Coronary Arteries Disease Risk, Elevated Cardiac Risk
Conditions
Keywords
Xenon, Cardiac safety, Cardiovascular risk, Non cardiac surgery, Atherosclerotic vascular surgery
Brief summary
The Primary Objective is to show non inferiority in cardiac safety (i.e myocardial necrosis-MN- assessed by positive cardiac Troponin I -cTnI- ultrasensitive assay) of a Xenon based general anesthesia procedure in patients with elevated cardiac risk scheduled for atherosclerotic vascular surgery (i.e patient with Coronary Arteries Disease risk) when compared to sevoflurane based general anesthesia procedure, postoperatively up to 3 days.
Detailed description
The Primary endpoint is defined as an increase above the 99th percentile of highly sensitive cardiac Troponin I (cTnI) at any time during the 72 h post operatively. Time frame 3 days post-op; Key secondary endpoint(s) are routine (Local laboratory) dosage of standard cardiac Troponin I (cTnI) at D1 (24h) and D3 (72 h) post operatively, and also in case of any suspicion of Myocardial Infarction , Routine cardiac safety monitoring.
Interventions
DRUGXenon
DRUGSevoflurane
Sponsors
Eurofins Biomnis
Monitoring Force Group
Inferential
Air Liquide Santé International
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SCREENING
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥ 18 years * Scheduled for atherosclerotic vascular elective surgery with presumed fast-track, * Cardiac ischaemic risk supported by: * History of myocardial infarction older than 1 month and/or * Documented Stable angina (asymptomatic ± medical treatment) and/or * History of coronary revascularisation, and/or * Surgical Risk Index (Lee index) ≥ 3. * Written informed consent
Exclusion criteria
* Unstable angina within the last 30 days, * Non controlled arterial Hypertension . * Severe Cardiac heart Failure (NYHA IV) * Severe Chronic Obstructive Pulmonary Disease * Patient already randomized in another ongoing clinical trial * Patient with recent myocardial infarction (M.I) (less than one month ) * Patient already included in a clinical trial * History of hypersensitivity to study drugs( i.e Xenon, propofol, sevoflurane, desflurane, isoflurane) * Malignant hyperthermia * Documented Elevated intracranial pressure * Preeclampsia or eclampsia * Pregnancy and lactation * Presumed uncooperativeness or legal incapacity
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Myocardial Necrosis (MN) | 3 Postoperative Days | Myocardial Necrosis: at least 1 value of serum cardiac troponin I above the 99th percentile (measurement performed by a central laboratory using the ABBOTT-ARCHITECT technique) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Myocardial Infarction (MI) | 3 Postoperative Days | Patients with Confirmed Myocardial Infarction (MI) by the Investigators |
| Number of Participants With Cerebro-Vascular Event | 3 postoperative days | Patients with Cerebro-Vascular Event in the FAS |
| Number of Participants With Life-Threatening Arrhythmia | 3 Postoperative Days | Patients with Life-Threatening Arrhythmia in the FAS |
| Number of Participants Who Died From Cardiac Origin | 3 postoperative days | No patient died from a cardiac cause during the 3 postoperative days. |
| Number of Participants With Composite Endpoint | 3 postoperative days | Patients with at least 1 event among MN assessed by central laboratory, MI, Cerebro-Vascular event, Life-Threatening Arrhythmia and Death from Cardiac Origin |
| Number of Participants With Cardiac Troponin I or T Above the 99th Percentile (Local Laboratories) | 3 Postoperative days | At least 1 value of serum cardiac troponin I or T above the 99th percentile (measurements performed by local laboratories using different techniques) |
| Vital Signs (SBP and DBP Changes) | From pre-induction to Postoperative Day 3 | Changes from baseline for Systolic and Diastolic Blood Pressure (SBP and DBP) |
| Vital Signs (Heart Rate Changes) | From pre-induction to Postoperative Day 3 | Changes from baseline for Heart Rate (HR) |
| Number of Participants With Chest Pain During the 3 Postoperative Days | From Day 0 until Postoperative Day 3 | Patients with Chest Pain reported at least once per day during the 3 Postoperative Days |
| Urine Output | From Day 0 until Postoperative Day 1 | Urine volume in milliliter (mL) during the first postoperative hours |
| Systolic Blood Pressure (SBP) | From pre-induction to recovery of anesthesia | Repeated Systolic Blood Pressure measurements during the perioperative period |
Countries
France
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Xenon 0.8-1.1 Minimal Alveolar Concentration in 30% oxygen (Group A) | 295 |
| Sevoflurane 0.8-1.1 Minimal Alveolar Concentration in 30% oxygen (Group B) | 295 |
| Total | 590 |
Baseline characteristics
| Characteristic | Xenon | Sevoflurane | Total |
|---|---|---|---|
| Age, Continuous | 70.6 years STANDARD_DEVIATION 10.3 | 71.2 years STANDARD_DEVIATION 10.2 | 70.9 years STANDARD_DEVIATION 10.2 |
| Participants with Baseline Cardiac Troponin (Central Laboratory) ≤ 99th percentile | 269 participants | 269 participants | 538 participants |
| Participants with Baseline Cardiac Troponin (Central Laboratory) > 99th percentile | 26 participants | 26 participants | 52 participants |
| Region of Enrollment France | 295 participants | 295 participants | 590 participants |
| Sex: Female, Male Female | 57 Participants | 52 Participants | 109 Participants |
| Sex: Female, Male Male | 238 Participants | 243 Participants | 481 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 79 / 292 | 84 / 294 |
| serious Total, serious adverse events | 17 / 292 | 17 / 294 |
Outcome results
Primary
Number of Participants With Myocardial Necrosis (MN)
Myocardial Necrosis: at least 1 value of serum cardiac troponin I above the 99th percentile (measurement performed by a central laboratory using the ABBOTT-ARCHITECT technique)
Time frame: 3 Postoperative Days
Population: Per protocol set (PPS): Randomised patients who started general anaesthesia induction and with no major protocol violations. Patients were assigned to the treatment groups as randomised, i.e. the treatment groups were based on the treatment allocated by randomisation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Xenon | Number of Participants With Myocardial Necrosis (MN) | 57 participants |
| Sevoflurane | Number of Participants With Myocardial Necrosis (MN) | 54 participants |
Comparison: The percentage of patients with MN during the 3 postoperative days in the sevoflurane group and in the xenon group was expected to be 20%. The margin of non-inferiority was 10%. Thus the sample size to prove non-inferiority was 252 patients per group with α = 0.025, a power of 0.80 and the following hypotheses: H0: Px-Pc ≥ 10%; H1: Px-Pc \< 10%.~As it was expected that approximately 15% of patients would be non-evaluable, a total of 600 patients were included.p-value: 0.005295% CI: [-6.7, 7.07]Difference of proportion
Secondary
Number of Participants Who Died From Cardiac Origin
No patient died from a cardiac cause during the 3 postoperative days.
Time frame: 3 postoperative days
Population: Full analysis set (FAS): Randomised patients who started general anaesthesia induction. Patients were assigned to the treatment groups as randomised, i.e. the treatment groups were based on the treatment allocated by randomisation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Xenon | Number of Participants Who Died From Cardiac Origin | 0 participants |
| Sevoflurane | Number of Participants Who Died From Cardiac Origin | 0 participants |
Secondary
Number of Participants With Cardiac Troponin I or T Above the 99th Percentile (Local Laboratories)
At least 1 value of serum cardiac troponin I or T above the 99th percentile (measurements performed by local laboratories using different techniques)
Time frame: 3 Postoperative days
Population: Full analysis set (FAS): Randomised patients who started general anaesthesia induction. Patients were assigned to the treatment groups as randomised, i.e. the treatment groups were based on the treatment allocated by randomisation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Xenon | Number of Participants With Cardiac Troponin I or T Above the 99th Percentile (Local Laboratories) | 27 participants |
| Sevoflurane | Number of Participants With Cardiac Troponin I or T Above the 99th Percentile (Local Laboratories) | 25 participants |
p-value: 0.771595% CI: [-3.9, 5.25]Difference of proportion
Secondary
Number of Participants With Cerebro-Vascular Event
Patients with Cerebro-Vascular Event in the FAS
Time frame: 3 postoperative days
Population: Full analysis set (FAS): Randomised patients who started general anaesthesia induction. Patients were assigned to the treatment groups as randomised, i.e. the treatment groups were based on the treatment allocated by randomisation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Xenon | Number of Participants With Cerebro-Vascular Event | 2 participants |
| Sevoflurane | Number of Participants With Cerebro-Vascular Event | 3 participants |
p-value: 0.653395% CI: [-1.82, 1.14]Difference of proportion
Secondary
Number of Participants With Chest Pain During the 3 Postoperative Days
Patients with Chest Pain reported at least once per day during the 3 Postoperative Days
Time frame: From Day 0 until Postoperative Day 3
Population: Treated set (TS): Randomised patients who received the study medication. Patients were assigned to the treatment groups as treated, i.e. the treatment groups were based on the treatment actually received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Xenon | Number of Participants With Chest Pain During the 3 Postoperative Days | Day 0 | 0 participants |
| Xenon | Number of Participants With Chest Pain During the 3 Postoperative Days | Day 2 | 1 participants |
| Xenon | Number of Participants With Chest Pain During the 3 Postoperative Days | Day 1 | 0 participants |
| Xenon | Number of Participants With Chest Pain During the 3 Postoperative Days | Day 3 | 2 participants |
| Sevoflurane | Number of Participants With Chest Pain During the 3 Postoperative Days | Day 1 | 2 participants |
| Sevoflurane | Number of Participants With Chest Pain During the 3 Postoperative Days | Day 0 | 0 participants |
| Sevoflurane | Number of Participants With Chest Pain During the 3 Postoperative Days | Day 3 | 3 participants |
| Sevoflurane | Number of Participants With Chest Pain During the 3 Postoperative Days | Day 2 | 2 participants |
Secondary
Number of Participants With Composite Endpoint
Patients with at least 1 event among MN assessed by central laboratory, MI, Cerebro-Vascular event, Life-Threatening Arrhythmia and Death from Cardiac Origin
Time frame: 3 postoperative days
Population: Full analysis set (FAS): Randomised patients who started general anaesthesia induction. Patients were assigned to the treatment groups as randomised, i.e. the treatment groups were based on the treatment allocated by randomisation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Xenon | Number of Participants With Composite Endpoint | 61 participants |
| Sevoflurane | Number of Participants With Composite Endpoint | 56 participants |
p-value: 0.605695% CI: [-4.74, 8.13]Difference of proportion
Secondary
Number of Participants With Life-Threatening Arrhythmia
Patients with Life-Threatening Arrhythmia in the FAS
Time frame: 3 Postoperative Days
Population: Full analysis set (FAS): Randomised patients who started general anaesthesia induction. Patients were assigned to the treatment groups as randomised, i.e. the treatment groups were based on the treatment allocated by randomisation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Xenon | Number of Participants With Life-Threatening Arrhythmia | 2 participants |
| Sevoflurane | Number of Participants With Life-Threatening Arrhythmia | 0 participants |
p-value: 0.155995% CI: [-0.26, 1.61]Difference of proportion
Secondary
Number of Participants With Myocardial Infarction (MI)
Patients with Confirmed Myocardial Infarction (MI) by the Investigators
Time frame: 3 Postoperative Days
Population: Full analysis set (FAS): Randomised patients who started general anaesthesia induction. Patients were assigned to the treatment groups as randomised, i.e. the treatment groups were based on the treatment allocated by randomisation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Xenon | Number of Participants With Myocardial Infarction (MI) | 5 participants |
| Sevoflurane | Number of Participants With Myocardial Infarction (MI) | 3 participants |
p-value: 0.476395% CI: [-1.19, 2.54]Difference of proportion
Secondary
Systolic Blood Pressure (SBP)
Repeated Systolic Blood Pressure measurements during the perioperative period
Time frame: From pre-induction to recovery of anesthesia
Population: Full analysis set (FAS): Randomised patients who started general anaesthesia induction. Patients were assigned to the treatment groups as randomised, i.e. the treatment groups were based on the treatment allocated by randomisation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Xenon | Systolic Blood Pressure (SBP) | Minimum SBP-Maintenance Time | 94.8 mm Hg | Standard Deviation 17.8 |
| Xenon | Systolic Blood Pressure (SBP) | Maximum SBP-Induction Time | 156.0 mm Hg | Standard Deviation 26.9 |
| Xenon | Systolic Blood Pressure (SBP) | Minimum SBP-Induction Time | 90.6 mm Hg | Standard Deviation 21.3 |
| Xenon | Systolic Blood Pressure (SBP) | Maximum SBP- Maintenance Time | 157.8 mm Hg | Standard Deviation 28 |
| Xenon | Systolic Blood Pressure (SBP) | Minimum SBP- Awakening Time | 123.8 mm Hg | Standard Deviation 25.1 |
| Xenon | Systolic Blood Pressure (SBP) | Maximum SBP-Awakening Time | 156.6 mm Hg | Standard Deviation 29.1 |
| Xenon | Systolic Blood Pressure (SBP) | Baseline | 146.1 mm Hg | Standard Deviation 21.6 |
| Sevoflurane | Systolic Blood Pressure (SBP) | Maximum SBP-Awakening Time | 153.4 mm Hg | Standard Deviation 27.6 |
| Sevoflurane | Systolic Blood Pressure (SBP) | Baseline | 147.3 mm Hg | Standard Deviation 23.6 |
| Sevoflurane | Systolic Blood Pressure (SBP) | Minimum SBP-Induction Time | 90.3 mm Hg | Standard Deviation 20.7 |
| Sevoflurane | Systolic Blood Pressure (SBP) | Minimum SBP-Maintenance Time | 83.8 mm Hg | Standard Deviation 14.2 |
| Sevoflurane | Systolic Blood Pressure (SBP) | Minimum SBP- Awakening Time | 117.6 mm Hg | Standard Deviation 23 |
| Sevoflurane | Systolic Blood Pressure (SBP) | Maximum SBP-Induction Time | 153.6 mm Hg | Standard Deviation 29.6 |
| Sevoflurane | Systolic Blood Pressure (SBP) | Maximum SBP- Maintenance Time | 144.6 mm Hg | Standard Deviation 26.1 |
Secondary
Urine Output
Urine volume in milliliter (mL) during the first postoperative hours
Time frame: From Day 0 until Postoperative Day 1
Population: Treated set (TS): Randomised patients who received the study medication. Patients were assigned to the treatment groups as treated, i.e. the treatment groups were based on the treatment actually received.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Xenon | Urine Output | 1279.0 mL | Standard Deviation 723.1 |
| Sevoflurane | Urine Output | 1324.4 mL | Standard Deviation 631.8 |
Secondary
Vital Signs (Heart Rate Changes)
Changes from baseline for Heart Rate (HR)
Time frame: From pre-induction to Postoperative Day 3
Population: Treated set (TS): Randomised patients who received the study medication. Patients were assigned to the treatment groups as treated, i.e. the treatment groups were based on the treatment actually received.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Xenon | Vital Signs (Heart Rate Changes) | HR-Day 1 | 6.35 beats per minute | Standard Deviation 12.03 |
| Xenon | Vital Signs (Heart Rate Changes) | HR-Day 2 | 8.81 beats per minute | Standard Deviation 13.64 |
| Xenon | Vital Signs (Heart Rate Changes) | HR-Day 3 | 6.44 beats per minute | Standard Deviation 11.72 |
| Sevoflurane | Vital Signs (Heart Rate Changes) | HR-Day 1 | 6.35 beats per minute | Standard Deviation 12.91 |
| Sevoflurane | Vital Signs (Heart Rate Changes) | HR-Day 2 | 9.85 beats per minute | Standard Deviation 12.93 |
| Sevoflurane | Vital Signs (Heart Rate Changes) | HR-Day 3 | 8.90 beats per minute | Standard Deviation 14.14 |
Secondary
Vital Signs (SBP and DBP Changes)
Changes from baseline for Systolic and Diastolic Blood Pressure (SBP and DBP)
Time frame: From pre-induction to Postoperative Day 3
Population: Treated set (TS): Randomised patients who received the study medication. Patients were assigned to the treatment groups as treated, i.e. the treatment groups were based on the treatment actually received.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Xenon | Vital Signs (SBP and DBP Changes) | SBP-Day 1 | -12.2 mm Hg | Standard Deviation 25.4 |
| Xenon | Vital Signs (SBP and DBP Changes) | SBP-Day 2 | -10.8 mm Hg | Standard Deviation 26.6 |
| Xenon | Vital Signs (SBP and DBP Changes) | SBP-Day 3 | -11.9 mm Hg | Standard Deviation 24.7 |
| Xenon | Vital Signs (SBP and DBP Changes) | DBP-Day 1 | -6.05 mm Hg | Standard Deviation 14.91 |
| Xenon | Vital Signs (SBP and DBP Changes) | DBP- Day 2 | -3.32 mm Hg | Standard Deviation 14.53 |
| Xenon | Vital Signs (SBP and DBP Changes) | DBP-Day 3 | -3.73 mm Hg | Standard Deviation 14.05 |
| Sevoflurane | Vital Signs (SBP and DBP Changes) | DBP- Day 2 | -1.46 mm Hg | Standard Deviation 13.41 |
| Sevoflurane | Vital Signs (SBP and DBP Changes) | SBP-Day 1 | -14.2 mm Hg | Standard Deviation 26.8 |
| Sevoflurane | Vital Signs (SBP and DBP Changes) | DBP-Day 1 | -6.15 mm Hg | Standard Deviation 15.1 |
| Sevoflurane | Vital Signs (SBP and DBP Changes) | SBP-Day 2 | -10.7 mm Hg | Standard Deviation 25.6 |
| Sevoflurane | Vital Signs (SBP and DBP Changes) | DBP-Day 3 | -2.61 mm Hg | Standard Deviation 13.9 |
| Sevoflurane | Vital Signs (SBP and DBP Changes) | SBP-Day 3 | -12.2 mm Hg | Standard Deviation 25 |