Trial Design and Oversight

The Norwegian Coronary Stent Trial (NORSTENT) was a multicenter, randomized trial conducted at all eight centers in Norway that perform PCI. The trial protocol is available with the full text of this article at NEJM.org. The trial was funded by the Norwegian Research Council and other not-for-profit organizations. The steering committee designed the study, gathered the data, and made the decision to submit the manuscript for publication. The first and second-to-last author analyzed the data, and the first, third, and last two authors wrote the first draft of the manuscript. All the authors vouch for the accuracy and completeness of the data and the analyses, as well as for the fidelity of this report to the trial protocol. The sponsors had no role in the design of the study, the gathering or analysis of the data, the writing of the manuscript, or the decision to submit the manuscript for publication.

The trial was approved by the Norwegian Regional Committee for Medical and Health Research Ethics–Region North. All the patients provided written informed consent.

Patients

Between September 15, 2008, and February 14, 2011, all the patients undergoing PCI in Norway were evaluated for enrollment. Eligible patients were men and women who were at least 18 years of age and who presented with stable angina or an acute coronary syndrome, had lesions in native coronary arteries or coronary-artery grafts (all of which were amenable for implantation of either drug-eluting stents or bare-metal stents), had a Norwegian national identification number and were able to communicate in Norwegian, and provided informed consent. Patients were excluded if they had previously been treated with a coronary stent, had a bifurcation lesion requiring treatment with a two-stent technique, had a serious medical condition other than coronary artery disease with a life expectancy of less than 5 years, were participating in another randomized trial, had intolerable side effects to any drug in use during PCI or contraindications to long-term dual-antiplatelet therapy or had been prescribed warfarin, or were not able to follow the trial protocol, as judged by the investigator.

Randomization and PCI Procedures

The patients were randomly assigned in a 1:1 ratio to receive drug-eluting stents or bare-metal stents after diagnostic angiography and before PCI. Each patient received as many stents as was judged to be clinically appropriate; the protocol specified that only stents of the randomly assigned type be placed in any patient. The assignment schedule was based on computer-generated random numbers. Randomization was performed in blocks of 8 to 20 patients, with stratification according to center.

Coronary stents for use in the trial were commercially available and in routine use in Norway during the trial period. All stents were purchased by the participating hospitals, and reimbursement was the same as for patients not enrolled in the trial. Patients, operators, and clinicians providing clinical care were aware of the types of stents that were being placed.

PCI was performed according to standard techniques at the discretion of each operator. The same type of stent (on the basis of the randomized assignment) was to be used in patients with multiple lesions and in staged procedures. All the patients in the two groups were prescribed aspirin at a daily dose of 75 mg indefinitely and clopidogrel at a daily dose of 75 mg for 9 months after the procedure regardless of the randomized assignment or the indication for PCI. Drugs for secondary prevention were prescribed according to current guidelines. Operators were encouraged to use the assigned type of stent if PCI was repeated during follow-up. Restenosis could be treated by means of balloon dilation, a cutting balloon, drug-eluting stents, or a combination of those methods at the discretion of the operator.

Follow-up and Outcomes

Clinical follow-up of the patients was performed according to routine practice at the participating centers. There were no per-protocol follow-up visits, and no routine follow-up coronary angiography was performed. A quality-of-life questionnaire was administered to a representative sample of 941 patients (10%) at baseline and was mailed to all the patients at 6, 12, 24, 36, 48, and 60 months.

The primary outcome was a composite of death from any cause and nonfatal spontaneous myocardial infarction at a median follow-up of 5 years, as specified in an amendment to the protocol made by the steering committee in May 2012. Secondary outcomes were subcategories of death; fatal and nonfatal spontaneous and periprocedural myocardial infarction and stroke; hospitalization for unstable angina pectoris; revascularization of a target lesion, target vessel, or nontarget vessel with PCI or coronary-artery bypass grafting (CABG); definite stent thrombosis; major bleeding episodes; and health-related quality of life.

The manual for definitions and classifications of outcomes is provided in the Supplementary Appendix, available at NEJM.org. Definite stent thrombosis was defined according to the Academic Research Consortium criteria.18 Bleeding was defined according to the Bleeding Academic Research Consortium (BARC) criteria.19

Outcome events were collected by means of electronic linkage to the Norwegian Patient Registry through December 31, 2014, with the use of a unique 11-digit Norwegian national identification number for each patient. The patient registry includes the codes of the International Classification of Diseases, 10th Revision (ICD-10), with respect to all the main diagnoses and up to 20 secondary diagnoses and all procedure codes from all hospitalizations in Norway. A broad search was performed to identify any hospitalization for cardiovascular disease with or without coronary angiography, PCI, or CABG and any hospitalization for suspected bleeding. Search criteria are provided in the Supplementary Appendix. Copies of discharge letters and medical-record notes from all hospitalizations that were identified by the electronic search were then obtained from the hospitals. The date and cause of death were obtained by linkage to the Norwegian Causes of Death Registry.

All outcomes were adjudicated by members of an end-points committee of clinical and interventional cardiologists and an epidemiologist who were unaware of the patients’ treatment assignments. The methods used for blinding are described in the Supplementary Appendix. All outcomes were assessed by at least two members of the end-points committee. In cases of disagreement, consensus was obtained. A few angiograms were reassessed by local investigators because the medical records were incomplete.

Disease-specific health status and quality of life were assessed by means of a validated Norwegian translation of the Seattle Angina Questionnaire, a 19-item survey that measures five domains of health status related to coronary artery disease: physical limitations, angina stability, angina frequency, treatment satisfaction, and quality of life.20,21 Each domain produces a summary score ranging from 0 to 100, with higher scores indicating fewer symptoms and better health status.

Statistical Analysis

For the calculation of sample size, we assumed that the 5-year incidence of the primary outcome would be 17%. The planned enrollment of 8000 patients, with a median follow-up time of 5 years, was expected to provide a statistical power of 93% to detect an absolute between-group difference in the incidence rate of the primary outcome of 3 percentage points (rate ratio, 1.18) and a power of 65% to detect a difference of 2 percentage points (rate ratio, 1.12), given a two-sided alpha value of 0.05. An independent data and safety monitoring board reviewed the data after one interim analysis, with formal stopping rules, as described in the study protocol. Because mortality in the study group as a whole was lower than expected, in March 2010 the steering committee decided to increase enrollment to 9000 patients and to follow all the patients until December 31, 2014.

Differences in baseline characteristics between the groups were tested with the independent-samples t-test for continuous variables, with the Pearson chi-square test for independent-observations binary variables, and with generalized estimating equations with the logit functions for binary variables that had repeated observations within some patients. Outcome analyses were performed according to the intention-to-treat principle with the use of time-to-event methods. In analyses of each outcome, follow-up continued until the occurrence of a trial outcome, emigration, or death or until December 31, 2014. Estimates of hazard ratios and 95% confidence intervals were obtained with the use of Cox proportional-hazards models and were adjusted for the trial center. Hazard ratios comparing drug-eluting stents with bare-metal stents were also assessed in subgroups. Possible differences in hazard ratios between subgroups were assessed by including cross-product terms between the intervention-group variable and indicator variables of subgroups and tested with likelihood-ratio tests. Kaplan–Meier survival analysis was used to compare the survival distributions between the two groups. The cumulative failure rate was estimated as one minus the Kaplan–Meier survivor function at 6 years of follow-up. Linear mixed models were used to estimate time-point–specific marginal mean scores on the Seattle Angina Questionnaire and to test for group differences. The reported P values are two-sided and have not been adjusted for multiple comparisons. P values of less than 0.05 were considered to indicate statistical significance.

The trial was registered at ClinicalTrials.gov on December 18, 2008. Owing to investigator oversight, 369 of the 9013 participating patients were enrolled between September 15, 2008, and the date of registration at ClinicalTrials.gov.