Authors: Michael W. Manning, M.D., Ph.D. et al
Anesthesiology 10 2017, Vol.127, 720-721.
To the Editor:
We read with interest the study by Roshanov et al.1 comparing outcomes in patients undergoing noncardiac surgery, following the withholding or continuing of an Angiotensin-converting Enzyme Inhibitor (ACEi) or Angiotensin II Receptor Blocker (ARB). Although this was a large and comprehensive retrospective study, several key issues should be considered when reviewing this article.
First and foremost is the practice of combining of both ACEis and ARBs for study analysis. ACEi and ARBs are two distinct classes of medications acting at very different regulatory points within the renin-angiotensin system.2 Moreover, their actions at these regulatory points produce distinct end effects.
A dual action enzyme, angiotensin-converting enzyme is responsible for both the conversion of angiotensin I to angiotensin II and the breakdown of bradykinin into nonactive molecules. As a result, ACEi prevents the generation of angiotensin II and increases circulating levels of bradykinin.3,4 While many of the beneficial effects of ACEi therapy have been attributed to reductions in angiotensin II, these benefits appear to be due to increased levels of bradykinin.5
Moreover, it is known that chronic ACEi use does not alter circulating levels of angiotensin II.6–9 Escape pathways of angiotensin II production exist; including chymase-mediated production, which result in production of angiotensin II and a return to pretreatment plasma levels during chronic ACEi use.10,11 The duration of ACEi use prior to surgery is not addressed in this study. This could significantly affect circulating angiotensin levels and, therefore, the interpretation of study results.
On the other hand, ARBs are highly specific antagonists of the angiotensin type 1 (AT1) receptor and block downstream signaling of these G-protein coupled receptors.3,12 While the classic actions of angiotensin II (salt and water reabsorption) are mediated via the AT1receptor, additional effects including vasoconstriction, fibrosis, cell proliferation, inflammation, cell migration, and increased myocardial contractility are also mediated via AT1 receptors.2
AT1 receptor blockade affords unopposed signaling via both the AT2and MAS receptors. These G-protein coupled receptors mediate many of the beneficial actions of angiotensin II, including vasodilatation, antifibrosis, antiapoptosis, and antiproliferative effects.2,3 Long-term use of ARBs inhibits the negative feedback loop of the renin-angiotensin system, resulting in elevated circulating levels of plasma angiotensin II,13 which is then available for signaling via the AT2 receptors in a protective manner.
Because these drugs work at different points and alter the signaling pathway so disparately, we believe that combining these two drugs together does not inform. It muddies the water, and potential benefits unique to a particular drug class may be overlooked.
In this study ACEi/ARB use was associated with intraoperative hypotension. This, in turn, was associated with significant postoperative hypotension. Interestingly, there was no association with ACEi/ARB use and the occurrence of postoperative hypotension, which appeared to be more strongly associated with the primary outcomes of 30-day mortality, stroke, and myocardial injury than the intraoperative hypotension. The postoperative use of these drugs is therefore critical and was not addressed in this study.
Furthermore, the effects of acute withdrawal of these medications have been overlooked, which may affect both intraoperative and postoperative blood pressure. Drenger et al.14 found that the worse outcomes observed in cardiac surgical patients were associated with withdrawal of ACEi, whereas the administration of, or immediate continuation of, ACEis after cardiac surgery was associated with improved outcomes.
The proper management of drug therapy for manipulating the renin-angiotensin system at the time of surgery remains poorly understood, yet is critical to the anesthesiologist. We fully agree that well-designed prospective studies are needed to fully tease out these critical issues; however, future studies must keep ACEis and ARBs separated in their analysis to fully inform and delineate their true effects in the preoperative period.
Michael W. Manning, M.D., Ph.D., Chandrika R. Garner, M.D., Emily G. Teeter, M.D. Duke University, Durham, North Carolina (M.W.M.).
Roshanov, 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; 126:16–27
Mehta, PK, Griendling, KK . Angiotensin II cell signaling: Physiological and pathological effects in the cardiovascular system. Am J Physiol Cell Physiol 2007; 292:C82–97
Farag, E, Maheshwari, K, Morgan, J, Sakr Esa, WA, Doyle, DJ . An update of the role of renin angiotensin in cardiovascular homeostasis. Anesth Analg 2015; 120:275–92
Witherow, FN, Helmy, A, Webb, DJ, Fox, KA, Newby, DE . Bradykinin contributes to the vasodilator effects of chronic angiotensin-converting enzyme inhibition in patients with heart failure. Circulation 2001; 104:2177–81
Yusuf, S, Sleight, P, Pogue, J, Bosch, J, Davies, R, Dagenais, G ; The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000; 342:145–53
van de Wal, RMA, Plokker, HWM, Lok, DJA, Boomsma, F, van der Horst, FAL, van Veldhuisen, DJ, van Gilst, WH, Voors, AA . Determinants of increased angiotensin II levels in severe chronic heart failure patients despite ACE inhibition. Int J Cardiol 2006; 106:367–72
Jorde, UP, Ennezat, PV, Lisker, J, Suryadevara, V, Infeld, J, Cukon, S, Hammer, A, Sonnenblick, EH, Le Jemtel, TH . Maximally recommended doses of angiotensin-converting enzyme (ACE) inhibitors do not completely prevent ACE-mediated formation of angiotensin II in chronic heart failure. Circulation 2000; 101:844–6
Jorde, UP, Vittorio, T, Katz, SD, Colombo, PC, Latif, F, Le Jemtel, TH . Elevated plasma aldosterone levels despite complete inhibition of the vascular angiotensin-converting enzyme in chronic heart failure. Circulation 2002; 106:1055–7
Pitt, B . “Escape” of aldosterone production in patients with left ventricular dysfunction treated with an angiotensin converting enzyme inhibitor: Implications for therapy. Cardiovasc Drugs Ther 1995; 9:145–9
Ferrario, CM, Ahmad, S, Nagata, S, Simington, SW, Varagic, J, Kon, N, Dell’italia, LJ . An evolving story of angiotensin-II-forming pathways in rodents and humans. Clin Sci (Lond) 2014; 126:461–9
Ahmad, S, Varagic, J, Groban, L, Dell’Italia, LJ, Nagata, S, Kon, ND, Ferrario, CM . Angiotensin-(1-12): A chymase-mediated cellular angiotensin II substrate. Curr Hypertens Rep 2014; 16:429
Burnier, M, Brunner, HR . Angiotensin II receptor antagonists. Lancet2000; 355:637–45
Oh, YJ, Lee, JH, Nam, SB, Shim, JK, Song, JH, Kwak, YL . Effects of chronic angiotensin II receptor antagonist and angiotensin-converting enzyme inhibitor treatments on neurohormonal levels and haemodynamics during cardiopulmonary bypass. Br J Anaesth 2006; 97:792–8
Drenger, B, Fontes, ML, Miao, Y, Mathew, JP, Gozal, Y, Aronson, S, Dietzel, C, Mangano, DT ; Investigators of the Ischemia Research and Education Foundation; Multicenter Study of Perioperative Ischemia Research Group: Patterns of use of perioperative angiotensin-converting enzyme inhibitors in coronary artery bypass graft surgery with cardiopulmonary bypass: Effects on in-hospital morbidity and mortality. Circulation 2012; 126:261–9