Trial Design and Oversight
This open-label, randomized, controlled, parallel-group trial was performed at 12 centers across Scotland. The trial, which has been described previously,9,10,13 was conducted with the approval of the South East Scotland Research Ethics Committee. The protocol, available with the full text of this article at NEJM.org, was designed by the grant applicants with input from the trial steering committee (see the Supplementary Appendix, available at NEJM.org).
The funders had no role in the design or conduct of the trial or in the collection, analysis, or reporting of data. The steering committee vouches for the accuracy and completeness of the data and the analyses and for the fidelity of the trial to the protocol.
Patient Population and Randomization
Patients 18 to 75 years of age who had stable chest pain and who had been referred by a primary care physician to an outpatient cardiology clinic were eligible for inclusion.9,10,13 Exclusion criteria are listed in the Supplementary Appendix. All participants provided written informed consent.
All patients underwent a routine clinical evaluation, including, if deemed appropriate, symptom-limited exercise electrocardiography. The symptoms, diagnosis, further investigations (stress imaging or invasive coronary angiography), and treatment strategy were documented at the end of the clinic visit, before recruitment or randomization. Patients were then randomly assigned in a 1:1 ratio to standard care plus CTA or to standard care alone; randomization was performed with the use of a Web-based system to ensure concealment of group assignment. The randomization incorporated the use of minimization to balance age, sex, body-mass index, diabetes mellitus, history of coronary heart disease, and atrial fibrillation.
Subsequent Investigations and Treatments
Management of the patient’s condition in the light of all available information was at the discretion of the attending clinician. Physicians caring for patients in the CTA group were prompted to consider the results of the CTA in their management decisions, and physicians caring for patients in the standard-care group were prompted to consider a prespecified cardiovascular risk score (the ASSIGN score, which ranges from 1 to 99, with higher scores indicating a higher risk of cardiovascular disease14) in their management decisions (additional details are provided in the Supplementary Appendix). Specifically, when there was evidence of nonobstructive (10 to 70% cross-sectional luminal stenosis) or obstructive coronary artery disease on the CTA, or when a patient had an ASSIGN score of 20 or higher, the attending clinician and primary care physician were prompted by the trial coordinating center to prescribe preventive therapies (e.g., aspirin and a statin).13
There were no trial-specific visits, and all follow-up information was obtained from data collected routinely by the Information and Statistics Division and the electronic Data Research and Innovation Service of the National Health Service (NHS) Scotland, as described previously.9,10 (Additional information is provided in the Supplementary Appendix.) The inpatient and day-case national data set contains episode-level data from all hospitals in Scotland, for events that occurred in Scotland or that occurred outside Scotland but resulted in a transfer to a hospital in Scotland. These data include diagnostic codes from discharge records, which were classified according to the International Classification of Diseases, 10th Revision, and procedural codes from the Classification of Interventions and Procedures of the Office of Population Censuses and Surveys, as described previously.9,10,15-17
Clinical End Points
The clinical end points that were assessed included death (cardiovascular death, noncardiovascular death, death from coronary heart disease, and death from any cause), myocardial infarction, and stroke. The primary end point was death from coronary heart disease or nonfatal myocardial infarction. There was no formal event adjudication, and end points were classified primarily on the basis of diagnostic codes. However, in cases of uncertainty, events and causes of death were categorized by two of the authors, who were unaware of the trial assignments.9
Process-of-Care End Points
Rates of invasive coronary angiography and coronary revascularization (including percutaneous coronary intervention and coronary-artery bypass grafting) were obtained from records of inpatient and day-case episodes and were cross-checked by review of individual coronary angiograms within the national Picture Archiving and Communications Systems.9,10 Documentation of patients’ medications was obtained from the Scottish National Prescribing Information System of the Information and Statistics Division of NHS Scotland (see the Supplementary Appendix).10
The original primary end point of the trial was the proportion of patients who received a diagnosis of angina pectoris caused by coronary heart disease at 6 weeks.9 However, because we acknowledged the potential long-term clinical consequences of a change in diagnosis, our prespecified primary long-term end point was the proportion of patients who died from coronary heart disease or had a nonfatal myocardial infarction at 5 years.13 On the basis of an estimated 5-year event rate of 13.1%, we hypothesized that the trial would have 80% power to detect a rate of the primary long-term end point that was 2.8 percentage points lower in the CTA group than in the standard-care group. A two-sided P value of less than 0.05 was considered to indicate statistical significance.13
All analyses were performed according to the intention-to-treat principle. Missing data were removed from the analyses, except for data on deaths, which were censored at the time the patient was lost from the trial. End points were analyzed with the use of Cox regression models, adjusted for center and minimization variables, and cumulative event curves were constructed. We also performed a post hoc 12-month landmark analysis, since we reasoned that any changes in the use of invasive coronary angiography and the incidence of coronary revascularization that were driven by the results of CTA should have been observed by this time point.
Data are reported as means and standard deviations, medians and interquartile ranges, and hazard ratios or odds ratios with 95% confidence intervals, as appropriate. Because there was no adjustment for multiplicity in the analysis of secondary end points, results are reported as point estimates and 95% confidence intervals. The confidence intervals have not been adjusted for multiplicity, so intervals should not be used to infer definitive treatment effects. All analyses were performed with the use of R software, version 3.4.3 (R Foundation for Statistical Computing). Anonymized data and R code used in the statistical analysis will be made available on request.