The RAS, Fibrinolysis and Cardiopulmonary Bypass
Condition: Coronary Artery Disease; Angiotensin Converting Enzyme; Angiotensin Receptor Blockers; Cardiopulmonary Bypass; Fibrinolysis; Inflammation
MeSH terms: Coronary Artery Disease; Inflammation
Study type: Interventional
Phase: Phase 4

Summary: 
      Each year over a million patients worldwide undergo cardiac surgery requiring cardiopulmonary
      bypass (CPB).1 CPB is associated with significant morbidity including hemodynamic
      instability, the transfusion of allogenic blood products, and inflammation. Blood product
      transfusion increases mortality after cardiac surgery. Enhanced fibrinolysis contributes to
      increased blood product transfusion requirements in the perioperative period. CPB activates
      the kallikrein-kinin system (KKS), leading to increased bradykinin concentrations.
      Bradykinin, acting through its B2 receptor, stimulates the release of nitric oxide,
      inflammatory cytokines and tissue-type plasminogen activator (t-PA). Based on data indicating
      that angiotensin-converting enzyme (ACE) inhibitors reduce mortality in patients with
      coronary artery disease, many patients undergoing CPB are taking ACE inhibitors. While
      interruption of the renin-angiotensin system (RAS) reduces inflammation in response to CPB,
      ACE inhibitors also potentiate the effects of bradykinin and may augment B2-mediated change
      in fibrinolytic balance and inflammation. In contrast, angiotensin II type 1 receptor
      antagonism does not potentiate bradykinin and does not inhibit bradykinin metabolism.

      Studies in animals suggest that bradykinin receptor antagonism inhibits reperfusion-induced
      increases in vascular permeability and neutrophil recruitment.A randomized, placebo
      controlled clinical trial of a bradykinin B2 receptor antagonist demonstrated some effect on
      survival in patients with systemic inflammatory response syndrome and gram-negative sepsis.
      In addition, we and others have shown bradykinin B2 receptor antagonism reduces vascular t-PA
      release during ACE inhibition. The current proposal derives from data from our laboratory and
      others elucidating the role of the KKS in the inflammatory, hypotensive and fibrinolytic
      response to CPB. Specifically, we have found that CPB activates the KKS and that ACE
      inhibition and smoking further increases bradykinin concentrations. During CPB, bradykinin
      concentrations correlate inversely with mean arterial pressure and directly with t-PA.
      Moreover, we have found that bradykinin receptor antagonism attenuates protamine-related
      hypotension following CPB. The current proposal tests the central hypothesis that the
      fibrinolytic and inflammatory response to cardiopulmonary bypass differ during
      angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor antagonism.
    


Intervention name(s): Placebo; Ramipril; Candesartan
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Placebo; Ramipril 2.5mg day 1 and 2 and then 5mg/d thereafter; Candesartan 16mg/d
Intervention MeSH terms: Candesartan; Candesartan cilexetil; Ramipril
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Angiotensin Converting Enzyme; Angiotensin Receptor Blockers; Cardiopulmonary Bypass; Fibrinolysis; Inflammation