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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  • 1. Perioperative use of RAAS Antagonists: Evidence and Controversy Moises Auron MD, FAAP Department of Hospital Medicine Cleveland Clinic
  • 2. 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.
  • 3. 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)
  • 4. 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.
  • 5. 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.
  • 6. J Intern Med. 2008 Sep;264(3):224-36.
  • 7. J Intern Med. 2008 Sep;264(3):224-36.
  • 8. 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.
  • 9. Effects of anesthesia on the BP
    • Increased venous pooling of blood
    • Decreased cardiac output
    • Arterial hypotension.
    Curr Pharm Des. 2003;9(9):763-76
  • 10. 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
  • 11. Intra-operative BP
    • Multilevel effect for maintenance of intra-operative BP
      • Adequate hydration
      • Sympathomimetics
      • AVP agonists (terlipressin)
  • 12. Pharmacogenomics of RAAS
    • Genetic susceptibility to the RAAS-antagonists 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.
  • 13. ACEI Am J Health Syst Pharm. 2004 May 1;61(9):899-912.
  • 14. ARB Circulation 2001;103;904-912.
  • 15.
    • EVIDENCE AGAINST
    • RAAS-ANTAGONISTS
  • 16. 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.
  • 17.
    • Sublingual captopril (12.5 mg and 25 mg) vs. placebo 25 minutes before ETI
    • N = 40
    • Captopril - increased BP (P frequent hypotensive episodes.

Anesth Analg. 2001 Jan;92(1):26-30. 21. 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. 22. Shirmer

  • Patients on chronic antiHTN with ACEI (N = 100) RCT.
  • 50 received ACEI in AM of surgery vs. 50 who didnt.
  • 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. 23. Licker

  • Pts with CAD undergoing non-cardiac surgery
  • N = 32; 16 receiving chronic ACEI and 16 didnt.
  • 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. 24. 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. 25. 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 peri-operative MI between groups (RR 0.41, 95% CI 0.07 to 2.53).

J Hosp Med. 2008 Jul;3(4):319-25. 26. Metaanalysis: Hypotension J Hosp Med. 2008;3:319325 27. Metaanalysis: AMI J Hosp Med. 2008;3:319325 28. EVIDENCE SUPPORTING RAAS-ANTAGONISTS 29.

  • 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

30.

  • Heropoulos
    • Assessment of hemodynamic and hormonal responses to:
      • ETI