Patients undergoing open heart surgery are at risk of suffering damage to the heart, brain and kidneys. This study is designed as a 2-by-2 randomized clinical trial with the purpose of investigating the organ protective effects of the glucagon-like-peptide-1 (GLP-1) agonist Exenatide versus placebo and restrictive versus liberal oxygenation during weaning from cardio-pulmonary bypass.

Brief Title

GLP-1 and Hyperoxia for Organ Protection in Heart Surgery

Official Title

Efficacy of a Glucagon-like-peptide-1 Agonist and Restrictive vs. Liberal Oxygen Supply in Patients Undergoing Coronary Artery Bypass Grafting or Aortic Valve Replacement - a 2-by-2 Factorial Designed, Randomized Clinical Study

Brief Summary

Patients undergoing open heart surgery are at risk of suffering damage to the heart, brain <br /> and kidneys. <br /> <br /> This study is designed as a 2-by-2 randomized clinical trial with the purpose of <br /> investigating the organ protective effects of the glucagon-like-peptide-1 (GLP-1) agonist <br /> Exenatide versus placebo and restrictive versus liberal oxygenation during weaning from <br /> cardio-pulmonary bypass.

Detailed Description

Patients with coronary artery disease (CAD) have associated atherosclerotic renal and
cerebral disease making these organs especially vulnerable to ischemia during open heart
surgery. At the Heart Center at Rigshospitalet in Copenhagen the investigators perform more
than 1000 open heart surgery operations yearly. The primary indication is CAD with or without
associated valvular disease.

Surgical treatment of patients with CAD is performed as coronary artery bypass grafting
(CABG) or off- pump coronary artery bypass grafting (OPCAB). CABG requires the use of
extracorporeal circulation, while this is not the case for OPCAB.

During extracorporeal circulation the heart is arrested and anticoagulated. Blood is exposed
to artificial surfaces and mechanical stress potentially resulting in increased risk of a
systemic inflammatory response syndrome (SIRS), arterial emboli and organ hypoperfusion with
the potential for multi organ failure.

The 30-day mortality following elective CABG is 1-2%, increasing to 7% if associated with
valve surgery. The elderly patients with reduced renal function and more concomitant disease
have a 30-day mortality as high as 20%. Patients dying following open heart surgery often
have severe heart failure including cardiogenic shock, occlusion of grafts or native coronary
arteries, renal failure, stroke/transient ischemic attack and severe inflammation prior to
death.

The incidence of renal failure requiring dialysis is dependent on renal function prior to
surgery. With more elderly patients having surgery this incidence is increasing. Renal
failure is often seen in conjunction with progression of heart failure or development of new
onset heart failure. Factors associated with brain involvement in cardiac surgery are macro
embolism, systemic hypotension, systemic venous hypertension and maldistribution of cerebral
blood flow. The incidence of postoperative cognitive deficits are above 50% depending on when
this is measured. After 12 months the figure is approximately 30%. Known factors associated
with cognitive deficits are age and duration of bypass, however type of surgery (valve
insertion), temperature, equipment (oxygenators, filters) and techniques of de-airing may be
important. For the neuropsychological deficits micro embolism, altered brain flow and a
systemic inflammatory response are probably involved. The incidence of these complications
during OPCAB is unknown, but expected to be slightly lower.

Many pharmacological interventions have been tested in order to protect the brain during
surgery with varying degree of success (Ketamine vs. Remifentanil, Glucose, insulin,
potassium solution; Platelet activate factor antagonist; Piracetam; Lidocaine; Ramacemide;
Clomethiozole. None of these has made it into clinical practice.

Glucagon-like-peptide-1 agonist - Background Exenatide has been proven effective in reducing
infarct size in a model of acute myocardial infarcts and reperfusion in swine. Several animal
studies and some clinical studies have been published demonstrating a beneficial effect of
glucagon-like-peptide-1 (GLP-1) analogs in the treatment of various degenerative neurological
diseases. The fact that type-2 diabetes has been shown to be associated with the development
of the development of Alzheimer's disease and Parkinson's disease has lead to the hypothesis
that insulin signaling impairment could be involved in the disease process. By the
introduction of incretins such as GLP-1 analogs as treatments options in type-2 diabetes,
increased awareness of potential role in the amelioration of symptoms associated with
neurodegenerative diseases have emerged. In fact GLP-1 analogs have beneficial effects on
memory formation and on synaptic plasticity in the brain in animal models, and prevent
detrimental effects of β-amyloid in a rat model. Clinical studies have yet to prove these
associations in humans. In addition it is well known that GLP-1 and analogs crosses the
blood-brain barrier. Regarding ischemic injury in stroke models GLP-1 analogs have also drawn
some attention. Exenatide (also known as exentide-4) infused after focal brain ischemia has
been shown to reduce infarct volume in mice.

In clinical testing in humans a recent randomized clinical study investigated the effect of
Exendin-4 (Exenatide) on final infarct size in myocardial infarction. Patients receiving
Exenatide tended to have a lower final infarct size and a larger salvage index evaluated by
cardiac magnetic resonance 3 months following index event. These findings have been confirmed
in later trials. Importantly the investigational drug was administered in acutely ill
patients, receiving acute revascularization for acute myocardial infarction, with no
increased risk of adverse events, and no excess adverse events including hypoglycemia or
pancreatitis were reported.

Restrictive vs. liberal oxygen administration during weaning from circulatory by-pass -
Background Weaning from cardiopulmonary bypass is a process completing the cardiac surgery
procedure, during which, the heart has been stopped, and the function of the heart and lungs
has been substituted by an extracorporeal blood pump and oxygenator. After completion of the
surgical procedure the heart is allowed to start beating, and will gradually take over the
function of the extracorporeal by-pass. Also the patient ventilated. During this process is
standard procedure to administer 100% FiO2 during the weaning process to ensure sufficient
oxygen supply to the heart and other organs. The FiO2 is often reduced according to the
patients needs during transfer to the intensive care unit.

This study hypothesize that a FiO2 of 50% is superior to the standard FiO2 of 100% in
reducing the incidence of the primary and secondary endpoints as described below, based on
the following background data.

Preclinical data suggest that hyperoxia increase cerebral damage and neurological dysfunction
following brain ischemia. Most data originates from cardiac arrest models in which a no-flow
state is induced and cerebral injury or neurological dysfunction is assessed. Fairly small
randomized controlled trials (RCT's) in humans have found increased levels of neuron-specific
enolase (NSE) but not S-100B in patients randomized to FiO2=100% compared to FiO2=30%.

Hyperoxia during and after ischemia has been investigated in several settings, and a final
consensus of its benefits and hazards has yet to be established. In the following the term
hyperoxia is used in situations where the FiO2 is increased to levels above 50% for
simplicity.

Hyperoxia may increase the risk of developing lung injury (hyperoxia-induced lung injury -
HALI), which carries a high morbidity and mortality. However, this condition seems to require
several days of extremely high FiO2 to be significant and various ventilation modes may have
a significant impact as well. The risk of HALI associated with shorter periods of hyperoxia
seems small.

Ischemia reperfusion injury has been investigated in smaller studies only in relation to
circulatory bypass with no significant impact on magnitude of increase in biomarkers related
to cardiac injury according to a review by. Oxygen administration during transport for
primary percutaneous coronary intervention (PCI) in patients with ST segment myocardial
infarction has recently been associated with increased release of creatinine kinasis and
larger final infarcts size on cardiac Magnetic Resonance Imaging (MRI). The impact of shorter
courses of oxygen supplement during weaning from circulatory bypass has yet to be
investigated. A direct influence of hyperoxia with an increase in systemic vascular
resistance has also been suggested, and hyperoxia may not be associated with improved tissue
oxygenation, while the clinical effects of this finding remain to be understood.

A recent systematic review and metaanalysis suggested that the risk of surgical site
infections may be reduced with hyperoxia. However, a larger RCT in abdominal surgery found an
increased mortality with hyperoxia, in particular in patients undergoing surgery for
malignancies.

In summary, hyperoxia may reduce risks associated with surgery with regards to surgical site
infections and possibly reperfusion injury, whereas the effects on overall benefit in term of
mortality may be detrimental. Further research is needed, and for the time being an equipoise
with regards to the benefits of hyperoxia when weaning patients from circulatory bypass
exits. Most patients will require some degree of oxygen supplement when lungs are ventilated
after apnea during circulatory bypass, hence this study pragmatically studies a restrictive
(FiO2=50%) vs. a liberal oxygenation strategy (FiO2=100%)

Following open heart surgery damage to brain, kidneys and the myocardium is frequently seen
due to organ ischemia. Animal experiments as well as small human studies suggest that a GLP-1
agonist may be able to reduce ischemic damage. Currently, there is no protective treatment
available.

A GLP-1 agonist has the potential to protect the brain, the kidneys and the heart during open
heart surgery. The treatment can easily be administered for a short time to a large
population at risk. Thus, a large scale randomized study testing the efficacy of a GLP-1
agonist against placebo can conclusively determine if patients will benefit from this
treatment given pre-operatively.

Restrictive vs. liberal oxygenation during weaning from circulatory bypass has not been
tested in clinical trails and as seen above an equipoise for assessing the net clinical
benefit of these strategies exists.

Clinical Hypothesis

1. A GLP-1 agonist started pre-operatively to patients undergoing coronary artery bypass
grafting will reduce mortality and morbidity due to damage to the heart, brain and
kidneys.

2. Restrictive oxygenation (FiO2=50%) during weaning from circulatory bypass during the
surgical procedure will reduce mortality and morbidity due to damage to the heart, brain
and kidneys as well as reduce significant surgical site infection (requiring surgical
debridement and/or prolonging hospitalization) compared to liberal oxygenation
(FiO2=100%).

Outcome Measures

Outcome measures are the tests that investigators perform to prove whether or not a treatment being tested in a clinical trial is having any effect.

Inclusion Criteria:

  -  Before any study-specific procedure, including assessments for screening, the
     appropriate written informed consent must be obtained.

  -  ≥ 18 years of age at the time of signing informed consent.

  -  Ischemic heart disease requiring coronary artery bypass grafting (multi-vessel
     coronary artery disease or coronary anatomy not suitable for percutaneous coronary
     intervention) and/or aortic valve disease scheduled for aortic valve replacement,
     irrespective of other concomitant valve surgery.

Exclusion Criteria:

  -  Active treatment with GLP-1 agonists

  -  Obstructive hypertrophic cardiomyopathy, active myocarditis, constrictive
     pericarditis, untreated hypothyroidism or hyperthyroidism or history of or active
     acute pancreatitis.

  -  Acute (i.e. off hours, within hours surgery), Sub-acute surgery (i.e. the following
     days) are eligible.

  -  Known allergy towards Exenatide/Byetta or albumin (vehicle).

  -  On the urgent waiting list for a heart transplant (UNOS category 1A or 1B, or
     equivalent). Patients on the non-urgent waiting list for a heart transplant (UNOS
     category 2 or 7, or equivalent) are eligible for inclusion in the study.

  -  Recipient of any major organ transplant (e.g. lung, liver, heart)

  -  Receiving or has received cytotoxic or cytostatic chemotherapy and/or radiation
     therapy for treatment of a malignancy within 6 month before randomization or clinical
     evidence of current malignancy, with the following exceptions: basal or squamous cell
     carcinoma of the skin, cervical intraepithelial neoplasia, prostate cancer (if stable
     localized disease, with a life expectancy of > 2.5 years in the opinion of the
     investigator)

  -  Currently enrolled in, or at least 30 days not yet elapsed since ending participation
     in other investigational drug trial(s) for the treatment of diabetes or malignant
     obesity investigating the use of GLP-1 agonists or receiving other investigational
     agent(s). Concomitant participation in other non-pharmacological trials is not an
     exclusion criterion.

  -  Recent (within 3 months) history of alcohol or illicit drug abuse disorder, based on
     self-report.

  -  Pregnant, based on investigator evaluation (e.g., positive human chorionic
     gonadotropin test) or currently breast feeding.

  -  Any condition (e.g., psychiatric illness) or situation that, in the investigator's
     opinion, could put the subject at significant risk, confound the study results, or
     interfere significantly with the subject's participation in the study.

  -  Previous participation in the trial.