Optimal lesion preparation prior to implantation of a bioresorbable magnesium - based scaffold

Coronary artery stenosis has for decades been treated with percutaneous coronary intervention with balloon dilatation and implantation of stents. The introduction of drugeluting stents have improved clinical outcomes by reducing the risk of in-stent restenosis compared to bare-metal stents, but an increase of late and very late stent thrombosis was seen. Data indicates a persisting cumulated risk over time, possibly due to a vessel reaction to the permanent metal-cage left inside the coronary artery. The introduction of bioresorbable scaffolds meant to reduce this risk, as the device dissolve over time leaving the vessel metal-free to restore natural vasomotion. However, lumen reduction and need for revascularization due to in-scaffold restenosis have occurred. 

This thesis investigates the lumen dimensions, vascular response, and clinical outcomes after implantation of a bioresorbable magnesium-based coronary scaffold (MgBRS) in a selected population of patients with stable angina. The findings in the thesis are based on results from the OPTIMIS study (Optimal Pre-dilatation Treatment before Implantation of a Magmaris bioresorbable scaffold In coronary artery Stenosis).

In study 1, we presented the design and rational of the OPTIMIS trial, which was a randomized controlled trial conducted at Odense University Hospital, Denmark enrolling patient from 2020 to 2023. Previous studies investigating the MgBRS have shown risk of lumen reduction over time. The overall hypothesis was that intense lesion preparation prior to implantation of the MgBRS might reduce the risk of lumen reduction. Eighty-two patients with stable angina and coronary artery lesions suitable for treatment with a MgBRS were included and randomly allocated to either lesion preparation with a scoring balloon or a standard non-compliant balloon. Patients were followed with serial clinical and angiographic follow-up combined with intravascular imaging (optical coherence tomography (OCT) and intravascular ultrasound (IVUS)) six and twelve months after implantation. The primary endpoint was minimal lumen area (MLA) at 6-month follow-up evaluated with OCT. 

Study 2 presented the main 6-month findings of the OPTIMIS trial. The primary endpoint was MLA at 6-month follow-up assessed with OCT. MLA at 6-month was significantly larger in the lesions pre-dilated with the scoring balloon compared to the standard noncompliant balloon, whereas mean lumen area did not differ. There was less malapposition both at baseline and follow-up, and no significant remodeling in the scoring balloon group, whereas negative remodeling was observed in lesions pre-dilated with standard non-compliant balloon.

Study 3 explored the multifactorial mechanisms behind lumen reduction after implantation of the MgBRS. The patients from the OPTIMIS trial were divided into two groups according to the MLA at 6-month follow-up: MLA ≤ 4 mm2 (n = 28) and MLA > 4 mm2 (n = 45). Match-framed analysis revealed, that the dominating mechanism behind lumen reduction (MLA ≤ 4 mm2 ) was vessel shrinkage or negative remodeling, but scaffold recoil and neointimal hyperplasia were also contributing factors. Furthermore, we found that vessel injury with a post-procedural intra-scaffold dissection flap was associated with an approximately 5-fold increased risk of lumen reduction. Lesion preparation with a standard non-compliant balloon, compared to a scoring balloon, was associated with an approximately 3-fold increased risk. 

Study 4 presented 12-month clinical and intravascular findings of the OPTIMIS study. Forty-four patients were invited to 12-month angiographic follow-up with OCT and IVUS to investigate the treatment effect of the scoring balloon compared to the standard noncompliant balloon over time. There was a significant reduction in MLA in both groups within the first six months, but MLA remained unchanged from 6- to 12-month follow-up. IVUS data revealed no change in mean lumen, plaque or vessel areas over time in the scoring balloon group, whereas mean lumen and vessel areas were significantly reduced the first 6 month after implantation, but were unchanged beyond 6-month. Even though, 12-month intravascular findings did not demonstrate a significant effect of predilatation with the scoring balloon compared to a standard non-compliant balloon, clinical follow-up revealed higher event rates in the standard non-compliant balloon group, compared to no events in the scoring balloon group.

The principal conclusions of the thesis are:
1. Lesion preparation with a scoring balloon prior to implantation of a MgBRS in a selected population of patients with stable angina is safe and efficient.
2. Lesions pre-dilated with the scoring balloon compared to the standard noncompliant balloon had larger MLA due to less negative remodeling and better vascular healing with less malapposition at 6-month follow-up. There was a significant lumen reduction within the first six months, but unchanged lumen dimensions from 6-month to 12-month in both groups.
3. Mechanisms behind lumen reduction was overall negative remodeling, but scaffold recoil and neointimal hyperplasia were contributing factors. Procedural factors such as pre-dilatation balloon type and post-procedural vessel injury were associated with lumen reduction.
4. Clinical follow-up revealed that the lesions pre-dilated with the scoring balloon were event-free. All events appeared in the standard non-compliant balloon group, with seven target lesion revascularizations, driven by restenosis occurring within the first six months.

The combined findings of the thesis provide a better understanding of vascular remodeling, arterial healing and mechanisms behind lumen reduction after treatment with a MgBRS. The thesis highlights the importance of pre-dilatation prior to implantation of the MgBRS, and explore the potential mechanisms and risk factors behind lumen reduction.