Nitrous oxide and perioperative cardiac morbidity (ENIGMA-II) Trial: Rationale and design

Acute Ischemic Heart Disease
Nitrous oxide and perioperative cardiac morbidity
(ENIGMA-II) Trial: Rationale and design
Paul S. Myles, MPH, MD, a,b,c,d Kate Leslie, MEpi, MD, e Philip Peyton, MBBS, MD, f Michael Paech, MB.BS, DM, g
Andrew Forbes, MSc, PhD, c Matthew T.V. Chan, MB.BS, FANZCA, h Daniel Sessler, MD, i
Philip J. Devereaux, MD, PhD, j Brendan S. Silbert, MBBS, FANZCA, k Konrad Jamrozik, MB.BS, DPhil, l
Scott Beattie, MD, PhD, m Neal Badner, MD, FRCP(C), n James Tomlinson, MB.BS, FRACP, a,b and Sophia Wallace,
BSc a the ANZCA Trials Group Melbourne, Victoria, Perth, WA, and Adelaide SA, Australia; Hong Kong, China;
Cleveland, OH; and Hamilton, Toronto, and London, Ontario, Canada

Background            Globally there are N200 million major surgical procedures undertaken annually, and about 20% of these
involve patients who have coronary artery disease. Many receive nitrous oxide, which impairs methionine synthase, thus
inhibiting folate synthesis and increasing postoperative homocysteine levels. Nitrous oxide anesthesia leads to postoperative
endothelial dysfunction, and there is some evidence that it increases myocardial ischemia and, possibly, myocardial
infarction. We have initiated the Nitrous oxide and perioperative cardiac morbidity (ENIGMA-II) Trial to test the hypothesis
that in inpatients undergoing anesthesia for major noncardiac surgery, avoidance of nitrous oxide will reduce the incidence
of death and major cardiovascular events.
Methods        ENIGMA-II is a 7,000-patient, international randomized trial involving patients at risk of coronary artery
disease undergoing noncardiac surgery. The patients, health care providers (except for the anesthesiologists), data
collectors, and outcome adjudicators are blinded to whether patients receive nitrous oxide–containing or nitrous oxide–free
anesthetic. The primary outcome is a composite of death and major nonfatal events (ie, myocardial infarction, cardiac arrest,
pulmonary embolism, and stroke) at 30 days after surgery.
Results At present, ENIGMA-II has randomized N1,000 patients in 22 hospitals in 5 countries. To date, patients' mean
age is 70 years, 66% are men, 38% have a history of coronary artery disease, 19% have a history of cerebrovascular
disease, and 84% have a history of hypertension. Most patients have undergone intra-abdominal 28%, vascular 32%, and
orthopedic 16% surgery.
Conclusions        The ENIGMA-II Trial will be the largest study yet conducted to ascertain the benefits and risks of
removing nitrous oxide from the gas mixture in anesthesia. The results of this large international trial will guide the clinical
care of the hundreds of millions of adults undergoing noncardiac surgery annually. (Am Heart J 2009;157:488-494.e1)

  Globally there are N230 million major surgical proce-                                     infarction [MI], nonfatal cardiac arrest, or nonfatal
dures undertaken annually,1 and given that cardiac and                                      stroke). These perioperative cardiovascular complica-
pediatric surgery only account for a few of major surgical                                  tions prolonged hospitalization and increase costs to the
cases, this suggests that N200 million adults undergo                                       health system.2-4 Recently, some of us undertook the
major noncardiac surgery annually. Millions of these                                        POISE (PeriOperative ISchemic Evaluation) trial,5 the
patients will have a major perioperative cardiovascular                                     largest perioperative cardiovascular noncardiac surgery
event (ie, cardiovascular death, nonfatal myocardial                                        trial conducted to date. In POISE, 6.4% of the patients had

From the   a
               Department of Anaesthesia and Perioperative Medicine, Alfred Hospital,       St Vincent's Hospital, Fitzroy, Victoria, Australia, lSchool of Population Health & Clinical
Melbourne, Victoria, Australia, bAcademic Board of Anaesthesia and Perioperative            Practice, University of Adelaide, SA, Australia, Department of Anaesthesia, University
Medicine, Monash University, Melbourne, Victoria, Australia, cDepartment of Epidemio-       Health Network, Toronto, Ontario, Canada, and Department of Anesthesiology,
logy and Preventive Medicine, Monash University; Melbourne, Victoria, Australia,            University of Western Ontario, London, Ontario, Canada.
 Australian National Health and Medical Research Council Centre for Clinical Research       Trial Registration: CT00430989.
Excellence in Therapeutics, Melbourne, Victoria, Australia, eDepartment of Anaesthesia      For ENIGMA-II Trial Organization and a list of committees see Appendix A, available online.
and Pain Management, Royal Melbourne Hospital, Melbourne, Victoria, Australia,              Submitted September 30, 2008; accepted November 25, 2008.
 Department of Anaesthesia, Austin Hospital, Heidelberg, Victoria, Australia, gThe School   Reprint requests: Paul S. Myles, MPH, MD, Department of Anaesthesia and Perioperative
of Medicine and Pharmacology, The University of Western Australia, Perth, WA, Australia,    Medicine, Alfred Hospital, Commercial Road, Melbourne, Victoria 3004, Australia.
 Department of Anaesthesia, Prince of Wales Hospital, The Chinese University of Hong        E-mail:
Kong, Hong Kong, China, iDepartment of Outcomes Research, The Cleveland Clinic,             0002-8703/$ - see front matter
Cleveland, OH, jDepartments of Clinical Epidemiology and Biostatististics and Medicine,     © 2009, Mosby, Inc. All rights reserved.
McMaster University, Hamilton, Ontario, Canada, kDepartment of Anaesthesia,                 doi:10.1016/j.ahj.2008.11.015
American Heart Journal
Volume 157, Number 3
                                                                                                               Myles et al 489

a major cardiovascular event (ie, cardiovascular death,          side effect and safety profile are thus thought to be well
nonfatal MI, or nonfatal cardiac arrest) within the first 30     understood. Its notable feature is that it allows a dose
days. A total of 2.7% of the patients died within the first 30   reduction of other anesthetic drugs that are usually
days, and 59% of the fatalities were adjudicated as a            more expensive and presumably more toxic. These
cardiovascular death. A perioperative MI has been                perceived benefits support critical evaluation of its
estimated to add $15,000 to the costs of a hospital stay,        safety in a large clinical trial.15
whereas a death adds an incremental cost of N$20,000.3,4
The cost of perioperative cardiac events is estimated at
$20 billion annually in the United States alone.2,6              Nitrous oxide, homocysteine, and
                                                                 cardiovascular events
                                                                   Nitrous oxide–induced inactivation of methionine
Nitrous oxide and anesthesia                                     synthase increases plasma homocysteine after sur-
   Despite some concerns regarding the safety and                gery.11-13 Importantly, a recent study showed that plasma
usefulness of nitrous oxide,7 it is still commonly used in       levels of homocysteine remain elevated for at least a week
anesthetic practice around the world. Because of its             after surgery with nitrous oxide anesthesia.16 Long-term
limited potency, the usual practice is to administer             elevation of plasma homocysteine concentration is an
nitrous oxide at concentrations as high as 70% in                independent risk factor for cardiovascular disease,17 and
oxygen (inspired oxygen 30%) along with a potent                 an acute increase in plasma homocysteine causes
inhalational anesthetic agent (eg, sevoflurane) or intra-        endothelial dysfunction18,19 and hypercoaguability.17
venous propofol to produce a depth of anesthesia                 Consequently, hyperhomocysteinemia is associated with
sufficient for surgery. The prevailing view has been that        increased risk of venous thromboembolism and stroke.20
nitrous oxide is a cheap, relatively “safe” drug that can          Plasma homocysteine concentration is acutely raised
reduce the exposure to other anesthetic drugs. We have           after oral methionine and is reliably associated with
previously summarized the perceived risks and benefits           endothelial dysfunction as measured by flow-mediated
of nitrous oxide.7                                               vasodilation.18,19 Nitrous oxide–induced elevation of
   Nitrous oxide interferes with vitamin B12 and folate          homocysteine concentration may mirror that produced
metabolism.8,9 It oxidizes the cobalt atom and irreversibly      by oral methionine, with a recent study demonstrating
inactivates the enzyme, methionine synthase. This                nitrous oxide-based anesthesia significantly impaired
impairs production of methionine (from homocysteine),            endothelial function as measured by flow-mediated
used to form tetrahydrofolate and thymidine during DNA           dilation in patients undergoing noncardiac surgery.13
synthesis. These adverse effects are time exposure–              Thus, nitrous oxide may also be a risk factor for
dependent and are probably greater in systemically               perioperative myocardial ischemia.
unwell patients.8 It is well established that prolonged            Badner et al11 randomly allocated 90 patients to
exposure to nitrous oxide can lead to a clinical syndrome        anesthesia with or without nitrous oxide. The nitrous
similar to pernicious anemia.7,10 Inhibition of methionine       oxide group had significantly increased homocysteine
synthase by nitrous oxide can be rapid and long-lasting:         levels and a higher incidence of myocardial ischemia
Exposure beyond a few hours reduces methionine                   (46% vs 25%, P b .05), more ischemic events (82 vs 53, P
synthase activity by 50%,8 and 12 to 24 hours of exposure        b .02), and had more ischemic events lasting 30 minutes
causes marked megaloblastic changes10 that can be                (23 vs 14, P b .05). This is a particularly relevant finding
ameliorated by administration of sufficient folate or            because it is known that the incidence of myocardial
vitamin B12.                                                     ischemia is highest in the hours after surgery and that it is
   Most relevant to those with coronary artery disease is        strongly associated with postoperative MI.2
that nitrous oxide results in increased plasma homo-
cysteine and myocardial ischemia after surgery.11-13 In
addition, nitrous oxide can increase pulmonary artery            Our recent studies
pressure and is contraindicated in pulmonary hyperten-             We recently completed a moderate-sized multicenter
sion.7 Nitrous oxide activates the sympathetic nervous           clinical trial of 2,050 patients undergoing noncardiac
system and can sensitize the myocardium to the                   surgery—the ENIGMA (Evaluation of Nitrous oxide In the
arrhythmogenic effects of epinephrine.14 Lastly, the             Gas Mixture for Anesthesia) Trial.15 Patients were
inclusion of nitrous oxide in the anesthetic gas mixture         assigned to a nitrous oxide, or nitrous oxide–free,
increases the likelihood of intraoperative or postopera-         anesthetic. We found that the avoidance of nitrous oxide
tive hypoxia.7                                                   decreased the risk of wound infection (odds ratio [OR]
   Nitrous oxide was the first anesthetic discovered and         0.7, P = .034), severe vomiting (OR 0.4, P b .001), and
remains a mainstay of anesthesia throughout the world;           pneumonia (OR 0.5, P = .031). In addition, patients given
it has probably been given to more than a billion                nitrous oxide had a greater length of stay in the intensive
patients since 1844. It thus has a long history, and its         care unit (ICU) (P = .02), suggesting an increased
American Heart Journal
490 Myles et al                                                                                                   March 2009

incidence of more serious complications. These findings       Study methods
were contrary to an earlier study that did not show these     Patient population
differences.21 However, in the ENIGMA Trial, we did not
                                                                ENIGMA-II will evaluate patients undergoing noncar-
equalize the inspired oxygen concentrations in both
                                                              diac surgery who are at risk of a perioperative major
groups, and so, it is possible that some of the benefits of
                                                              cardiac event (Table I). We will enroll 7,000 patients in
avoiding nitrous oxide could be attributed to supple-
                                                              30 to 40 participating sites in Australasia, Asia, North
mental oxygen. The proposed trial (ENIGMA-II) will
                                                              America, and Europe. Centers will obtain institutional
address this issue.
                                                              review board approval before enrolling patients, and all
  The ENIGMA Trial was not designed for and had
                                                              patients must provide informed consent to participate
insufficient power to detect a difference in the less
                                                              in ENIGMA-II.
common, but serious complications of MI or death. We
nevertheless identified a possible increased risk of          Assessment for eligibility
confirmed MI in patients receiving nitrous oxide, 1.3%
                                                                After first obtaining agreement from anesthesiologists
versus 0.7% (adjusted P = .19). Interestingly, if patients
                                                              at each site, all elective noncardiac surgery patients are
with new electrocardiogram (ECG) changes or cardiac
                                                              screened for eligibility. The patients who are eligible but
enzyme elevation, but not both (ie, unconfirmed MIs), are
                                                              not recruited into the trial are recorded in a study log that
included, there was a marked increase in the nitrous
                                                              includes the reasons for the lack of participation.
oxide group, 30 versus 10 cases (P = .002); this requires
further study. There were 10 postoperative deaths (1.0%)      Allocation and randomization
in the nitrous oxide group and 4 (0.4%) in the control           After the patient's consent has been obtained, center
group (P = .26).                                              personnel will telephone a central 24-hour interactive
  ENIGMA participants were an unselected group of             voice recognition system that prompts the researcher or
surgical patients, but the findings suggest that nitrous      study coordinator to identify their study site, and
oxide may be particularly detrimental in those at risk of     randomly allocates patients to a treatment group (1:1)
cardiac events.                                               from a computer-generated list. Randomization is strati-
  In summary, there is an established association between     fied by site. The sample size is sufficiently large to ensure
nitrous oxide and hyperhomocysteinemia, and flow-             comparable baseline characteristics, including surgical
mediated vasodilation, after surgery. There is also           risk factors, surgical technique, anesthetic technique, and
evidence from a small clinical trial and post hoc results     other aspects of perioperative care. ENIGMA-II is an
from the ENIGMA Trial to suggest that avoidance of            intention-to-treat trial. Any participant who is enrolled
nitrous oxide may lead to a reduction in postoperative        and randomized to treatment group is followed for the
cardiac events and mortality.                                 duration of the trial.

Trial objectives                                              Definitions of end points
  The overall study goal of the ENIGMA-II Trial is to         Primary end point
assess whether removal of nitrous oxide from the                The primary end point is a composite of death and
anesthetic gas mixture reduces the incidence of major         major nonfatal cardiovascular events (MI, cardiac
perioperative cardiac events in patients with, or at risk     arrest, pulmonary embolism, and stroke) at 30 days
of, coronary artery disease who are undergoing major          after surgery.
noncardiac surgery. Specifically, we will test the
                                                              Secondary end points
hypothesis that in inpatients undergoing anesthesia for
major noncardiac surgery, avoidance of nitrous oxide            Secondary end points include the following: (i) MI, (ii)
will reduce the incidence of death and major                  cardiac arrest, (iii) pulmonary embolism, (iv) stroke, (v)
cardiovascular events. The study is funded by the             wound infection, (vi) severe nausea and vomiting, all up
Australian National Health and Medical Research               to 30 days after surgery; plus (vii) duration of stay in the
Council (ID 436677).                                          ICU and hospital. For specific definitions, please see
                                                              Table II.
                                                                Data pertaining to study end points are sent to a
Trial design                                                  separate end point adjudication committee (see below).
  The ENIGMA-II study is a multicenter, international,          Death: All deaths within 30 days of surgery from
randomized, parallel-group, controlled trial, with patients   any cause.
randomly allocated to either nitrous oxide–containing           Myocardial infarction: requires any one of the
(70% nitrous oxide in oxygen [inspired oxygen fraction        following criterion:
0.3]) or nitrous oxide–free (70% nitrogen in oxygen             1. A typical rise of troponin or a typical fall of an
[inspired oxygen fraction 0.3]) anesthetic.                        elevated troponin with at least one value above the
American Heart Journal
Volume 157, Number 3
                                                                                                                                                  Myles et al 491

  Table I. Specific inclusion and exclusion criteria                                   Table II. Baseline characteristics for the first 929 patients
                                                                                       recruited into the ENIGMA-II Trial (% unless otherwise specified)
Inclusion criteria
1. Adult males and females aged ≥45 years, undergoing noncardiac
     surgery and general anesthesia expected to exceed 2 h                           Age, mean (SD), y                                                       70 (9.4)
2. At increased risk of cardiac events, defined as any of the following:             Male sex                                                                66
    a) History of coronary artery disease as indicated by a history of any           ASA physical status
     one of the following:                                                              I                                                                     0.6
  i. Angina                                                                             II                                                                   33
  ii. MI                                                                                II                                                                   62
  iii. Segmental wall motion abnormality on echocardiography or a                       IV                                                                    3.9
     fixed defect on radionuclide imaging                                            Impaired exercise ability⁎                                              28
  iv. A positive exercise stress test for cardiac ischemia                           Preexisting major medical conditions
  v. A positive radionuclide exercise, echocardiographic exercise, or                   Hypertension                                                         84
     pharmacological cardiovascular stress test for cardiac ischemia                    Coronary artery disease                                              38
  vi. Coronary revascularization (CABG or PTCA)                                         Previous MI                                                          25
  vii. Angiographic evidence of atherosclerotic stenosis ≥50% of the                    Previous CABG or angioplasty                                         21
     diameter of any coronary artery                                                    Myocardial ischemia on perfusion scan                                13
  viii. ECG with pathological Q waves in 2 contiguous leads                             Heart failure                                                         9.3
 b) Heart failure                                                                       Peripheral vascular disease                                          30
 c) Cerebrovascular disease thought due to atherothrombotic disease                     Previous stroke or TIA                                               19
 d) Undergoing aortic or peripheral vascular surgery; or                                High cholesterol                                                     45
 e) 3 or more of the following risk factors:                                            Diabetes                                                             36
      ▪ Age ≥70 y                                                                       Asthma/COPD                                                          17
      ▪ Any history of congestive heart failure                                         Infection/Fever                                                       3.9
      ▪ Diabetes and currently taking an oral hypoglycemic agent or insulin             Other                                                                36
        therapy                                                                      Medications
      ▪ Current treatment for hypertension                                              Aspirin within the past 5 d                                          32
      ▪ Preoperative serum creatinine N175 μmol/L (N2.0 mg/dL)                          NSAID within the past 2 d                                             5.8
      ▪ Current or previous high total cholesterol ≥6.2 mmol/L                          Clopidogrel                                                           3.6
        (N240 mg/dL)                                                                    Ticlopidine                                                           0.2
      ▪ History of a transient ischemic attack (ie, a transient focal neurological      Warfarin last 7 d                                                     4.7
       deficit that lasted b24 h and thought to be vascular in origin)                  Heparin                                                               7.8
      ▪ Emergency/Urgent surgery (ie, surgery which must be undertaken                  COX-II inhibitor                                                      2.4
       within 24 h of acute presentation to hospital)                                   Nitrate                                                              11
      ▪ High-risk type of surgery (ie, intrathoracic or intraperitoneal)                Statin                                                               56
                                                                                        ACE inhibitor/ARB                                                    54
Exclusion criteria                                                                      Amiodarone                                                            2.0
1. Having cardiac surgery                                                               β-Blocker                                                            41
2. Marked impairment of gas-exchange expected to require                                Diuretic                                                             25
  Fio2 N0.5 intraoperatively                                                            Calcium channel blocker                                              36
3. Specific circumstances where nitrous oxide is contraindicated                        Digoxin                                                               3.9
    (eg, volvulus, pulmonary hypertension, raised intracranial pressure) or             Insulin                                                               9.6
    the anesthesiologist plans to use supplemental oxygen (eg, colorectal               Oral hypoglycemic                                                    26
    surgery)                                                                            Antibiotic                                                            7.4
4. Nitrous oxide is unavailable for use
                                                                                     ASA, American Society of Anesthesiologists; TIA, transient ischemic attack; COPD,
PTCA, Percutaneous transluminal coronary intervention.                               chronic obstructive pulmonary disease; NSAID, nonsteroidal anti-inflammatory drug;
                                                                                     COX, cyclooxygenase; ACE, angiotensin-converting enzyme; ARB, angiotensin
                                                                                     receptor blocker.
                                                                                     ⁎ Estimated b3 metabolic equivalents.

       99th percentile of the upper reference limit, detected                                 depression [≥1 mm], or symmetric inversion of
       at its peak post surgery in a patient without a                                        T waves ≥1 mm) in at least 2 contiguous leads
       documented alternative explanation for an elevated                                  D. coronary artery intervention (ie, percutaneous
       troponin (eg, pulmonary embolism).22 This criterion                                     coronary intervention or coronary artery bypass
       also requires that one of the following must also exist:                                graft surgery [CABG] surgery)
       A. ischemic signs or symptoms (ie, chest, arm, neck,                                E. new or presumed new cardiac wall motion
          or jaw discomfort; shortness of breath, pulmon-                                     abnormality on echocardiography or new or pre-
          ary edema)                                                                          sumed new fixed defect on radionuclide imaging
       B. development of pathologic Q waves present in                                  2. Pathologic findings of an acute or healing MI
          any 2 contiguous leads that are ≥30 milliseconds                              3. Development of new pathological Q waves on an
       C. the ECG changes indicative of ischemia (ie, ST                                   ECG if troponin levels were not obtained or were
          segment elevation [≥2 mm in leads V1, V2, or V3                                  obtained at times that could have missed the
          or ≥1 mm in the other leads], ST segment                                         clinical event
American Heart Journal
492 Myles et al                                                                                                   March 2009

   Cardiac arrest: Defined as a successful resuscitation        Study medications and duration
from either documented or presumed ventricular                    After induction of anesthesia, patients allocated to the
fibrillation or sustained ventricular tachycardia               nitrous oxide group will have their anesthesia main-
or asystole.                                                    tained with 70% nitrous oxide (inspired) in 30% oxygen
   Pulmonary embolism: high probability on VQ scan or           and 1 of 4 other hypnotic agents (isoflurane, sevoflur-
documented on pulmonary angiogram or spiral com-                ane, desflurane, or propofol) at the discretion of the
puted tomography or at autopsy.                                 anesthesiologist. Patients allocated to the nitrous oxide–
   Stroke: cerebral infarction or intracerebral hemorrhage      free group will receive 30% oxygen in an oxygen/
on computed tomography or magnetic resonance ima-               medical air mixture and have their anesthesia main-
ging scan, or new neurological signs (paralysis, weakness,      tained with one of the above hypnotic agents (also
or speech difficulties) lasting N24 hours or leading to         according to anesthesiologist preference). In both
earlier death.                                                  cases, depth of anesthesia can be adjusted according to
   Severe nausea and vomiting: at least 2 episodes of           clinical judgment and/or data from depth of anesthesia
severe nausea or vomiting N6 hours apart, or if requiring       monitoring devices (if available). All other perioperative
N2 doses of antiemetic medication.                              clinical care will be according to standard practice. All
   Wound infection: associated with purulent discharge          relevant factors will be recorded on a trial case
and/or a positive microbial culture.                            report form.
   ICU stay: including initial ICU admission and additional
time after any readmission.
   Hospital stay: from the start (date, time) of surgery
                                                                Study procedures, blinding,
until actual hospital discharge.
                                                                and follow-up
End point adjudication committee                                  Anesthesiologists will have knowledge of group after
  The committee consists of an internal medicine                randomization (for safe use of nitrous oxide), but
physician with board-equivalent anesthesiology training         administration and group identity will be concealed
and 2 cardiac anesthesiologists. Their role is to verify each   from the surgeon. Anesthesiologists participating in the
of the study end points and to resolve any uncertainty as       conduct of the study will receive education explaining
to any of the above outcomes.                                   the importance of, reasoning for, and methods to
                                                                ensure blinding from surgeons and others. The
Surgical and anesthetic techniques                              anesthetic machine flow meters will be concealed
   Preoperative demographic characteristics and                 from the surgical staff, using drapes or cardboard
details of each patient's medical and surgical history are      screen. To ensure blinding of all the other staff, the
recorded. They will also undergo a 12-lead ECG,                 anesthesiologist will place the original anesthesia
chest x-ray, pathology testing, and other routine               record after surgery in a sealed opaque envelope; the
investigations.                                                 envelope is to be stored in the patient's hospital
   On the day of surgery, patients are allocated to 1           record and should not be opened until after the 30-
of the 2 treatment groups. All other perioperative              day follow-up unless there is a clinical imperative.
clinical care is according to standard practice at each         Patients, surgeons, and research staff collecting data
site, as this is an effectiveness trial designed to             and interviewing patients postoperatively will be blind
represent “real-world” practice.23 This includes choice         to treatment allocation.
of anesthetic drugs, analgesic regimens and/or regio-
nal analgesia techniques, antiemetics, and initiation or        Collection of data
continuation of perioperative cardiac medications                  Data are collected by local research staff and
including anticoagulant and antiplatelet therapy. These         entered onto a paper case report form. All data are
vary and are allowable in the trial. All such relevant          subsequently entered onto a database on the study
perioperative data are recorded on the study case               Web site ( This is managed by
report form.                                                    Monash University's Center for Clinical Research
   Blood is collected postoperatively at 6 to 12, 24, 48,       Excellence in Therapeutics (Melbourne, Australia),
and 72 hours for cardiac enzyme (troponin and/or                where all data and processes are reviewed each day
creatine kinase-MB) levels, and a 12-lead ECG is                at the data management center (see below). Data
performed on days 1 and 3 after surgery to detect MI.           fields are checked, and in conjunction with the local
Additional tests are ordered if clinically indicated (eg,       site research staff, missing data or inconsistencies are
chest pain, dyspnea, circulatory instability). In addition,     corrected, before being automatically downloaded on
patients are contacted by telephone at 30 days and              to a confirmed database. At the end of the trial, site-
their medical record reviewed to ascertain if they have         specific data will be sent to each site investigator on
experienced any adverse outcomes.                               a CD-ROM for long-term storage.
American Heart Journal
Volume 157, Number 3
                                                                                                                       Myles et al 493

Statistical considerations                                          Table III. Types of surgery, anesthetic techniques, and
                                                                    intraoperative nonanesthetic drug administration for the first 929
Sample size and power                                               patients recruited into the ENIGMA-II Trial (%)
  The recently revised international guidelines for the
                                                                  Type of surgery
diagnosis of MI22 should result in an increase in cardiac             Vascular                                                     32
events because of increased sensitivity (ie, identifying              Orthopedic                                                   16
small infarcts). The sample size is based on a clinically             Colorectal                                                   15
important (≥25%) reduction in cardiac events or death,                General (noncolorectal)                                      13
from 8% to 6%. These estimates are based on our
                                                                      Spinal                                                         8.1
previous research and large observational studies.5,24 A              Craniotomy                                                     1.5
type I error of 0.05 and a type II error of 0.1 require           Urology                                                            8.8
7,000 patients to be included in this study. We tested            Head and neck                                                      5.2
these assumptions with our ENIGMA Trial database.                 Plastics                                                           1.2
                                                                  Intraoperative cardiac drugs
When the above trial entry criteria were used, we
                                                                      β-Blocker                                                    33
identified 656 comparable patients (313 nitrous oxide                 Clonidine                                                     3.3
group, 343 control). Nitrous oxide was associated with            Antiemetic prophylaxis                                           62
a higher incidence of reported MI (OR 2.4, 95%                        Dexamethasone                                                58
confidence interval [CI] 1.1-5.3, exact P = .029) and a               5-HT3 antagonist                                               4.7
                                                                      Droperidol/Haloperidol                                       16
trend to increased mortality (OR 7.3, 95% CI 0.80-50,                 Other
exact P = .07).                                                   Major regional block                                             26
                                                                  Bispectral index monitoring                                      51
Statistical methods
  All patients who are randomly allocated to study drug           the true incidence of cardiac events and death in this
administration will be considered as comprising the               population and will provide important information for
intention-to-treat population for all primary, secondary,         future patients and their families, as well as for govern-
and safety analyses. Baseline characteristics of the 2            ment and other health care agencies. The relative clinical
treatment groups will be tabulated using appropriate              importance can be determined (impact on daily living,
summary statistics.                                               social activities, requirement for rehospitalization, long-
  Stratification will be by center, but not other factors as      term disability). In addition, the most important risk
these are likely to be balanced in this large trial. Intention-   factors for serious postoperative complications can be
to-treat analyses will be undertaken. The cumulative              identified. Thus, the database will be examined using a
incidence of the combined end point will be analyzed              variety of exploratory regression techniques to address
using Fisher exact test, with covariate adjustment                each of these issues.
performed by logistic regression. Results will be                    We also plan to conduct an exploratory analysis for
expressed with risk ratios and exact 95% CIs. Other               cointerventions believed to reduce perioperative cardiac
secondary end points will be compared with Cox                    events. There are several interventions believed to reduce
proportional hazards and Wilcoxon rank sum tests.                 perioperative cardiac events in surgical patients with
  Two interim analyses are planned for the ENIGMA-II              known or suspected coronary artery disease,3,5 but all
Trial. These will be performed after enrolment of 3,000           have been based on small trials or meta-analysis of small
and 5,000 patients, that is, at 43% and 71% of the target         trials. We plan to use propensity scores and logistic
recruitment number of 7,000. The study statistician (A. F.)       regression analysis to investigate the following factors:
will perform the interim analyses, and the results will           perioperative β-blockade,5,6 perioperative statin thera-
discussed by the Data Safety and Monitoring Committee             py,25 intraoperative hypothermia,26 spinal or epidural
(DSMC), according to an agreed charter. The interim               local analgesic block,27,28 and perioperative calcium
analysis will be adjusted according to an O'Brien and             antagonists,29 with corresponding null hypotheses that
Fleming Type I error spending function, using a                   none of these factors are associated with the incidence of
combined P value b.05.                                            postoperative cardiac events in surgical patients with
                                                                  elevated cardiovascular risk.
Planned substudies
  ENIGMA-II will support a cohort study of the incidence,
clinical importance, risk factors, and economic costs of          Data safety and monitoring committee
cardiac events and mortality in patients undergoing                 The DSMC consists of a clinical epidemiologist (Chair),
anesthesia for major surgery. This will provide a unique          anesthesiologist independent statistician, and a clinical
opportunity to collect extensive and accurate data on             pharmacologist. The DSMC will discuss the interim
7,000 surgical patients with known or suspected cor-              results and vote for continuation or stopping the trial.
onary artery disease. This will allow reliable estimation of      This will be communicated to the Steering Committee
American Heart Journal
494 Myles et al                                                                                                                                   March 2009

according to a stopping rule of P b .001 for the primary                          10. Amos RJ, Amess JA, Hinds CJ, et al. Incidence and pathogenesis of
study end point and consideration of other evidence                                   acute megaloblastic bone marrow change in patients receiving
relevant to the recommendation of the DSMC. The                                       intensive care. Lancet 1982;2:835-8.
                                                                                  11. Badner NH, Beattie WS, Freeman D, et al. Nitrous oxide-induced
conduct of the DSMC is to be guided by the paper by
                                                                                      elevated homocysteine concentrations are associated with increased
DeMets et al.30
                                                                                      myocardial ischemia in patients undergoing carotid endarterectomy.
                                                                                      Anesth Analg 2000;91:1073-9.
Current status of the trial                                                       12. Myles PS, Chan MTV, Leslie K, et al. Effect of nitrous oxide on plasma
                                                                                      homocysteine and folate in patients undergoing major surgery. Br J
   ENIGMA-II is currently recruiting patients in 23 centers
                                                                                      Anaesth 2008;100:780-6.
within 5 countries and has randomized 1,258 patients as                           13. Myles PS, Chan MTV, Kaye DM, et al. Effect of nitrous oxide
of November 2008. Tables II and III report on character-                              anesthesia on plasma homocysteine and endothelial function.
istics of the first 929 patients enrolled in the trial. These                         Anesthesiology 2008;109:657-63.
data demonstrate a cohort of patients at increased risk of                        14. Hynes MD. Catecholamine mechanisms in the stimulation of mouse
cardiovascular events after surgery.                                                  locomotor activity by nitrous oxide and morphine. Eur J Pharmacol
                                                                                  15. Myles PS, Leslie K, Chan MTV, et al. Avoidance of nitrous oxide for
Conclusion                                                                            patients undergoing major surgery: a randomized controlled trial.
                                                                                      Anesthesiology 2007;107:221-31.
   Exposure to nitrous oxide impairs methionine
                                                                                  16. Ermens AA, Refsum H, Rupreht J, et al. Monitoring cobalamin
synthase, folate and DNA production, and increases
                                                                                      inactivation during nitrous oxide anesthesia by determination of
homocysteine levels. These adverse effects are likely to                              homocysteine and folate in plasma and urine. Clin Pharmacol Ther
be enhanced in at-risk patients; we will thus focus our                               1991;49:385-93.
trial on patients with coronary artery disease and those                          17. Mayer EL, Jacobsen DW, Robinson K. Homocysteine and coronary
with risk factors for coronary artery disease. When                                   atherosclerosis. J Am Coll Cardiol 1996;27:517-27.
considering the widespread use of nitrous oxide around                            18. Bellamy MF, McDowell IF, Ramsey MW, et al. Hyperhomocysteine-
the world, small differences in outcome would have                                    mia after an oral methionine load acutely impairs endothelial function
major implications for surgical practice.                                             in healthy adults. Circulation 1998;98:1848-52.
                                                                                  19. Chambers JC, McGregor A, Jean-Marie J, et al. Demonstration of rapid
                                                                                      onset vascular endothelial dysfunction after hyperhomocysteinemia: an
                                                                                      effect reversible with vitamin C therapy. Circulation 1999;99:1156-60.
Disclosures                                                                       20. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular
  None of the authors has declared any conflict of                                    disease: evidence on causality from a meta-analysis. BMJ 2002;325:
interest.                                                                             1202-9.
                                                                                  21. Fleischmann E, Lenhardt R, Kurz A, et al. Nitrous oxide and risk of
                                                                                      surgical wound infection: a randomised trial. Lancet 2005;366:1101-7.
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American Heart Journal
494.e1 Myles et al                                                                                        March 2009

Appendix A. ENIGMA-II trial                                  End Point Adjudication Committee: James W.
                                                           Tomlinson, David R. McIlroy, Neal Badner
organization and Committees                                  Clinical Pharmacologist: Henry Krum
  Sponsor: Alfred Hospital, Melbourne, Australia             Statistician: Andrew Forbes
  Funding sources: Australian National Health and            Data and Safety Monitoring Committee: Konrad
Medical Research Council (NHMRC) project grant             Jamrozik (Chair), John Rigg, Henry Krum; Independent
ID 436677                                                  Statistician, Philip Ryan
  Steering Committee: Paul Myles (Chair and Principal        Data Management and Quality Control: Sophia Wallace,
Investigator), Kate Leslie, Phil Peyton, Mike Peach,       Adam Meehan
Brendan Silbert, Philip J Devereaux, Dan Sessler, Andrew     Website Design and Maintenance: Adam Meehan
Forbes, Scott Beattie; Research Manager, Sophia Wallace
  Chief and Associate Investigators: Paul Myles, Kate
Leslie, Phil Peyton, Mike Peach, Brendan Silbert,
Philip J. Devereaux, Dan Sessler, Andrew Forbes
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