Perioperative Use Of Renin-angiotensin-aldosterone System Antagonists

Perioperative use of RAAS Antagonists: Evidence and Controversy Moises Auron MD, FAAP Department of Hospital Medicine Cleveland Clinic

Objectives • Appraise the evidence supporting the current perioperative management of Renin-Angiotensin-Aldosterone system (RAAS) antagonists in non-cardiac surgery. • Appraise the existence of newer RAAS antagonists such as Aliskiren (direct renin inhibitor) and its management in the perioperative setting.

Introduction • The renin-angiotensin-aldosterone system (RAAS) antagonists (RAAS-antagonists) include: – Angiotensin-converting enzyme inhibitors (ACEI) – Angiotensin II receptor subtype 1 blockers (ARB) – Direct renin inhibitors (Aliskiren) – Aldosterone antagonists (Spironolactone, Eplerenone)

RAAS antagonists: indications • • • • •

Hypertension Congestive heart failure Coronary artery disease Diabetic nephropathy Prevention of progression of chronic renal failure 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.

RAAS antagonists and surgery • Intra-operative hypotension after induction of anesthesia • Post-operative acute renal failure • Not associated with increased mortality • All based on small studies Anesth Analg. 1999 Nov;89(5):1143-55. Anesth Analg. 2001 Nov;93(5):1111-5.

J Intern Med. 2008 Sep;264(3):224-36.

J Intern Med. 2008 Sep;264(3):224-36.

Pharmacology of RAAS antagonists: perioperative implications • Sympathetic blockade • Increase in the bioavailability of the vasodilatory agents: – Bradykinin – Nitric oxide – Prostacyclines

• Inhibition of the vasoconstrictor effects of angiotensin II • Reduction in the secretion of aldosterone and ADH – Decrease in renal salt and water reabsorption.

• Pleiotropic effects – inhibition of the different angiotensin peptides as well as both renin and pro-renin receptors Circulation. 2000 Jul 18;102(3):351-6. J Intern Med. 2008 Sep;264(3):224-36.

Effects of anesthesia on the BP • Increased venous pooling of blood • Decreased cardiac output • Arterial hypotension.

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Intra-operative BP • Maintained by: – RAAS – Sympathetic nervous system – Arginine-vasopressine (AVP) • Secretion stimulated as well by Angiotensin II

Curr Pharm Des. 2003;9(9):763-76

Intra-operative BP • Multilevel effect for maintenance of intraoperative BP – Adequate hydration – Sympathomimetics – AVP agonists (terlipressin)

Pharmacogenomics of RAAS • Genetic susceptibility to the RAASantagonists affected by single nucleotide polymorphism (SNP) mutations in: – Angiotensinogen – Angiotensin receptor 1 – Angiotensin receptor 2.

• Affects intraoperative hemodynamic response to RAAS-antagonists. Circulation. 2007 Feb 13;115(6):725-32. J Mol Med. 2008 Jun;86(6):637-41.

ACEI

Am J Health Syst Pharm. 2004 May 1;61(9):899-912.

ARB

Circulation 2001;103;904-912.

EVIDENCE AGAINST RAAS-ANTAGONISTS

Cleveland Clinic: IMPACT • Current practice: discontinue both ACEI and ARB on the morning of surgery. • 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.

Cleve Clin J Med. 2006 Mar;73 Suppl 1:S82-7.

McCarthy • Sublingual captopril (12.5 mg and 25 mg) vs. placebo 25 minutes before ETI • N = 40 • Captopril - increased ↓BP (P <0.05) within 3 minutes after ETI – No significant difference between both doses.

Anaesthesia. 1990 Mar;45(3):243-5.

Coriat • HTN patients on chronic ACEI randomized 2 groups, - administration of ACEI in AM of surgery vs. withdrawn. • Requirement of ephedrine: – Captopril (n = 36) 64% vs. 12% (P<0.05) – Enalapril (n = 20) 100% vs. 18% (P<0.005)

Anesthesiology. 1994 Aug;81(2):299-307.

Brabant • Hemodynamic response to induction between ARB, beta-blockers (BB), Ca channel blockers (CB) and ACEI. • ↓BP : SBP ↓ of > 30% from the preoperative value or an absolute SBP < 90 mm Hg. – ARB (12 of 12) – BB/CB-treated patients (27 of 45) – ACEI (18 of 27) (P< 0.05). • ARB group – increased refractory to adrenergic agents (4 of 12) vs. BB/CB group (0 of 45) vs. ACEI (1 of 27).

• ↓BP - responsive to a vasopressin agonist. Anesth Analg. 1999 Dec;89(6):1388-92.

Bertrand • Patients on chronic therapy with ARB (N = 37) • 18 D/C ARB the day before sx vs. 19 received ARB 1 h prior to induction. • ARB in AM of surgery - > frequent episodes and longer duration of ↓BP. – ↓BP - refractory to adrenergic agents, requiring terlipressin. – ARB dose < 10 hours of induction - > frequent hypotensive episodes. Anesth Analg. 2001 Jan;92(1):26-30.

Comfere • Patients on chronic anti-HTN treatment with ACEI/ARB (N = 267) • 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) Anesth Analg. 2005 Mar;100(3):636-44.

Shirmer • Patients on chronic antiHTN with ACEI (N = 100) RCT. • 50 received ACEI in AM of surgery vs. 50 who didn’t. • BP and HR were significantly lower in the ACEI group requiring supportive adrenergic agonists – 17 of 50 in the ACEI vs. 5 of 50 in the withdrawal group. Anaesthesist. 2007 Jun;56(6):557-61.

Licker • Pts with CAD undergoing non-cardiac surgery • N = 32; 16 receiving chronic ACEI and 16 didn’t. • Induction-related ↓BP: 9 (ACEI) vs. 2 (control). – Diminished response to phenylephrine in the ACEI group. – Decreased -adrenergic vasoconstrictive response?

Can J Anaesth. 2000 May;47(5):433-40.

Kheterpal • Prospective observational study: N= 12,381 • Diuretics + ACEI/ARB increased ↓BP and requirement for vasopressors vs. ACEI alone or when combination with Ca-vs. • Propensity score matching and ROC curve analysis was done to control for comorbidities that may acquaint for hemodynamic variations between groups. J Cardiothorac Vasc Anesth. 2008 Apr;22(2):180-6.

Rosenman • Systematic review • Random-effects meta-analysis (incorporates within-study and between-study variability) • 5 studies; N = 434 • 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). • No difference noted in incidence of perioperative MI between groups (RR 0.41, 95% CI 0.07 to 2.53). J Hosp Med. 2008 Jul;3(4):319-25.

Metaanalysis: Hypotension

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Metaanalysis: AMI

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EVIDENCE SUPPORTING RAASANTAGONISTS

• None of the studies showed any significant difference in postoperative complications. • No proof of association between ↓BP and: – Major CV complications – Stroke – Renal failure – ICU LOS – Increased mortality

• Heropoulos – Assessment of hemodynamic and hormonal responses to: • ETI • Incision • Limb-tourniquet inflation

– RCT; N = 30 patients undergoing limb surgery – Enalaprilat vs. placebo. • - 1.25 mg IV 20 min prior to induction vs. 0.625 mg IV at the onset of tourniquet-associated hypertension.

– Venous blood samples for PRA and catecholamine (preintubation, 3 min post-intubation, 3 min post-incision, at onset of tourniquet hypertension, 3 min post-extubation and 1 hr postoperatively) • No significant differences in catecholamine levels. Anesth Analg. 1995 Mar;80(3):58390. Drugs. 2007;67(7):1053-76.

Tohmo and Karanko • Pre-operative enalapril in balanced hypotensive anesthesia for cerebrovascular surgery. • Controlled ↓BP - minimize intraoperative bleeding. RCT vs. placebo. • Enalapril ↓ HTN response to ETI, ↓ postoperative vasodilators, more stable BP control. • “Preoperative fasting may be the contributor to peri-operative ↓BP - improper fluid balance and Na2+ depletion - prevented by ensuring proper intravascular volume status” J Neurosurg Anesthesiol. 1993 Jan;5(1):13-21. Acta Anaesthesiol Scand. 1996 Jan;40(1):132-3.

ACE and Atrial Fibrillation • Non surgical patients - ACEI - 50% reduction in the risk of developing new-onset atrial fibrillation (AF) • White – Preop ACEI or ARB and postop AF following cardiac surgery (CABG or valvular surgery) – N = 338 patients (175 (51.8%) received preoperative ACEI or ARB). – No association found between preop ACEI/ARB and reduction in postop AF (adjusted OR 0.71, 95% CI 0.42 to 1.20). – Larger number of patients is needed. Eur J Cardiothorac Surg. 2007 May;31(5):817-20.

Boldt • RCT (N = 88) • CABG • 4 groups of 22 patients each – – – –

intravenous enalapril enoximone (phosphodiesterase inhibitor) clonidine placebo (normal saline).

• Enalapril - following induction of anesthesia lower levels of cardiac enzyme release – Cardioprotective effect of RAAS-antagonists against ischemia/reperfusion injury Heart. 1996 Sep;76(3):207-13.

Pigott • N = 40 patients undergoing CABG • All patients were on chronic ACEI – 20 continued – 20 suspended

• No significant difference between the groups in the frequency of hypotension during anesthesia. • The group that withheld ACEI had postoperative hypertension that required vasodilators Br J Anaesth. 1999 Nov;83(5):715-20.

PERI-OPERATIVE RAASANTAGONISTS AND RENAL FUNCTION

Colson • RCT (N = 18) • Short-term (2 days) pre-op captopril vs. placebo in CABG • Captopril - better preserved RPF and GFR during CPB vs. placebo treated patients.

Anesthesiology. 1990 Jan;72(1):23-7.

Licker – RCT (N = 20) – 11 – i.v. enalapril 50 mcg/kg; 9 – NS 0.9% at induction of anesthesia for aortic surgery. – After infra-renal aortic cross • Enalapril - ↑ DO2, ↑ splachnic perfusion, ↑GFR @ 24 h post-op. (43)

Br J Anaesth. 1996 May;76(5):632-9.

Benedetto • RCT (N= 536) • Effect of pre-op ACEI on AKI (↓GFR > 50%) – CABG. • Preop ACEI (N = 281) - ↓ post-op AKI (O.R. 0.48; 95% CI, 0.23 to 0.77; P < 0.04) • Incidence of AKI requiring dialysis: – 2.4% in ACEI group vs. 6.3% in controls (P = 0.03). (44) Ann Thorac Surg. 2008 Oct;86(4):1160-5.

Cittanova • Prospective study (N = 249) - aortic surgery • 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) Anesth Analg. 2001 Nov;93(5):1111-5.

Kincaid • Retrospective (N= 1209) – CABG • Preop ACEI along with intra-op aprotinin – ARF (OR 2.9, 95% CI 1.4 to 5.8, P < 0.0001).

Ann Thorac Surg. 2005 Oct;80(4):1388-93

RAAS-ANTAGONISTS IN NEURAXIAL ANESTHESIA

• Thoracic epidural anesthesia – resultant ↓BP from attenuation of efferent sympathetic drive – ↑ vasopressin concentrations – renin activity remains unchanged.

Eur J Anaesthesiol. 1992 Jan;9(1):63-9. Anesthesiology. 1994 May;80(5):992-9.

• Hohne – Assessment of the initial (first 20 minutes) hemodynamic effect of ACEI in spinal anesthesia for lower body procedures. – RCT (21 on chronic ACEI vs. 21 control) – Decrease in BP was similar. – Plasma vasopressin and norepinephrine levels increased. Acta Anaesthesiol Scand. 2003 Aug;47(7):891-6.

Aliskiren • Direct renin inhibitor • Long half life (30 - 40h) • Increased renal vasodilatory effect vs. ACEI and ARB. (59) • Low oral bioavailability – Terminal half life is 24 hrs.

• Weak antihypertensive (second-line agent) 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.

Conclusions • RAAS-antagonists - associated with a variable incidence of hypotension during the initial 30 minutes after induction of anesthesia in noncardiac surgery • These hypotensive episodes have not been linked to any significant postoperative complications. • The ACEI/ARB should be held at least 10 hours or for one dose before the induction of anesthesia.

Conclusions (cont.) • Careful hemodynamic monitoring • Prevention of hypovolemia • When to continue RAAS-antagonists? – Complicated hypertensive patient – Chronic heart failure of ischemic heart disease – Cardiac surgery – Requires discussion with anesthesiologist