Trial Design

The Determination of the Role of Oxygen in Suspected Acute Myocardial Infarction (DETO2X-AMI) trial was a multicenter, parallel-group, open-label, registry-based, randomized, controlled trial in which routine supplemental oxygen therapy was compared with ambient air in the treatment of patients with suspected myocardial infarction who did not have hypoxemia at baseline. The trial used the national comprehensive Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) (see the Supplementary Appendix, available with the full text of this article at NEJM.org)11 for patient enrollment and data collection.

The trial design and methods have been described and published previously.12 Approval of the protocol was obtained from the regional ethics review board in Gothenburg and the Swedish Medical Products Agency. The trial sponsor was the Karolinska Institutet. Trial and data management, monitoring, and statistical analyses were performed at the Uppsala Clinical Research Center at Uppsala University. The trial was conducted and the manuscript written by the authors (details are provided in the Supplementary Appendix), who decided to submit the manuscript for publication. The authors vouch for the accuracy and completeness of the data and all analyses and for the fidelity of the trial to the protocol and statistical analysis plan, which are available at NEJM.org. The funding agencies had no access to the trial data and no role in the trial design, implementation, or reporting. No sponsorship or funding from industry or for-profit sources was received for the trial.

Patients

Patients who presented to the ambulance services, emergency departments, coronary care units, or catheterization laboratories of participating hospitals were evaluated for eligibility. Trial participants were required to be 30 years of age or older and to have symptoms suggestive of myocardial infarction (defined as chest pain or shortness of breath) for less than 6 hours, an oxygen saturation of 90% or higher on pulse oximetry, and either electrocardiographic changes indicating ischemia13 or elevated cardiac troponin T or I levels on admission (i.e., above the locally defined decision limit for the identification of myocardial infarction). To allow complete follow-up through the Swedish National Population Registry, only Swedish citizens who had a unique personal identification number were enrolled.

Patients who were receiving ongoing oxygen therapy, as well as those who presented with a cardiac arrest or had a cardiac arrest between presentation and enrollment (for whom high-flow oxygen therapy would normally be provided), were excluded. If supplemental oxygen therapy had been administered for less than 20 minutes before evaluation for enrollment, a new evaluation was allowed after discontinuation of oxygen delivery and 10 minutes of washout.

Trial Procedures

Patients who met all inclusion criteria and no exclusion criteria were asked to provide oral consent followed by written confirmation within 24 hours, as described in the Supplementary Appendix. After oral consent was obtained, patients were randomly assigned to receive either oxygen therapy (at 6 liters per minute for 6 to 12 hours delivered through an open face mask) or ambient air. Unrestricted 1:1 randomization following a computer-generated list was performed with the use of an online randomization module embedded in SWEDEHEART. For patients in the oxygen group, oxygen therapy was initiated directly on site immediately after randomization.

Any treatment outside the trial protocol was left to the discretion of the treating physician. Oxygen saturation was documented at the beginning and at the end of the treatment period. If it was deemed clinically necessary, particularly in cases of hypoxemia (defined as an oxygen saturation <90%) caused by circulatory or respiratory failure, supplemental oxygen outside the protocol was provided, which was reported separately.

End Points and Follow-up

The primary end point was death from any cause within 365 days after randomization, assessed in the intention-to-treat population. Secondary end points included death from any cause within 30 days after randomization, rehospitalization with myocardial infarction, rehospitalization with heart failure, and cardiovascular death (as described in the Supplementary Appendix), as well as composites of these end points, assessed at 30 days and 365 days.

Analyses of death, rehospitalization with myocardial infarction, and the composite of death or rehospitalization with myocardial infarction are included in this report. Data on the end points of rehospitalization with heart failure and cardiovascular death are not available from SWEDEHEART and must be obtained from the Swedish National Inpatient and Outpatient Registries. Owing to a delay of up to 12 months from the date of database lock for the Swedish National Board of Health and Welfare to make these data available, analyses of these end points are not included in this report.

Mortality data were obtained from the Swedish National Population Registry, which includes the vital status of all Swedish citizens. All other variables were obtained from SWEDEHEART, which is monitored on a regular basis.11 Diagnoses at discharge are listed according to codes from the International Classification of Diseases, 10th Revision (ICD-10).

The end of follow-up was December 30, 2016, which was 365 days after the last patient underwent randomization. To allow for any lag in registry reporting, the final database was extracted from SWEDEHEART on February 28, 2017, including data on any linked deaths that occurred through December 30, 2016, and reported in the population registry as of February 14, 2017. Five patients who were never included in SWEDEHEART were followed up manually for data on mortality by the investigators in January 2017. No central adjudication or trial-specific patient follow-up was performed.

Through restriction of access to the randomization list to authorized SWEDEHEART personnel, the trial team and steering committee were kept unaware of the study-group assignments until the locking of the database. Accumulated data without study-group information were available for the monitoring of progress throughout the trial.

Statistical Analysis

The sample size was calculated from published data14,15 and analyses from SWEDEHEART for the years 2005 through 2010. The 1-year total mortality among patients with myocardial infarction was estimated to be 14.4%. A clinically relevant effect of supplemental oxygen was defined as a 20% lower relative risk of death from any cause within 1 year in the oxygen group than in the ambient-air group. With the chi-square test, to be able to reject the null hypothesis at a significance level of 0.05 (two-sided) with a power of 0.90, a total of 2856 patients per group were needed. To control for patients crossing over or not completing the trial, the planned sample size was increased to 3300 patients per group, which resulted in a total of 6600 patients.

The results were analyzed according to the intention-to-treat principle.16 Randomization numbers assigned unintentionally, such as by clicking the wrong box or randomly assigning the wrong patient record in SWEDEHEART, were recorded in the clean file documentation and removed from the analysis database. A supplementary per-protocol analysis was conducted in which patients were excluded if they were reported as having not completed participation in the trial through the end of the treatment period, unless the noncompletion was due to hypoxemia.

The time-to-event analysis of death from any cause within 365 days after randomization is presented as Kaplan–Meier curves. Hazard ratios were calculated with the use of a Cox proportional-hazards model, with adjustment for age in years (as a linear covariate on the log-hazard scale) and sex.17 Estimates of differences between the study groups are presented with two-tailed 95% confidence intervals and associated P values. A two-tailed P value of less than 0.05 was considered to indicate statistical significance. Eleven prespecified subgroup analyses (as defined in the Supplementary Appendix) were performed with the use of proportional-hazards models with adjustment for age and sex and formal tests for interaction. All analyses were conducted with SAS software, version 9.4 (SAS Institute).