PCI vs. CABG in the Treatment of Unprotected Left Main Stenosis

Design:

Randomised open multicentre trial.

Patients:

Number 1,200

Randomisation:

PCI with DES vs CABG

Individuals for inclusion will be recruited among the patients referred to the participating centers for LMCA treatment. The patients will not be recruited by advertising and will receive no honorarium for participation.

Primary and secondary endpoints will be assessed by an independent endpoint committee (IEC). The endpoint committee will consist of experienced cardiac surgeons and cardiologists.

Follow-up All patients will be seen at the outpatient clinic of the participating centers after one month and after 1, 2 ,3 ,4 and 5 years. The outpatient visit may be substituted with a telephone contact and subsequent investigation and documentation of possible study events (MACCE). Finally, there will be a 10-year registry assessment of total mortality.

The index angiograms will be assessed by the QCA-laboratories at the Department of Cardiology, Aarhus University Hospital, Skejby, Denmark. The left main lesion and the non-left main lesions will be described and classified and a SYNTAX SCORE calculated.

The angiography obtained during the PCI-procedure will be used as index angiography. There should be at least two cine-runs before the procedure and after the procedure with the same angulations and proceeded by 0.1 mg intracoronary nitroglycerine (documented on the angiogram). The diagnostic/guiding catheter should be well visible, near the center of the angiogram and filled with dye. The index lesion should be well visible, near the centre of the angiogram and shown without foreshortening. There should be an angulation difference between the two baseline angiograms of at least 30 degrees. Between the pre and post angiograms all balloon inflations and stent implantations should be documented by short cine-runs.

Statistics and data management:

The statistical analyses will be performed at the Department of Clinical Epidemiology, Aarhus University Hospital.

Analysis population:

The results will be analyzed according to the intention-to-treat principle, i.e. patients randomized to a certain group will be followed and assessed irrespectively of the actual treatment. Protocol violations will be noted and the responsible centers notified.

Sample size calculations:

Primary endpoint of 2-year MACCE Sample size calculation is based on the combined primary endpoint of death, stroke, non-index treatment related MI and new revascularization (PCI or CABG) after 2 years.

The study is planned as a non-inferiority study, where an experimental treatment of a disease (E, here PCI) is compared to a standard treatment (S, here CABG). E is not allowed to be more than clinically insignificantly inferior to S to be declared non-inferior. Calculations are based on the following:

• mean follow-up time 24 months
• all event curves are exponential
• zero dropout
• randomization into 2 equally sized groups
• α = 0.05 (one-sided)
• 1- β (power) = 80% The non-inferiority limit is based on a 12 months MACCE rate of 12% in the CABG and 16% in the PCI group (the SYNTAX study). With exponential event curves (S(t)=exp(-λ*t)) this corresponds to a hazard ratio of 1.36, PCI versus CABG, and, with t in months, λ=0.0107 in the CABG group. In continuation if this, the present study uses hazard ratio 1.35, E versus S, as limit for non-inferiority, and λ=0.011 to describe MACCE in the CABG group. These figures correspond to a 24-month MACCE rate of 30% and 23% in the PCI and CABG group, respectively.

The above preconditions and assumptions result in a necessary number of patients in each randomization group of 593 (and a total number of events - in both groups - of 275). Consequently, 1,186 patients should be randomized.

By including 600 patients in each group, possible dropouts before follow-up and treatment estimation errors are accounted for.

Data management The study is reported to Danish Data Protection Agency, and the agency's guidelines for data management will be followed. Dedicated case record forms will be used and faxed to PCI research, Cardiac Cath. Lab., Aarhus University Hospital, Skejby, 8200 Aarhus N, Denmark. Data will be stored in an Access database and double data entry will be used as quality control. There will be a log of accesses and attempt of accesses. Back-up data and original data will be encrypted.

Monitoring of the study:

The study will be monitored according to the GCP rules by independent professionals. During the study period, monitors will have regular contact to the participating departments to ensure that the trial is conducted in compliance with the protocol, GCP and applicable regulatory requirements.

The monitors will ensure that the used products are all right and will review source documents for verification of consistency with the data recorded in the CRFs. The monitors will also provide information and support to the investigator(s).

Investigators and other responsible personnel must be available during the monitoring visits, audits and inspections and should devote sufficient time to these processes.

The investigator should provide a CV or equivalent documentation of suitability to be responsible for the trial. All investigators and other responsible personnel should be listed together with their function in the trial on the signature list.

Publication:

Results, positive as well as negative, will be published in an international cardiovascular journal. Publication and author issues will be decided by the steering committee on basis of general involvement in the study (drafting of protocol, core lab. function, endpoint committee membership, etc.) and on number of included patients. Thus, the sequence of authors will be determined by the inclusions rates of the participating centres and the most including centre will be offered the position as first author.