Fluoroscopy with MRA fusion image guidance in endovascular iliac artery interventions: study protocol for a randomized controlled trial (3DMR-Iliac-roadmapping study)

The hypothesis of this trial is that the use of the 3D image fusion technique will result in a significant reduction of the amount of administered iodinated contrast agent during endovascular iliac artery interventions compared with the endovascular iliac artery procedures without the use of the 3D image fusion technique.

This is a prospective randomized, controlled, multicenter trial. The flow diagram of the trial is shown in Fig. 2. The SPIRIT figure can be found in Fig. 3 and the checklist is available in Additional file 1.

The primary endpoint is the amount of administered iodinated contrast agent (mL). The intra-arterial iodinated contrast agents Ultravist (300 mg/mL; Bayer Vital, Leverkusen, Germany) and Xenetix (300 mg/mL; Guerbet, Roissy, France) will be used during all interventions of the Maastricht University Medical Center (MUMC) and St. Antonius Hospital (SAH), respectively.

Secondary endpoints are the following:

The study cohort will comprise 106 patients (> 18 years) with symptomatic common iliac artery (CIA) and/or external iliac artery (EIA) stenoses or occlusions and Rutherford category 1–6, a recent (< 6 months) diagnostic MRA from the pelvis through the lower extremities, and an indication of endovascular intervention (PTA or recanalization). Participants will be randomized 1:1 to the control or study group (i.e. standard PTA or recanalization with or without the 3D image fusion technique). Patients will be included from the MUMC and SAH. Inclusion and exclusion criteria are summarized in Table 1.

Randomization will be performed by the investigators with the use of an automated web-based randomization and electronic data capture software (MACRO 4.6.0, https://​ecrf.​ctcm.​nl/​macro). Randomization will be performed according to minimization; for a difference of 2 between the two groups (control and study group), there is a 90% chance that the next individual will be allocated to the group with the smallest number of patients. Stratification factors are the site (MUMC or SAH), weight (≤ 90 or > 90 kg), and estimated glomerular filtration rate (eGFR) (≤ 60 or > 60 mL/min/1.73m²). It is expected that the site, weight and eGFR have the biggest impact on the outcome measures. First, the groups should be similar regarding renal function because this may affect outcome. It can be argued that in patients with a reduced renal function, physicians are more careful with the amount of administered contrast. Thus, by using the eGFR as a stratification factor, this bias will be minimized. Second, the radiation dose is taken into account, which is dependent on the patients’ weight. Therefore, stratification on weight is important. Third, it is not preferable to have one of the sites primarily performing the interventions with the 3D fusion technique and vice versa, since that would influence the user experience and is possibly also be related to the amount of contrast volume that is administered and the radiation dose that is used. Hence, these stratification factors were chosen to keep the distribution between the groups equal. Owing to the nature of the study, randomization will not be blinded for patients or physicians.

The study will be conducted in accordance with the principles of the Declaration of Helsinki and the Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch Wetenschappelijk Onderzoek met Mensen). The local medical ethical committees of both hospitals have approved the study protocol (NL47680.068.14, version 1.4). The study protocol was registered at the Netherlands Trial Register at www.​trialregister.​nl on 16 December 2014 (registration number: NTR5008). All patients will give written informed consent before study inclusion and randomization. Patient participation is voluntary; the participant can request to stop participation to the study at any time.

The sample size was calculated using a two-tailed t-test with null hypothesis E(D) = 0 (no difference between the groups) and alternative hypothesis E(D) ≠ 0 (groups are different). A type I error (α) of 0.05 with z-value Z_α ≈ 1.96 was accepted resulting inwith N the sample size and σ_D the expected standard deviation. When assuming the alternative hypothesis is true E(D) = τ the power (π(τ)) can be calculated bywith Φ being the Phi coefficient. When accepting a power of at least 0.90, the alternative hypothesis for E(D) = τ can be estimated by

Alternatively, this can be written with as

For a type II error of 0.1, the z-value (Z_β) becomes approximately 1.28

Given that half of the proportion of the study patients is randomized into the control group (q₀ = 0.5) and the other half in the study group (q₁ = 1 − q₀ = 0.5), the sample size (N) can then be estimated by

Based on earlier research [9], we expect that τ = 20 mL of administered contrast volume may be reduced with the use of the 3D image fusion technique by reducing the number of contrast runs by at least two. Full-strength iodinated contrast is diluted 50:50 with a normal saline solution because a lower concentration of iodinated contrast agent has been shown not to compromise image quality during DSA of PAD patients [10]. To achieve a reduction of 20 mL per procedure with a mean volume of 60 mL and corresponding standard deviation of σ_D = 30 mL, the sample size N becomes a total of 96 patients. Therefore, 48 patients will be needed in each group. Adjusting for an anticipated loss to follow-up of 10%, the total sample size will be 106 patients. An interim analysis will be performed halfway through, after inclusion of the first 40 patients, to assess the efficacy of the 3D fusion technique compared to the control group.

Normal distribution of the data will be tested. Normally distributed data will be represented as the mean and 95% confidence interval; non-normally distributed data will be represented as the median and interquartile range. Continuous variables will be analyzed with the independent samples t-test or Mann–Whitney U test for normally and non-normally distributed data, respectively. Categorical data will be analyzed with the χ² test. All tests will be two-sided and considered significant when P < 0.05.

The aim of the endovascular treatment is to obtain a patent CIA and/or EIA (i.e. < 30% residual stenosis or a reduction of the mean pressure gradient to < 10 mmHg [11]), resulting in an improved blood flow to the legs. In case of a flow limiting dissection, > 30% residual stenosis, or acute elastic recoil after PTA, additional stent placement will be performed. If indicated, other arteries will be treated in addition to the CIA and/or EIA during the same intervention. The physician will choose an ipsilateral or contralateral technique (or rendezvous procedure), depending on the location of the lesion. The analysis will not include data of patients with solely diagnostic DSAs.

Before the start of the intervention, the patient will be placed supine on the angiography table. The contrast pump and table contrast agent will be diluted 50:50 with a normal saline solution. For patients randomized into the study group, a non-contrast-enhanced CBCT will be created at the beginning of the intervention using the flat panel detector of the C-arm angiography system (Allura Xper FD20; Philips Healthcare). The CBCT will be automatically transferred to the 3D XtraVision workstation (Philips Healthcare). Subsequently, a manual 3D-3D registration will be performed between the preprocedural MRA and CBCT based on bony landmarks, such as vertebrae and the femoral heads, and the flow lumen on the MRA will be matched to the border of the calcifications as seen on the CBCT. The time required to perform the registration will be recorded.

After the registration, the physician will visually score the fusion accuracy of the entire iliac vasculature between the overlay and the initial DSA run. This fusion accuracy will be determined directly after the DSA is created and will be categorized as accurate (< 2 mm), mismatch (2–5 mm), or inaccurate (> 5 mm). An overlay that is inaccurate will be manually translated or reregistered to achieve a more accurate overlay that will be used during the intervention. Subsequently, the intervention will be performed according to the standard of care procedure and contrast runs will be performed when needed.

DSAs will be performed with 15 mL at 12 mL/s or 8 mL at 4 mL/s using a catheter in the aorta or CIA, respectively. A completion DSA will be created to confirm procedural success. DSA runs, whether or not in combination with the overlay (for the study group), will be stored. Primary and secondary endpoints will be registered, as well as baseline characteristics and procedural details, including ipsilateral or contralateral, length and location of the lesion, type of PTA balloon or stent, and number of stents.

All patients will receive 5000 IU of heparin during the intervention. The patients will receive bed rest after the intervention according to the physician’s prescription. All patients will be prescribed acetylsalicylic acid (ASA or aspirin) at 80 mg/d. The PTA and recanalization procedures are generally performed as outpatient procedures. Patient participation in the study will be completed after discharge. Any complication that occurs between the signed informed consent and hospital discharge will be recorded. There is no further follow-up period for this study.

Data will be collected by use of an electronic case report form (eCRF), which will be prospectively maintained from the time the patient signs the informed consent until the completion of the study. Patient data will be anonymized; each individual will be given a unique study number (site code [MUMC/ANTO] and index number). Each center can only view and add eCRF data from its own site. At the end of the study, the eCRFs of both sites will be become available to both centers.

A Data and Safety Monitoring Board (DSMB) will not be appointed for this study. A qualified monitor of the Clinical Trial Center Maastricht (CTCM) will monitor the study, which will ensure that the study is conducted according to ICH-GCP guidelines. Visits are conducted at the start of the study, after inclusion of five patients, halfway through, and at completion of the study. A monitoring report will be sent to the investigator after each visit.

Adverse events and serious adverse events will be recorded on the eCRFs. They will comprise a description of the event, type of complication (i.e. access site, systemic, organ-specific), severity, start date, end date, whether suspected to be intervention related, any action that is undertaken, and the outcome. Serious adverse events will be reported to the accredited METC through the “Toetsingsonline” page of the website of the Central Committee on Research Involving Human Subjects (in Dutch: Centrale Commissie Mensgebonden Onderzoek, CCMO [www.​ccmo.​nl]). The investigator will report serious adverse device events resulting from the use of the 3D image fusion technique to the accredited METC, the manufacturer, and the Inspection for Healthcare (in Dutch: Inspectie voor Gezondheidszorg [IGZ]).

The METC has approved the study protocol. Currently, 40 patients have been enrolled in the 3DMR-Iliac-Roadmapping study. The expected project completion for this trial is December 2018.