedural complications 4/194 (2%), all of which were described as “minor” vascular issues. This contrasts with previously published literature, where complication rates are similar overall (2.9-3.6%), but significant complications such as tamponade, effusion and stroke were more frequently reported (nearly 50% of overall).2,3 Further, female sex has been identified by multiple authors as a predictor of complications in this population.1,4,5 Given these important limitations, a thoughtful approach is important when considering the broad applications of these findings. It is also important to consider how these findings fit into the landscape of perioperative and procedural management of atrial fibrillation. The American Association for Thoracic Surgery (AATS) consensus guidelines list concomitant surgical ablation for atrial fibrillation during cardiac surgery as a Class I indication for improving short term (<30 day) survival, and a Class IIa indication for improving longer term (>30 day) survival.6 A multicenter retrospective analysis from 2019 found an association between improved short- and long-term survival in cardiac surgical patients that underwent surgical ablation as part of a variety of primary operations. 7 In their study, after risk adjustment, patients undergoing surgical ablation had improved 5-year survival (HR 0.69, CI 0.51-0.92), and the effect was observed across all concomitant operations.7 Though this trial did include patients with depressed LVEF (<40%), no sub-analysis of this population was performed, and to date there is a lack of high-quality evidence corroborating the mortality benefits of surgical ablation specifically in the reduced LVEF population. Given both the surgical as well as the medical data, it appears that prospective investigation of surgical ablation in this population is warranted. Anesthesiologists must be aware of the effects of all commonly prescribed goal direct medical therapy (GDMT) agents in this patient population. For example, in the Castle HTx intervention arm: 68% of patients were being treated with sacubitril-valsartan (Entrestoâ, Novartis AG, Basel, Switzerland), 32% of patients with either an angiotensin converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB), and 24% were being treated with a sodium glucose transport protein 2 (SGLT2) inhibitor.1 ACEi and ARB use has been inconsistently associated with perioperative vasoplegia after cardiac and non-cardiac surgical procedures.8-11 Patients presenting for catheter-based procedures are a relatively unexplored area with regard to this topic. The decision to withhold afterload reduction in end stage heart failure patients is complex given that increased afterload can precipitate decompensated heart failure while perioperative hypotension can contribute to acute kidney injury. A thoughtful approach that includes a review of institutional protocols regarding perioperative administration of these agents should be followed in patients presenting for atrial fibrillation ablation. Given its relatively recent release, data regarding the association between sacubitril-valsartan and perioperative hypotension is mostly limited to case reports and case series, with no definitive conclusions that can be made in the catheter-based population.12 SGLT2 inhibitors, which function by blocking the reabsorption of glucose in the nephron, have seen a rapidly growing list of indications for use in the heart failure population.13,14,15 The notable side effects with this class of medications, euglycemic ketoacidosis as well as genital infections and an initial concern for urinary tract infections (due to the resultant glycosuria), have important implications in the perioperative period.16,17,18 In one large meta-analysis, an association with urinary tract infections was disproven but genital infections seem to be more frequent in the SGLT2 inhibitor group.18 Most organizations recommend withholding SGLT2 inhibitors 3-4 days before surgery and restarting them when oral intake has normalized to reduce the risk of euglycemic DKA.16,17,19 Though the incidence of hypoglycemia with SGLT2 inhibitors is low, anesthesiologists may consider assessing glucose levels during longer ablation procedures, particularly because patients receiving these agents are frequently diabetic and often receiving other glucose lowering medications. Finally, the rise of glucagon-like peptide-1 receptor agonists (GLP-1) like semaglutide will likely further complicate management of these patients. There is increasing evidence that weight loss in the overweight/obese patient population plays an important role in the management of this population.20,21 Glucagon like peptides-1 agonists are being widely used to achieve this goal in this patient population. Emerging evidence in the preserved LVEF heart failure population suggests that GLP-1 agonists may have a role in symptom reduction and quality of life improvement and future work may translate this to low LVEF patients presenting for anesthetic management.22,23 Notably, GLP-1 agonists delay gastric emptying, and may predispose patients to aspiration events at the time of anesthetic induction. Though high-quality evidence is still lacking on this topic, the American Society of Anesthesiologists has recommended holding the oral forms for a day preoperatively, and the weekly injectable for a week preoperatively. 24 A notable finding in the supplemental index of CASTLE HTx trial was the very low procedure time.1 Specifically, “skin-to-skin” or procedure start to finish time was 96 ± 20 minutes, which is dramatically faster than that seen in large observational studies which found an average procedure time of 180 minutes (interquartile range, 25th to 75th percentile, of 140-230).25 This discrepancy could be due to a number of factors including two experienced providers per case with ≥ 400 procedures each. Some of the aforementioned differences in procedural complications in CastleHTx may be partially attributable to these shorter procedural durations and experienced providers. The far shorter procedure times (nearly 50%) has several important implications with regard to the widespread use of this procedure in the end stage heart failure population. First, contemporary ablation catheters continuously infuse fluid in order to achieve better current delivery to the cardiac tissue and achieve more durable lesions through the irrigant's cooling effect. This will often result in volumes of up to 30 milliliters/minute during ablation, which could have important implications in the heart failure population and necessitate the use of diuretic therapy to avoid heart failure exacerbation.26 Second, duration of anesthesia is also likely associated with increased fluid administration due to the need for infusions and medication administration, a modifiable risk with vigilant care, in addition to the inherent risks of anesthetizing the heart failure population. As an extension of the results of this trial, it may be possible that in non-compliant heart failure patients who otherwise meet criteria, ablation could be part of a staged procedure to reduce long term morbidity. Though both arms of Castle-HTx received GDMT, it would be interesting to study whether ablation alone could provide mortality benefit in the non-compliant population. Further, patients unwilling to continue anticoagulation (or those with a contraindication) may benefit from a combined ablation and left atrial appendage occlusion device, followed with a shorter duration of anticoagulation. This would require a case-by-case evaluation given that stopping anticoagulation after atrial fibrillation ablation is not consistent with current guidelines.27 Perhaps in the future, a hybrid structural heart and atrial fibrillation ablation approach may assist patients that would prefer to avoid long term anticoagulation. Retrospective reviews do suggest that this approach is possible, but further research is needed to assess safety and efficacy in the heart failure population.28,29 As the treatment of atrial fibrillation finds expanding use in ever more high-risk populations, anesthesiologists are tasked with not only understanding the nature of the procedures patients will receive, but also the growing body of literature surrounding the care of advanced heart failure patients. Additionally, the impact of SGLT-2 inhibitors, afterload reducing medications such as sacubitril-valsartan, and novel anticoagulants in the perioperative period has not yet been fully appreciated and requires both vigilance and research from the anesthesia community. Combined ablation-structural interventions are likely to play a larger role in certain patient cohorts and cardiac anesthesiologists are likely to be called upon for imaging guidance. Anesthesiologists will play a central role in meeting the needs of the growing heart failure population and it is imperative that our community engages in the meaningful delivery of high-level care, research, patient safety advocacy. 1Scheinman MA, Rutherford JD. The Development of Cardiac Arrhythmia Ablation: A Conversation With Melvin A. Scheinman, MD. Circulation. 2017 Mar 28;135(13):1191-1193. doi: 10.1161/CIRCULATIONAHA.117.027956. PMID: 28348089.2Sohns C, Fox H, Marrouche NF, Crijns HJGM, Costard-Jaeckle A, Bergau L, Hindricks G, Dagres N, Sossalla S, Schramm R, Fink T, El Hamriti M, Moersdorf M, Sciacca V, Konietschke F, Rudolph V, Gummert J, Tijssen JGP, Sommer P; CASTLE HTx Investigators. Catheter Ablation in End-Stage Heart Failure with Atrial Fibrillation. N Engl J Med. 2023 Aug 27.3Mol D, Houterman S, Balt JC, Bhagwandien RE, Blaauw Y, Delnoy PH, van Driel VJ, Driessen AH, Folkeringa RJ, Hassink RJ, van Huysduynen BH, Luermans JG, Ouss AJ, Stevenhagen YJ, van Veghel D, Westra SW, de Jong JS, de Groot JR; Netherlands Heart Registration Ablation Registration Committee. Complications in pulmonary vein isolation in the Netherlands Heart Registration differ with sex and ablation technique. Europace. 2021 Feb 5;23(2):216-225. doi: 10.1093/europace/euaa255. Erratum in: Europace. 2021 Aug 6;23(8):1332. PMID: 33141152.4Gupta A, Perera T, Ganesan A, Sullivan T, Lau DH, Roberts-Thomson KC, Brooks AG, Sanders P. Complications of catheter ablation of atrial fibrillation: a systematic review. Circ Arrhythm Electrophysiol. 2013 Dec;6(6):1082-8. doi: 10.1161/CIRCEP.113.000768. Epub 2013 Nov 15. PMID: 24243785.5Yves De Greef, Edwin Ströker, Bruno Schwagten, Kaspars Kupics, Jeroen De Cocker, Gian-Battista Chierchia, Carlo de Asmundis, Dirk Stockman, Ian Buysschaert, Complications of pulmonary vein isolation in atrial fibrillation: predictors and comparison between four different ablation techniques: Results from the MIddelheim PVI-registry, EP Europace, Volume 20, Issue 8, August 2018, Pages 1279–1286, https://doi.org/10.1093/europace/eux2336Ad N, Damiano RJ Jr, Badhwar V, Calkins H, La Meir M, Nitta T, Doll N, Holmes SD, Weinstein AA, Gillinov M. Expert consensus guidelines: Examining surgical ablation for atrial fibrillation. J Thorac Cardiovasc Surg. 2017 Jun;153(6):1330-1354.e1. doi: 10.1016/j.jtcvs.2017.02.027. Epub 2017 Mar 2. PMID: 28390766.7Iribarne A, DiScipio AW, McCullough JN, Quinn R, Leavitt BJ, Westbrook BM, Robich MP, Sardella GL, Klemperer JD, Kramer RS, Weldner PW, Olmstead EM, Ross CS, Malenka DJ; Northern New England Cardiovascular Disease Study Group. Surgical Atrial Fibrillation Ablation Improves Long-Term Survival: A Multicenter Analysis. Ann Thorac Surg. 2019 Jan;107(1):135-142. doi: 10.1016/j.athoracsur.2018.08.022. Epub 2018 Oct 6. PMID: 30300644.8Noubiap JJ, Nouthe B, Sia YT, Spaziano M. Effect of preoperative renin-angiotensin system blockade on vasoplegia after cardiac surgery: A systematic review with meta-analysis. World J Cardiol. 2022 Apr 26;14(4):250-259.9Milne B, Gilbey T, Ostermann M, Kunst G. Pro: We Should Stop ACE Inhibitors Early Before Cardiac Surgery to Prevent Postoperative Acute Kidney Injury. J Cardiothorac Vasc Anesth. 2020 Oct;34(10):2832-2835.10Disque A, Neelankavil J. Con: ACE Inhibitors Should Be Stopped Prior to Cardiovascular Surgery. J Cardiothorac Vasc Anesth. 2016 Jun;30(3):820-2. doi: 10.1053/j.jvca.2016.01.016.11Roshanov PS, Rochwerg B, Patel A, Salehian O, Duceppe E, Belley-Côté EP, Guyatt GH, Sessler DI, Le Manach Y, Borges FK, Tandon V, Worster A, Thompson A, Koshy M, Devereaux B, Spencer FA, Sanders RD, Sloan EN, Morley EE, Paul J, Raymer KE, Punthakee Z, Devereaux PJ. Withholding versus Continuing Angiotensin-converting Enzyme Inhibitors or Angiotensin II Receptor Blockers before Noncardiac Surgery: An Analysis of the Vascular events In noncardiac Surgery patIents cOhort evaluatioN Prospective Cohort. Anesthesiology. 2017 Jan;126(1):16-27.12Haider L, Hugon-Vallet E, Constantin JP, Riad Z, Sebbag L, Mewton N. ARNI Pre-Operative Use and Vasoplegic Syndrome in Patients Undergoing Heart Transplantation or Left Ventricular Assist Device Surgery. Med Sci (Basel). 2021 Dec 21;10(1):2.13McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Bělohlávek J, Böhm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukát 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, Sjöstrand 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):1995-2008.14Packer 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, Böhm 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):1413-1424.15Solomon SD, McMurray JJV, Claggett B, de Boer RA, DeMets D, Hernandez AF, Inzucchi SE, Kosiborod MN, Lam CSP, Martinez F, Shah SJ, Desai AS, Jhund PS, Belohlavek J, Chiang CE, Borleffs CJW, Comin-Colet J, Dobreanu D, Drozdz J, Fang JC, Alcocer-Gamba MA, Al Habeeb W, Han Y, Cabrera Honorio JW, Janssens SP, Katova T, Kitakaze M, Merkely B, O'Meara E, Saraiva JFK, Tereshchenko SN, Thierer J, Vaduganathan M, Vardeny O, Verma S, Pham VN, Wilderäng U, Zaozerska N, Bachus E, Lindholm D, Petersson M, Langkilde AM; DELIVER Trial Committees and Investigators. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2022 Sep 22;387(12):1089-1098.16Thiruvenkatarajan V, Jesudason D, Nanjappa N, Meyer EJ, Van Wijk RM. Perioperative Management of Glucose-lowering Drugs: Comment. Anesthesiology. 2021 Feb 1;134(2):349-350.17Preiser JC, Provenzano B, Mongkolpun W, Halenarova K, Cnop M. Perioperative Management of Oral Glucose-lowering Drugs in the Patient with Type 2 Diabetes. Anesthesiology. 2020 Aug;133(2):430-438.18Puckrin R, Saltiel MP, Reynier P, Azoulay L, Yu OHY, Filion KB. SGLT-2 inhibitors and the risk of infections: a systematic review and meta-analysis of randomized controlled trials. Acta Diabetol. 2018 May;55(5):503-514.19FDA Revises Labels of SGLT2 Inhibitors for Diabetes to Include Warnings About Too Much Acid in the Blood and Serious Urinary Tract Infections. FDA; (2021). Available online at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-revises-labels-sglt2-inhibitors-diabetes-include-warnings-about-too-much-acid-blood-and-serious accessed: 10/8/202320Heidenreich, PA et al 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines J Am Coll Cardiol. 2022 May, 79 (17) e263–e42121Hindricks G et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC European Heart Journal, Volume 42, Issue 5, 1 February 2021, Pages 373–49822Kosiborod MN, Abildstrøm SZ, Borlaug BA, Butler J, Rasmussen S, Davies M, Hovingh GK, Kitzman DW, Lindegaard ML, Møller DV, Shah SJ, Treppendahl MB, Verma S, Abhayaratna W, Ahmed FZ, Chopra V, Ezekowitz J, Fu M, Ito H, Lelonek M, Melenovsky V, Merkely B, Núñez J, Perna E, Schou M, Senni M, Sharma K, Van der Meer P, von Lewinski D, Wolf D, Petrie MC; STEP-HFpEF Trial Committees and Investigators. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2023 Sep 21;389(12):1069-1084. doi: 10.1056/NEJMoa2306963. Epub 2023 Aug 25. PMID: 37622681.23Pérez-Belmonte LM, Sanz-Cánovas J, García de Lucas MD, Ricci M, Avilés-Bueno B, Cobos-Palacios L, Pérez-Velasco MA, López-Sampalo A, Bernal-López MR, Jansen-Chaparro S, Miramontes-González JP, Gómez-Huelgas R. Efficacy and Safety of Semaglutide for the Management of Obese Patients With Type 2 Diabetes and Chronic Heart Failure in Real-World Clinical Practice. Front Endocrinol (Lausanne). 2022 Jun 24;13:851035. doi: 10.3389/fendo.2022.851035. PMID: 35813629; PMCID: PMC9263111.24https://www.asahq.org/about-asa/newsroom/news-releases/2023/06/patients-taking-popular-medications-for-diabetes-and-weight-loss-should-stop-before-elective-surgery accessed: 10/8/2325Loring Z, Holmes DN, Matsouaka RA, Curtis AB, Day JD, Desai N, Ellenbogen KA, Feld GK, Fonarow GC, Frankel DS, Hurwitz JL, Knight BP, Joglar JA, Russo AM, Sidhu MS, Turakhia MP, Lewis WR, Piccini JP. Procedural Patterns and Safety of Atrial Fibrillation Ablation: Findings From Get With The Guidelines-Atrial Fibrillation. Circ Arrhythm Electrophysiol. 2020 Sep;13(9):e007944.26Chopra N, Amin AK, Gupta A, Fu EY, Nichols AJ, Nelson SD, Kleman JM, Kleman JM, Kidwell GA, Billakanty SR. Clinical Impact of Saline Volume Infused Through Irrigated-Tip Ablation Catheter in Low Acuity Paroxysmal Atrial Fibrillation Ablation Patients. J Atr Fibrillation. 2018 Dec 31;11(4):2093. doi: 10.4022/jafib.2093.27Kadire SR, Al-Khatib SM, Calkins H. Anticoagulation after Ablation for Atrial Fibrillation. N Engl J Med. 2021 Jul 29;385(5):466-468.28Phillips KP, Walker DT, Humphries JA. Combined catheter ablation for atrial fibrillation and Watchman® left atrial appendage occlusion procedures: Five-year experience. J Arrhythm. 2016 Apr;32(2):119-26. doi: 10.1016/j.joa.2015.11.001.29Ke JY, Jin LS, Lin YN, Xu J, Liu WK, Fu JY, Li L, Chen YL, Qiu YX, Li YC. Combined atrial fibrillation ablation and left atrial appendage closure: Watchman vs. LAmbre devices. Front Cardiovasc Med. 2022 Nov 2;9:1011037. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.