Perioperative Use Of RAAS Antagonists


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A review of the existing evidence that supports the current practice in perioperative medicine regarding Renin-angiotensin-aldosterone system antagonists, mainly ACE inhibitors and Angiotensin type 1 receptor blockers (ARB's).
Presented as the Cleveland Clinic Hospital Medicine Grand Rounds on April 1, 2009. CME AMA Category 1 - 1 hour.

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Perioperative Use Of RAAS Antagonists

  1. 1. Perioperative use of RAAS Antagonists: Evidence and Controversy Moises Auron MD, FAAP Department of Hospital Medicine Cleveland Clinic
  2. 2. Objectives <ul><li>Appraise the evidence supporting the current perioperative management of Renin-Angiotensin-Aldosterone system (RAAS) antagonists in non-cardiac surgery. </li></ul><ul><li>Appraise the existence of newer RAAS antagonists such as Aliskiren (direct renin inhibitor) and its management in the perioperative setting. </li></ul>
  3. 3. Introduction <ul><li>The renin-angiotensin-aldosterone system (RAAS) antagonists (RAAS-antagonists) include: </li></ul><ul><ul><li>Angiotensin-converting enzyme inhibitors (ACEI) </li></ul></ul><ul><ul><li>Angiotensin II receptor subtype 1 blockers (ARB) </li></ul></ul><ul><ul><li>Direct renin inhibitors (Aliskiren) </li></ul></ul><ul><ul><li>Aldosterone antagonists (Spironolactone, Eplerenone) </li></ul></ul>
  4. 4. RAAS antagonists: indications <ul><li>Hypertension </li></ul><ul><li>Congestive heart failure </li></ul><ul><li>Coronary artery disease </li></ul><ul><li>Diabetic nephropathy </li></ul><ul><li>Prevention of progression of chronic renal failure </li></ul>Ann Intern Med. 2008 Jan 1;148(1):16-29. J Card Fail. 2008 Apr;14(3):181-8. J Gen Intern Med. 2006 Dec;21(12):1242-7. Lancet. 2005 Dec 10;366(9502):2026-33. Curr Pharm Des. 2007;13(13):1335-45.
  5. 5. RAAS antagonists and surgery <ul><li>Intra-operative hypotension after induction of anesthesia </li></ul><ul><li>Post-operative acute renal failure </li></ul><ul><li>Not associated with increased mortality </li></ul><ul><li>All based on small studies </li></ul>Anesth Analg. 1999 Nov;89(5):1143-55. Anesth Analg. 2001 Nov;93(5):1111-5.
  6. 6. J Intern Med. 2008 Sep;264(3):224-36.
  7. 7. J Intern Med. 2008 Sep;264(3):224-36.
  8. 8. Pharmacology of RAAS antagonists: perioperative implications <ul><li>Sympathetic blockade </li></ul><ul><li>Increase in the bioavailability of the vasodilatory agents: </li></ul><ul><ul><li>Bradykinin </li></ul></ul><ul><ul><li>Nitric oxide </li></ul></ul><ul><ul><li>Prostacyclines </li></ul></ul><ul><li>Inhibition of the vasoconstrictor effects of angiotensin II </li></ul><ul><li>Reduction in the secretion of aldosterone and ADH </li></ul><ul><ul><li>Decrease in renal salt and water reabsorption. </li></ul></ul><ul><li>Pleiotropic effects </li></ul><ul><ul><li>inhibition of the different angiotensin peptides as well as both renin and pro-renin receptors </li></ul></ul>Circulation. 2000 Jul 18;102(3):351-6. J Intern Med. 2008 Sep;264(3):224-36.
  9. 9. Effects of anesthesia on the BP <ul><li>Increased venous pooling of blood </li></ul><ul><li>Decreased cardiac output </li></ul><ul><li>Arterial hypotension. </li></ul>Curr Pharm Des. 2003;9(9):763-76
  10. 10. Intra-operative BP <ul><li>Maintained by: </li></ul><ul><ul><li>RAAS </li></ul></ul><ul><ul><li>Sympathetic nervous system </li></ul></ul><ul><ul><li>Arginine-vasopressine (AVP) </li></ul></ul><ul><ul><ul><li>Secretion stimulated as well by Angiotensin II </li></ul></ul></ul>Curr Pharm Des. 2003;9(9):763-76
  11. 11. Intra-operative BP <ul><li>Multilevel effect for maintenance of intra-operative BP </li></ul><ul><ul><li>Adequate hydration </li></ul></ul><ul><ul><li>Sympathomimetics </li></ul></ul><ul><ul><li>AVP agonists (terlipressin) </li></ul></ul>
  12. 12. Pharmacogenomics of RAAS <ul><li>Genetic susceptibility to the RAAS-antagonists affected by single nucleotide polymorphism (SNP) mutations in: </li></ul><ul><ul><li>Angiotensinogen </li></ul></ul><ul><ul><li>Angiotensin receptor 1 </li></ul></ul><ul><ul><li>Angiotensin receptor 2. </li></ul></ul><ul><li>Affects intraoperative hemodynamic response to RAAS-antagonists. </li></ul>Circulation. 2007 Feb 13;115(6):725-32. J Mol Med. 2008 Jun;86(6):637-41.
  13. 13. ACEI Am J Health Syst Pharm. 2004 May 1;61(9):899-912.
  14. 14. ARB Circulation 2001;103;904-912.
  15. 15. <ul><li>EVIDENCE AGAINST </li></ul><ul><li>RAAS-ANTAGONISTS </li></ul>
  16. 16. Cleveland Clinic: IMPACT <ul><li>Current practice: discontinue both ACEI and ARB on the morning of surgery. </li></ul><ul><li>Based on several small, controlled, randomized studies which found an increased frequency of refractory hypotension requiring intensive intravenous fluids and vasopressors after the induction of anesthesia when RAAS-antagonists were not discontinued preoperatively. </li></ul>Cleve Clin J Med. 2006 Mar;73 Suppl 1:S82-7.
  17. 17. <ul><li>Sublingual captopril (12.5 mg and 25 mg) vs. placebo 25 minutes before ETI </li></ul><ul><li>N = 40 </li></ul><ul><li>Captopril - increased ↓BP (P <0.05) within 3 minutes after ETI </li></ul><ul><ul><li>No significant difference between both doses. </li></ul></ul>McCarthy Anaesthesia. 1990 Mar;45(3):243-5.
  18. 18. Coriat <ul><li>HTN patients on chronic ACEI - randomized 2 groups, - administration of ACEI in AM of surgery vs. withdrawn. </li></ul><ul><li>Requirement of ephedrine: </li></ul><ul><ul><li>Captopril (n = 36) 64% vs. 12% (P<0.05) </li></ul></ul><ul><ul><li>Enalapril (n = 20) 100% vs. 18% (P<0.005) </li></ul></ul>Anesthesiology. 1994 Aug;81(2):299-307.
  19. 19. Brabant <ul><li>Hemodynamic response to induction between ARB, beta-blockers (BB), Ca channel blockers (CB) and ACEI. </li></ul><ul><li>↓ BP : SBP ↓ of > 30% from the preoperative value or an absolute SBP < 90 mm Hg. </li></ul><ul><ul><li>ARB (12 of 12) </li></ul></ul><ul><ul><li>BB/CB-treated patients (27 of 45) </li></ul></ul><ul><ul><li>ACEI (18 of 27) (P < 0.05 ) . </li></ul></ul><ul><ul><ul><li>ARB group – increased refractory to adrenergic agents (4 of 12) vs. BB/CB group (0 of 45) vs. ACEI (1 of 27). </li></ul></ul></ul><ul><li>↓ BP - responsive to a vasopressin agonist. </li></ul>Anesth Analg. 1999 Dec;89(6):1388-92.
  20. 20. Bertrand <ul><li>Patients on chronic therapy with ARB (N = 37) </li></ul><ul><li>18 D/C ARB the day before sx vs. 19 received ARB 1 h prior to induction. </li></ul><ul><li>ARB in AM of surgery - > frequent episodes and longer duration of ↓BP. </li></ul><ul><ul><li>↓ BP - refractory to adrenergic agents, requiring terlipressin. </li></ul></ul><ul><ul><li>ARB dose < 10 hours of induction - > frequent hypotensive episodes. </li></ul></ul>Anesth Analg. 2001 Jan;92(1):26-30.
  21. 21. Comfere <ul><li>Patients on chronic anti-HTN treatment with ACEI/ARB (N = 267) </li></ul><ul><li>Incidence of ↓BP during the first 30 minutes after induction of anesthesia was more frequent in patients whose most recent ACEI/ARB was taken < 10 h. (60% vs. 46%, O.R. 1.74 (95% C.I. 1.03 to 2.93, P = 0.04) </li></ul>Anesth Analg. 2005 Mar;100(3):636-44.
  22. 22. Shirmer <ul><li>Patients on chronic antiHTN with ACEI (N = 100) RCT. </li></ul><ul><li>50 received ACEI in AM of surgery vs. 50 who didn’t. </li></ul><ul><li>BP and HR were significantly lower in the ACEI group requiring supportive adrenergic agonists </li></ul><ul><ul><li>17 of 50 in the ACEI vs. 5 of 50 in the withdrawal group. </li></ul></ul>Anaesthesist. 2007 Jun;56(6):557-61.
  23. 23. Licker <ul><li>Pts with CAD undergoing non-cardiac surgery </li></ul><ul><li>N = 32; 16 receiving chronic ACEI and 16 didn’t. </li></ul><ul><li>Induction-related ↓BP: 9 (ACEI) vs. 2 (control). </li></ul><ul><ul><li>Diminished response to phenylephrine in the ACEI group. </li></ul></ul><ul><ul><li>Decreased -adrenergic vasoconstrictive response? </li></ul></ul>Can J Anaesth. 2000 May;47(5):433-40.
  24. 24. Kheterpal <ul><li>Prospective observational study: N= 12,381 </li></ul><ul><li>Diuretics + ACEI/ARB increased ↓BP and requirement for vasopressors vs. ACEI alone or when combination with Ca-vs. </li></ul><ul><li>Propensity score matching and ROC curve analysis was done to control for comorbidities that may acquaint for hemodynamic variations between groups. </li></ul>J Cardiothorac Vasc Anesth. 2008 Apr;22(2):180-6.
  25. 25. Rosenman <ul><li>Systematic review </li></ul><ul><li>Random-effects meta-analysis (incorporates within-study and between-study variability) </li></ul><ul><li>5 studies; N = 434 </li></ul><ul><li>Preoperative RAAS-antagonists on the day of surgery – increased likelihood of ↓BP requiring vasopressors after induction ( RR 1.50 , 95% CI 1.15 to 1.96). </li></ul><ul><li>No difference noted in incidence of peri-operative MI between groups (RR 0.41, 95% CI 0.07 to 2.53). </li></ul>J Hosp Med. 2008 Jul;3(4):319-25.
  26. 26. Metaanalysis: Hypotension J Hosp Med. 2008;3:319–325
  27. 27. Metaanalysis: AMI J Hosp Med. 2008;3:319–325
  29. 29. <ul><li>None of the studies showed any significant difference in postoperative complications. </li></ul><ul><li>No proof of association between ↓BP and: </li></ul><ul><ul><li>Major CV complications </li></ul></ul><ul><ul><li>Stroke </li></ul></ul><ul><ul><li>Renal failure </li></ul></ul><ul><ul><li>ICU LOS </li></ul></ul><ul><ul><li>Increased mortality </li></ul></ul>
  30. 30. <ul><li>Heropoulos </li></ul><ul><ul><li>Assessment of hemodynamic and hormonal responses to: </li></ul></ul><ul><ul><ul><li>ETI </li></ul></ul></ul><ul><ul><ul><li>Incision </li></ul></ul></ul><ul><ul><ul><li>Limb-tourniquet inflation </li></ul></ul></ul><ul><ul><li>RCT; N = 30 patients undergoing limb surgery </li></ul></ul><ul><ul><li>Enalaprilat vs. placebo. </li></ul></ul><ul><ul><ul><li>- 1.25 mg IV 20 min prior to induction vs. 0.625 mg IV at the onset of tourniquet-associated hypertension. </li></ul></ul></ul><ul><ul><li>Venous blood samples for PRA and catecholamine (pre-intubation, 3 min post-intubation, 3 min post-incision, at onset of tourniquet hypertension, 3 min post-extubation and 1 hr postoperatively) </li></ul></ul><ul><ul><ul><li>No significant differences in catecholamine levels. </li></ul></ul></ul>Anesth Analg. 1995 Mar;80(3):583-90. Drugs. 2007;67(7):1053-76.
  31. 31. <ul><li>Pre-operative enalapril in balanced hypotensive anesthesia for cerebrovascular surgery. </li></ul><ul><li>Controlled ↓BP - minimize intraoperative bleeding. RCT vs. placebo. </li></ul><ul><li>Enalapril ↓ HTN response to ETI, ↓ postoperative vasodilators, more stable BP control. </li></ul><ul><li>“ Preoperative fasting may be the contributor to peri-operative ↓BP - improper fluid balance and Na 2+ depletion - prevented by ensuring proper intravascular volume status” </li></ul>Tohmo and Karanko J Neurosurg Anesthesiol. 1993 Jan;5(1):13-21. Acta Anaesthesiol Scand. 1996 Jan;40(1):132-3.
  32. 32. ACE and Atrial Fibrillation <ul><li>Non surgical patients - ACEI - 50% reduction in the risk of developing new-onset atrial fibrillation (AF) </li></ul><ul><li>White </li></ul><ul><ul><li>Preop ACEI or ARB and postop AF following cardiac surgery (CABG or valvular surgery) </li></ul></ul><ul><ul><li>N = 338 patients (175 (51.8%) received preoperative ACEI or ARB). </li></ul></ul><ul><ul><li>No association found between preop ACEI/ARB and reduction in postop AF (adjusted OR 0.71, 95% CI 0.42 to 1.20). </li></ul></ul><ul><ul><li>Larger number of patients is needed. </li></ul></ul>Eur J Cardiothorac Surg. 2007 May;31(5):817-20.
  33. 33. Boldt <ul><li>RCT (N = 88) </li></ul><ul><li>CABG </li></ul><ul><li>4 groups of 22 patients each </li></ul><ul><ul><li>intravenous enalapril </li></ul></ul><ul><ul><li>enoximone (phosphodiesterase inhibitor) </li></ul></ul><ul><ul><li>clonidine </li></ul></ul><ul><ul><li>placebo (normal saline). </li></ul></ul><ul><li>Enalapril - following induction of anesthesia - lower levels of cardiac enzyme release </li></ul><ul><ul><li>Cardioprotective effect of RAAS-antagonists against ischemia/reperfusion injury </li></ul></ul>Heart. 1996 Sep;76(3):207-13.
  34. 34. Pigott <ul><li>N = 40 patients undergoing CABG </li></ul><ul><li>All patients were on chronic ACEI </li></ul><ul><ul><li>20 continued </li></ul></ul><ul><ul><li>20 suspended </li></ul></ul><ul><li>No significant difference between the groups in the frequency of hypotension during anesthesia. </li></ul><ul><li>The group that withheld ACEI had postoperative hypertension that required vasodilators </li></ul>Br J Anaesth. 1999 Nov;83(5):715-20.
  36. 36. Colson <ul><li>RCT (N = 18) </li></ul><ul><li>Short-term (2 days) pre-op captopril vs. placebo in CABG </li></ul><ul><li>Captopril - better preserved RPF and GFR during CPB vs. placebo treated patients. </li></ul>Anesthesiology. 1990 Jan;72(1):23-7.
  37. 37. Licker <ul><ul><li>RCT (N = 20) </li></ul></ul><ul><ul><li>11 – i.v. enalapril 50 mcg/kg; 9 – NS 0.9% at induction of anesthesia for aortic surgery. </li></ul></ul><ul><ul><li>After infra-renal aortic cross </li></ul></ul><ul><ul><ul><li>Enalapril - ↑ DO 2 , ↑ splachnic perfusion, ↑GFR @ 24 h post-op. (43) </li></ul></ul></ul>Br J Anaesth. 1996 May;76(5):632-9.
  38. 38. Benedetto <ul><li>RCT (N= 536) </li></ul><ul><li>Effect of pre-op ACEI on AKI (↓GFR > 50%) – CABG. </li></ul><ul><li>Preop ACEI (N = 281) - ↓ post-op AKI (O.R. 0.48; 95% CI, 0.23 to 0.77; P < 0.04) </li></ul><ul><li>Incidence of AKI requiring dialysis: </li></ul><ul><ul><li>2.4% in ACEI group vs. 6.3% in controls (P = 0.03). (44) </li></ul></ul>Ann Thorac Surg. 2008 Oct;86(4):1160-5.
  39. 39. Cittanova <ul><li>Prospective study (N = 249) - aortic surgery </li></ul><ul><li>Chronic treatment with ACEI (withheld in AM) - only factor associated with significative postoperative renal impairment (O.R. 2.01 95% C.I. 1.05 to 3.83) </li></ul>Anesth Analg. 2001 Nov;93(5):1111-5.
  40. 40. Kincaid <ul><li>Retrospective (N= 1209) – CABG </li></ul><ul><li>Preop ACEI along with intra-op aprotinin – ARF (OR 2.9, 95% CI 1.4 to 5.8, P < 0.0001). </li></ul>Ann Thorac Surg. 2005 Oct;80(4):1388-93
  42. 42. <ul><li>Thoracic epidural anesthesia – resultant ↓BP from attenuation of efferent sympathetic drive </li></ul><ul><ul><li>↑ vasopressin concentrations </li></ul></ul><ul><ul><li>renin activity remains unchanged. </li></ul></ul>Eur J Anaesthesiol. 1992 Jan;9(1):63-9. Anesthesiology. 1994 May;80(5):992-9.
  43. 43. <ul><li>Hohne </li></ul><ul><ul><li>Assessment of the initial (first 20 minutes) hemodynamic effect of ACEI in spinal anesthesia for lower body procedures. </li></ul></ul><ul><ul><li>RCT (21 on chronic ACEI vs. 21 control) </li></ul></ul><ul><ul><li>Decrease in BP was similar. </li></ul></ul><ul><ul><li>Plasma vasopressin and norepinephrine levels increased. </li></ul></ul>Acta Anaesthesiol Scand. 2003 Aug;47(7):891-6.
  44. 44. Aliskiren <ul><li>Direct renin inhibitor </li></ul><ul><li>Long half life (30 - 40h) </li></ul><ul><li>Increased renal vasodilatory effect vs. ACEI and ARB. (59) </li></ul><ul><li>Low oral bioavailability </li></ul><ul><ul><li>Terminal half life is 24 hrs. </li></ul></ul><ul><li>Weak antihypertensive (second-line agent) </li></ul>J Am Coll Cardiol. 2008 Feb 5;51(5):519-28. Circulation. 2008 Aug 12;118(7):773-84. Am J Health Syst Pharm. 2008 Jul 15;65(14):1323-32.
  45. 45. Conclusions <ul><li>RAAS-antagonists - associated with a variable incidence of hypotension during the initial 30 minutes after induction of anesthesia in non-cardiac surgery </li></ul><ul><li>These hypotensive episodes have not been linked to any significant postoperative complications. </li></ul><ul><li>The ACEI/ARB should be held at least 10 hours or for one dose before the induction of anesthesia. </li></ul>
  46. 46. Conclusions (cont.) <ul><li>Careful hemodynamic monitoring </li></ul><ul><li>Prevention of hypovolemia </li></ul><ul><li>When to continue RAAS-antagonists? </li></ul><ul><ul><li>Complicated hypertensive patient </li></ul></ul><ul><ul><li>Chronic heart failure of ischemic heart disease </li></ul></ul><ul><ul><li>Cardiac surgery </li></ul></ul><ul><ul><li>Requires discussion with anesthesiologist </li></ul></ul>