Nitrous oxide and perioperative cardiac morbidity (ENIGMA-II) Trial: Rationale and design
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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 m Melbourne, Victoria, Australia, bAcademic Board of Anaesthesia and Perioperative Practice, University of Adelaide, SA, Australia, Department of Anaesthesia, University n 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. d Australian National Health and Medical Research Council Centre for Clinical Research Trial Registration: www.clinicaltrials.gov 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. f 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. h Department of Anaesthesia, Prince of Wales Hospital, The Chinese University of Hong E-mail: firstname.lastname@example.org 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 Variable 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 (www.enigma2.org.au). 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 Neurosurgery 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. 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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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