Patients Prone to Recurrence after Endovascular Treatment: Periprocedural Results of the PRET Randomized Trial on Large and Recurrent Aneurysms

Randomization

Randomized allocation was through the Web-based PRET application package (designed by MediSciNet, Stockholm, Sweden), ensuring that allocation was concealed before the decision to include a patient. From the moment of randomization, the patient was in the trial and accounted for in the analysis (intention-to-treat). PRET-1 and PRET-2 patient groups were randomized separately; treatment groups were matched according to the following minimization criteria: rupture status (yes, no); if the aneurysm was unruptured, planned use of an adjunct device (yes, no).

Embolization Procedure

Endovascular operators were not blinded to treatment allocation. Patients were masked to allocation unless they specifically requested otherwise. Standard local procedures were followed. Any locally approved bare platinum coil with controlled detachment was permitted, as were any assist devices believed necessary by the operator, provided they had local regulatory approval, excluding flow diverters, irrespective of intended use indicated at randomization. Antiplatelet and anticoagulation regimens were left to individual operator judgment, according to the clinical practice at each site.

When treatment allocation was to “platinum,” types of coils other than bare platinum were forbidden. When treatment allocation was to “hydrogel,” any coil of the hydrogel family was allowed but any bare platinum coil could also be used if the operator believed it was in the patient's best interest. Recommendations concerning hydrogel coil use pertaining to type, size, and sequence of introduction were issued but not enforced. No minimum percentage of hydrogel coils was prescribed; the protocol required “the substitution, as far as possible, of platinum by hydrogel coils, the operator always being allowed to use the coils he/she believes is appropriate at any time during the procedure.”¹⁴ Other technical considerations such as steaming of hydrogel coils and the type of bare platinum coil were left entirely to the operator's discretion. The goal of the procedure was to occlude the aneurysm as completely as possible, keeping the risks of the procedure as low as possible.¹⁴

Trial Monitoring

Monitoring of trial data quality was Web-based and was performed by periodic review of data stored in the data base. Blinded data were prepared for periodic reviews at prespecified intervals by an independent Data Safety and Monitoring Committee (DSMC) to ensure patient safety. A DSMC Charter predefined all trial-monitoring procedures. Unblinding criteria were prespecified in the DSMC Charter, but the need for unblinding did not arise during the conduct of the trial.

Data Collection

Data capture and management were held independent of the Steering Committee, sponsor, and funder on the secure servers of MedSciNet, ensuring FDA 21 Code of Federal Regulations Part 11, Good Clinical Practice requirements compliance. The Registration form included the following: demographics (age, sex); other aneurysms; subarachnoid hemorrhage; date and World Federation of Neurological Societies grade at the time of randomization if SAH occurred; mRS grade (if no SAH); whether the target aneurysm was a symptomatic, additional or incidental aneurysm; aneurysm location and dimensions (maximum size, length, width, and neck size); and planned use of adjunct devices. The procedure form included the following: the use of adjunct devices (mainly stents; balloon-assistance, virtually in routine use for such difficult aneurysms in many PRET centers; these were not recorded); aneurysm occlusion grade based on the Montreal grading system¹⁶ as judged by the operator; medication used during the procedure; and clinical outcome and complications during treatment (categorized as hemorrhagic, thromboembolic, or other). The total length of each type of coil was also recorded. Because the HydroSoft, HydroFrame, and HydroFill (MicroVention, Tustin, California) were marketed at different times in July 2008, April 2011, and April 2012, respectively, after the launch of the PRET trial in June 2007, a single new entry mentioning “hydrogel-core” coils was added to the Case Report Forms in December 2007, to indicate the use of those newer coil types.

The discharge form included dates of admission and discharge, discharge destination (home, hospital, rehabilitation center), whether the patient was discharged with a prescription for antiplatelet therapy, any imaging performed after the procedure, any new neurologic or imaging changes, whether ventricular shunting was performed during hospitalization, any adverse event, and mRS score at discharge. Follow-up forms (at 1, 6, 12, and 18 months) were all designed on the same pattern, including questions regarding new symptoms (including headaches, fever, or chills), neurologic events, new imaging findings, other treatments, any admission since the last assessment, and the modified Rankin Scale as the clinical outcome measure. Adverse events were reported at any time during the trial, and automatic notification was sent to the study monitor immediately. The present article is limited to procedural results, including events occurring within 30 days of treatment (or more if within the initial admission) as reported in the procedure and discharge forms (n = 444, including 14 patients with no further follow-up), 1-month follow-up (392 patients) form, or later (38 patients). Imaging studies (procedural and follow-ups) were anonymized and sent to the core laboratory (P.W. White, Newcastle University, Newcastle upon Tyne, United Kingdom) for central adjudication, and follow-up angiographic results will be the object of a future publication. The angiographic results given here were the ones reported by local investigators at the end of treatment.

Safety End Points

The protocol hypothesized that “the number of adverse events was similar for both hydrogel and platinum groups, and that morbidity and mortality related to treatment remained unchanged for both PRET-1 and PRET-2 patients.”¹⁴ All adverse events were reviewed by an independent Adverse Event Committee and categorized as the following: 1) related to the illness (SAH for example), 2) related to coil embolization, or 3) unrelated. The protocol also prespecified that morbidity would be defined per patient, according to the mRS score. Adverse events reports and individual case report forms were cross-checked to determine the safety of coil embolization (periprocedure and ≥30 days after if events occurred during the same admission) for each patient, categorized as the following: 1) death or dependency (mRS >2) at 30 days (unrelated to the coiling procedure when no adverse events were reported; related if any serious adverse event was reported), 2) any stroke or neurologic event periprocedure or within 30 days, without dependency (mRS 0–2), 3) any procedural or predischarge complication or adverse event, and 4) uneventful hospitalization and procedure (no complication). Other safety indices are also reported, including procedural complications (sorted as hemorrhagic, thromboembolic, or others), neurologic deteriorations after the procedure or at discharge, mRS at discharge and 1 month, discharge destination, location at 1 month, and length of hospitalization (mean-median number of days and number of patients hospitalized for >5 days for unruptured aneurysms and >15 days for SAH). The number and severity of adverse events are also reported per group. To detect inflammatory complications potentially related to coils, we reviewed all adverse events within 30 days: new imaging findings (when performed and reported); new headaches; fever or chills or cranial nerve deficits up to 30 days after the procedure; and the number of patients in whom ventricular drainage was performed.

Statistical Methods

All analyses were performed by the trial statistician (M.C.), according to the published trial protocol.¹⁴ Analyses were intent-to-treat. Categoric variables were compared by using the Fisher exact test, and continuous variables, by using the Student t test. To evaluate the possibility of different results for PRET-1 and PRET-2, we stratified descriptive and safety analyses by group. All analyses were done with SPSS, Version 21 (IBM, Armonk, New York) by using a significance level of 5%.

Roles of the Sponsor and Funding Source

The trial was sponsored by the Centre Hospitalier de l'Université de Montréal and funded by MicroVention Terumo Incorporated. The sponsor and funder had no part in study design, data collection, analysis, or reporting and had no direct or indirect access to the data or source documents. The Steering Committee bears the sole responsibility for all aspects of the trial.