HD-PCI is a multicenter, randomized, registry-based, open-label, cluster crossover trial of lower-dose (70 units/kg) versus higher-dose (100 units/kg) UFH dosing policy at the hospital level for elective PCI ( Figure 1 ) (ClinicalTrials.gov Identifier NCT04049591). We have reported our trial methodology in accordance with the CONSORT statement for cluster randomized crossover trials where applicable (Table S1).

HD PCI trial flow diagram. Kg , kilograms; U , units; UFH , unfractionated heparin.

The Population Health Research Institute (PHRI) in Hamilton, Ontario, is the coordinating center for the HD-PCI trial. The PHRI was responsible for the randomization process, overseeing the overall trial organization, and coordinating all participating centers. In partnership with the PHRI, ICES (previously known as the Institute for Clinical Evaluative Sciences) in Toronto, Ontario, is responsible for maintaining the registry database, ensuring data consistency, providing statistical expertise, and conducting the analyses. Table S2 denotes the members of the Steering Committee, Coordination Center, and Investigators. The use of ICES data in this study is authorized under Section 45 of Ontario’s Personal Health Information Protection Act.

A grant from the PHRI funded the HD-PCI trial. The coordinating center (PHRI) and the HD-PCI trial steering committee are solely responsible for the design, data analysis, manuscript writing, and decision to submit for publication of this trial. Local institutional review boards approved the study protocol of all participating centers. Given the cluster design and the fact that both study interventions fall within the current standard of care, a waiver of individual consent was obtained from ethics committees in accordance with the criteria proposed by the Tri-Council Policy Statement (TCPS 2). The HD-PCI trial fulfilled TCPS 2 criteria in that: (1) the study posed minimal risk to patients; (2) waiver of consent did not adversely affect patient rights and welfare; (3) it would have been impracticable to carry out the research if prior consent is required; and (4) patients and/or families were systematically provided with information about the study using an information brochure in the waiting areas and questions were answered by medical personnel as needed. As approved by ethics, no patient-level opt-out mechanism was implemented, as both heparin dosing policies were deemed safe, and no individual patient identifiers were collected. Given the low risk of foreseeable research-attributable harm to participants and the delay in obtaining data to perform an interim analysis (≥ 1 year of lead time to obtain registry data) an independent data safety monitoring board was not deemed necessary or practical after consensus with the executive committee. Given the privacy rules in the province of Ontario that permit this work without consent, the data is coded and cannot be shared.

The inclusion and exclusion criteria are outlined in Table I . In brief, only outpatient, elective patients receiving PCI were included. Hospitals were deemed eligible if located in Ontario, Canada, and PCI and relevant outcome data were submitted to the CorHealth Ontario registry. Participating sites had to agree to manage patients according to the lower or higher dose UFH policy during the given treatment period. Repeat enrollments will be excluded.

While most operators in the 11 hospitals had clinical equipoise and wished to participate, 3 operators opted out before the start of the trial (2 operators from the same center, and 1 operator from another center). Patients who underwent a PCI performed by operators who did not want to participate will be excluded from the analysis. Patients under the age of 18 and patients who underwent chronic total occlusion (CTO) PCI will be excluded. Furthermore, patients undergoing diagnostic catheterization or PCI for a non-ST-elevation myocardial infarction or a ST-elevation myocardial infarction will also be excluded. Non-residents of Ontario, who are excluded from follow-up through the CorHealth Ontario registry, will be automatically excluded from the database.

The central unstratified randomization schedule was generated by the PHRI with clusters as rows and periods as columns. Clusters were randomly assigned to one of 2 treatment strategies across periods using permuted blocks of size 2, and within each period, permuted blocks of size 4 were used to ensure an even distribution across clusters and periods. The first week of the 17-week treatment period was considered a washout period, allowing healthcare professionals to adapt to the policy change, and will not be included in the analysis. The washout period duration was determined after consensus among all site leads. Each center acted as its control, with 4 randomization time points and 4 crossovers, totaling eight 16-week treatment allocation periods, for a total study duration of approximately 2.6 years. Therefore, after the initial randomization, each center was aware of the assigned treatment for that period and the next one.

Treatment periods with lower versus higher doses of UFH were randomized for each cluster, followed by a crossover period before another randomization occurred. The lower-dose UFH policy consisted of a 70 units/kg bolus of intravenous or intra-arterial UFH. In comparison, the higher-dose UFH policy consisted of a 100 units/kg bolus of intravenous or intra-arterial UFH ( Table II ). The choice between intravenous and intra-arterial administration was left to the discretion of the treating physician. UFH dosing was rounded to the nearest thousand. Both policies were to be respected for the assigned treatment period. Visual aids with the relevant dosing charts were placed in the catheterization laboratories during the appropriate treatment period. Patients, healthcare professionals and research personnel were not blinded to the intervention.

We recommended administering UFH at least 1 minute before inserting a guidewire into the coronary arteries. The maximum initial bolus dose should not have exceeded 10,000 units. Patients who received heparin for the initial diagnostic procedure and then underwent ad-hoc procedures received an additional dose of heparin to reach the policy dose before guidewire insertion. In either treatment period, if patients underwent a prolonged procedure, defined as lasting more than 45 minutes since the last UFH administration, operators were allowed to administer additional UFH guided by the ACT, as per standard local practice. We did not recommend a target ACT. Based on operator feedback and steering committee meetings, the time to the first ACT was dropped to 30 minutes on September 21, 2022. Operators were allowed to assess ACT and administer additional UFH at any time if there was a concern for patient safety (i.e., thrombus formation in the vessel or on the equipment) but otherwise had to wait 45 minutes or 30 minutes (as of September 21, 2022) before the first ACT.

Treatment allocation adherence was monitored at each participating hospital for each treatment period. Adherence logs were completed by nurses, medical radiation technologists and research personnel. The logs included the treatment period policy dose, the patient’s weight, the bolus dose, and any additional doses administered after the bolus. Adherence was judged adequate if the initial bolus dose matched the treatment period policy dose.