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Cardiovascular Safety of Xenon in General Anaesthesia, in Patient With Cardiovascular Risk in Non Cardiac Surgery (CARVASAXe)

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ClinicalTrials.gov Identifier: NCT01120405
Recruitment Status : Completed
First Posted : May 11, 2010
Results First Posted : June 17, 2014
Last Update Posted : June 17, 2014
Sponsor:
Collaborators:
Eurofins Biomnis
MONITORING FORCE GROUP CROs
INFERENTIAL
Information provided by (Responsible Party):
Air Liquide Santé International

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Single (Participant);   Primary Purpose: Screening
Conditions Elevated Cardiac Risk
Coronary Arteries Disease Risk
Interventions Drug: Xenon
Drug: Sevoflurane
Enrollment 600
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Xenon Sevoflurane
Hide Arm/Group Description 0.8-1.1 Minimum Alveolar Concentration in 30 % oxygen (Group A) 0.8-1.1 Minimum Alveolar Concentration in 30 % oxygen (Group B)
Period Title: Overall Study
Started 298 302
Completed 271 269
Not Completed 27 33
Arm/Group Title Xenon Sevoflurane Total
Hide Arm/Group Description 0.8-1.1 Minimal Alveolar Concentration in 30% oxygen (Group A) 0.8-1.1 Minimal Alveolar Concentration in 30% oxygen (Group B) Total of all reporting groups
Overall Number of Baseline Participants 295 295 590
Hide Baseline Analysis Population Description
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.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 295 participants 295 participants 590 participants
70.6  (10.3) 71.2  (10.2) 70.9  (10.2)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 295 participants 295 participants 590 participants
Female
57
  19.3%
52
  17.6%
109
  18.5%
Male
238
  80.7%
243
  82.4%
481
  81.5%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
France Number Analyzed 295 participants 295 participants 590 participants
295 295 590
Participants with Baseline Cardiac Troponin (Central Laboratory)  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 295 participants 295 participants 590 participants
> 99th percentile 26 26 52
≤ 99th percentile 269 269 538
1.Primary Outcome
Title Number of Participants With Myocardial Necrosis (MN)
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Xenon Sevoflurane
Hide Arm/Group Description:
0.8-1.1 Minimum Alveolar Concentration in 30 % oxygen (Group A)
0.8-1.1 Minimum Alveolar Concentration in 30 % oxygen (Group B)
Overall Number of Participants Analyzed 273 261
Measure Type: Number
Unit of Measure: participants
57 54
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Xenon, Sevoflurane
Comments

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.

Type of Statistical Test Non-Inferiority or Equivalence
Comments Non-inferiority of xenon over sevoflurane is accepted if the upper bound of the two-sided 95% CI around the estimated difference is below the prespecified non-inferiority margin of 10%.
Statistical Test of Hypothesis P-Value 0.0052
Comments [Not Specified]
Method Difference of proportion
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference of proportion
Estimated Value 0.19
Confidence Interval (2-Sided) 95%
-6.70 to 7.07
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Number of Participants With Cardiac Troponin I or T Above the 99th Percentile (Local Laboratories)
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Xenon Sevoflurane
Hide Arm/Group Description:
0.8-1.1 Minimum Alveolar Concentration in 30 % oxygen (Group A)
0.8-1.1 Minimum Alveolar Concentration in 30 % oxygen (Group B)
Overall Number of Participants Analyzed 295 295
Measure Type: Number
Unit of Measure: participants
27 25
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Xenon, Sevoflurane
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7715
Comments [Not Specified]
Method Difference of proportion
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference of proportion
Estimated Value 0.68
Confidence Interval (2-Sided) 95%
-3.90 to 5.25
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Number of Participants With Myocardial Infarction (MI)
Hide Description Patients with Confirmed Myocardial Infarction (MI) by the Investigators
Time Frame 3 Postoperative Days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Xenon Sevoflurane
Hide Arm/Group Description:
0.8-1.1 Minimum Alveolar Concentration in 30 % oxygen (Group A)
0.8-1.1 Minimum Alveolar Concentration in 30 % oxygen (Group B)
Overall Number of Participants Analyzed 295 295
Measure Type: Number
Unit of Measure: participants
5 3
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Xenon, Sevoflurane
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4763
Comments [Not Specified]
Method Difference of proportion
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference of proportion
Estimated Value 0.68
Confidence Interval (2-Sided) 95%
-1.19 to 2.54
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Number of Participants With Cerebro-Vascular Event
Hide Description Patients with Cerebro-Vascular Event in the FAS
Time Frame 3 postoperative days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Xenon Sevoflurane
Hide Arm/Group Description:
0.8-1.1 Minimum Alveolar Concentration in 30 % oxygen (Group A)
0.8-1.1 Minimum Alveolar Concentration in 30 % oxygen (Group B)
Overall Number of Participants Analyzed 295 295
Measure Type: Number
Unit of Measure: participants
2 3
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Xenon, Sevoflurane
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6533
Comments [Not Specified]
Method Difference of proportion
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference of proportion
Estimated Value -0.34
Confidence Interval (2-Sided) 95%
-1.82 to 1.14
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Number of Participants With Life-Threatening Arrhythmia
Hide Description Patients with Life-Threatening Arrhythmia in the FAS
Time Frame 3 Postoperative Days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Xenon Sevoflurane
Hide Arm/Group Description:
0.8-1.1 Minimum Alveolar Concentration in 30 % oxygen (Group A)
0.8-1.1 Minimum Alveolar Concentration in 30 % oxygen (Group B)
Overall Number of Participants Analyzed 295 295
Measure Type: Number
Unit of Measure: participants
2 0
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Xenon, Sevoflurane
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1559
Comments [Not Specified]
Method Difference of proportion
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference of proportion
Estimated Value 0.68
Confidence Interval (2-Sided) 95%
-0.26 to 1.61
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Number of Participants Who Died From Cardiac Origin
Hide Description No patient died from a cardiac cause during the 3 postoperative days.
Time Frame 3 postoperative days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Xenon Sevoflurane
Hide Arm/Group Description:
0.8-1.1 Minimum Alveolar Concentration in 30 % oxygen (Group A)
0.8-1.1 Minimum Alveolar Concentration in 30 % oxygen (Group B)
Overall Number of Participants Analyzed 295 295
Measure Type: Number
Unit of Measure: participants
0 0
7.Secondary Outcome
Title Number of Participants With Composite Endpoint
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Xenon Sevoflurane
Hide Arm/Group Description:
0.8-1.1 Minimum Alveolar Concentration in 30 % oxygen (Group A)
0.8-1.1 Minimum Alveolar Concentration in 30 % oxygen (Group B)
Overall Number of Participants Analyzed 295 295
Measure Type: Number
Unit of Measure: participants
61 56
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Xenon, Sevoflurane
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6056
Comments [Not Specified]
Method Difference of proportion
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference of proportion
Estimated Value 1.69
Confidence Interval (2-Sided) 95%
-4.74 to 8.13
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Systolic Blood Pressure (SBP)
Hide Description Repeated Systolic Blood Pressure measurements during the perioperative period
Time Frame From pre-induction to recovery of anesthesia
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Xenon Sevoflurane
Hide Arm/Group Description:
0.8-1.1 Minimum Alveolar Concentration in 30 % oxygen (Group A)
0.8-1.1 Minimum Alveolar Concentration in 30 % oxygen (Group B)
Overall Number of Participants Analyzed 295 295
Mean (Standard Deviation)
Unit of Measure: mm Hg
Baseline 146.1  (21.6) 147.3  (23.6)
Minimum SBP-Induction Time 90.6  (21.3) 90.3  (20.7)
Minimum SBP-Maintenance Time 94.8  (17.8) 83.8  (14.2)
Minimum SBP- Awakening Time 123.8  (25.1) 117.6  (23.0)
Maximum SBP-Induction Time 156.0  (26.9) 153.6  (29.6)
Maximum SBP- Maintenance Time 157.8  (28.0) 144.6  (26.1)
Maximum SBP-Awakening Time 156.6  (29.1) 153.4  (27.6)
9.Secondary Outcome
Title Vital Signs (SBP and DBP Changes)
Hide Description Changes from baseline for Systolic and Diastolic Blood Pressure (SBP and DBP)
Time Frame From pre-induction to Postoperative Day 3
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Xenon Sevoflurane
Hide Arm/Group Description:
0.8-1.1 Minimum Alveolar Concentration in 30 % oxygen (Group A)
0.8-1.1 Minimum Alveolar Concentration in 30 % oxygen (Group B)
Overall Number of Participants Analyzed 292 294
Mean (Standard Deviation)
Unit of Measure: mm Hg
SBP-Day 1 -12.2  (25.4) -14.2  (26.8)
SBP-Day 2 -10.8  (26.6) -10.7  (25.6)
SBP-Day 3 -11.9  (24.7) -12.2  (25.0)
DBP-Day 1 -6.05  (14.91) -6.15  (15.10)
DBP- Day 2 -3.32  (14.53) -1.46  (13.41)
DBP-Day 3 -3.73  (14.05) -2.61  (13.90)
10.Secondary Outcome
Title Vital Signs (Heart Rate Changes)
Hide Description Changes from baseline for Heart Rate (HR)
Time Frame From pre-induction to Postoperative Day 3
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Xenon Sevoflurane
Hide Arm/Group Description:
0.8-1.1 Minimal Alveolar Concentration in 30% oxygen (Group A)
0.8-1.1 Minimal Alveolar Concentration in 30% oxygen (Group B)
Overall Number of Participants Analyzed 292 294
Mean (Standard Deviation)
Unit of Measure: beats per minute
HR-Day 1 6.35  (12.03) 6.35  (12.91)
HR-Day 2 8.81  (13.64) 9.85  (12.93)
HR-Day 3 6.44  (11.72) 8.90  (14.14)
11.Secondary Outcome
Title Number of Participants With Chest Pain During the 3 Postoperative Days
Hide Description Patients with Chest Pain reported at least once per day during the 3 Postoperative Days
Time Frame From Day 0 until Postoperative Day 3
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Xenon Sevoflurane
Hide Arm/Group Description:
0.8-1.1 Minimum Alveolar Concentration in 30 % oxygen (Group A)
0.8-1.1 Minimum Alveolar Concentration in 30 % oxygen (Group B)
Overall Number of Participants Analyzed 292 294
Measure Type: Number
Unit of Measure: participants
Day 0 0 0
Day 1 0 2
Day 2 1 2
Day 3 2 3
12.Secondary Outcome
Title Urine Output
Hide Description Urine volume in milliliter (mL) during the first postoperative hours
Time Frame From Day 0 until Postoperative Day 1
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Xenon Sevoflurane
Hide Arm/Group Description:
0.8-1.1 Minimum Alveolar Concentration in 30 % oxygen (Group A)
0.8-1.1 Minimum Alveolar Concentration in 30 % oxygen (Group B)
Overall Number of Participants Analyzed 292 294
Mean (Standard Deviation)
Unit of Measure: mL
1279.0  (723.1) 1324.4  (631.8)
Time Frame Adverse Events observed after the start of study drug administration and during postoperative 3-day period
Adverse Event Reporting Description Participants at risks are the patients from the Treated Set, ie randomised patients who received the study medication.
 
Arm/Group Title Xenon Sevoflurane
Hide Arm/Group Description 0.8-1.1 Minimum Alveolar Concentration in 30 % oxygen (Group A) 0.8-1.1 Minimum Alveolar Concentration in 30 % oxygen (Group B)
All-Cause Mortality
Xenon Sevoflurane
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Xenon Sevoflurane
Affected / at Risk (%) Affected / at Risk (%)
Total   17/292 (5.82%)   17/294 (5.78%) 
Cardiac disorders     
Myocardial Infarction   3/292 (1.03%)  3/294 (1.02%) 
Cardio-respiratory arrest   0/292 (0.00%)  2/294 (0.68%) 
Acute Coronary Syndrome   1/292 (0.34%)  0/294 (0.00%) 
Acute Myocardial Infarction   1/292 (0.34%)  0/294 (0.00%) 
Arrhythmia supraventricular   0/292 (0.00%)  1/294 (0.34%) 
Atrial Fibrillation   1/292 (0.34%)  0/294 (0.00%) 
Bradyarrhythmia   0/292 (0.00%)  1/294 (0.34%) 
Subendocardial ischemia   0/292 (0.00%)  1/294 (0.34%) 
Hepatobiliary disorders     
Gallblader Necrosis   0/292 (0.00%)  1/294 (0.34%) 
Injury, poisoning and procedural complications     
Post Procedural Haemorrhage   2/292 (0.68%)  3/294 (1.02%) 
Post Procedural Haematoma   2/292 (0.68%)  2/294 (0.68%) 
Procedural Hypotension   1/292 (0.34%)  1/294 (0.34%) 
Graft thrombosis   1/292 (0.34%)  0/294 (0.00%) 
Operative Haemorrhage   1/292 (0.34%)  0/294 (0.00%) 
Shunt Trombosis   1/292 (0.34%)  0/294 (0.00%) 
Wound   1/292 (0.34%)  0/294 (0.00%) 
Investigations     
Troponin Increased   1/292 (0.34%)  2/294 (0.68%) 
Metabolism and nutrition disorders     
Diabetic Ketoacidosis   1/292 (0.34%)  0/294 (0.00%) 
Nervous system disorders     
Ischaemic Stroke   0/292 (0.00%)  2/294 (0.68%) 
Agitation   1/292 (0.34%)  0/294 (0.00%) 
Cerebrovascular Accident   1/292 (0.34%)  0/294 (0.00%) 
Confusional State   1/292 (0.34%)  0/294 (0.00%) 
Loss of Consciousness   0/292 (0.00%)  1/294 (0.34%) 
Transient Ischaemic Attack   0/292 (0.00%)  1/294 (0.34%) 
Psychiatric disorders     
Aggression   1/292 (0.34%)  0/294 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Hypoxia   0/292 (0.00%)  3/294 (1.02%) 
Vascular disorders     
Peripheral Ischaemia   2/292 (0.68%)  1/294 (0.34%) 
Hypertension   0/292 (0.00%)  1/294 (0.34%) 
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Xenon Sevoflurane
Affected / at Risk (%) Affected / at Risk (%)
Total   79/292 (27.05%)   84/294 (28.57%) 
General disorders     
Hyperthermia   13/292 (4.45%)  17/294 (5.78%) 
Pain   8/292 (2.74%)  15/294 (5.10%) 
Injury, poisoning and procedural complications     
Procedural Pain   21/292 (7.19%)  23/294 (7.82%) 
Procedural Hypertension   24/292 (8.22%)  14/294 (4.76%) 
Procedural Nausea   21/292 (7.19%)  12/294 (4.08%) 
Procedural Vomiting   16/292 (5.48%)  10/294 (3.40%) 
Vascular disorders     
Hypertension   17/292 (5.82%)  20/294 (6.80%) 
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Air Liquide Sante International may delay publication or disclosure for a term not exceeding eighteen (18) months with effect from the request in the event that Air Liquide Sante International wishes to seek protection of the results of the Trial by industrial property rights.
Results Point of Contact
Name/Title: Yannick LE MANACH, MD, PhD
Organization: Population Health Research Institute - Mc Master University, Hamilton CANADA
Phone: 0012892606840
Responsible Party: Air Liquide Santé International
ClinicalTrials.gov Identifier: NCT01120405     History of Changes
Other Study ID Numbers: EudraCT #2010-018703-28
First Submitted: May 4, 2010
First Posted: May 11, 2010
Results First Submitted: March 20, 2014
Results First Posted: June 17, 2014
Last Update Posted: June 17, 2014