TicIn for the Treatment of coronAry lesioNs – PlAque Regression AnD stabilISation with drug Eluting balloons (TITAN-PARADISE)

Background: Vulnerable plaques are defined as coronary lesions presenting a higher risk of evolution to an acute myocardial infarction due to their composition. The presence of vulnerable plaques is associated with more than 4-fold increase in the incidence of major cardiac adverse events (MACE). Yet, non-flow-limiting vulnerable plaques are usually not interventionally treated but rather managed with optimized medical therapy, similar to the management of patients without non-flow-limiting vulnerable plaques. Medical therapy (including lipid-lowering drugs) can stabilize vulnerable plaques to a certain extent but patients vs. those without vulnerable plaques still incur in a 4-fold higher risks of clinical events. Percutaneous coronary intervention (PCI) with implantation of drug eluting stents (DES) or bioresorbable scaffold (BVS) have been shown to reduce MACEs, but may yield the risk of restenosis and/or stent/scaffold thrombosis over time and is not currently recommended in these patients. More effective and safer therapies to reduce the risk of MACEs associated with vulnerable plaques remain an unmet clinical need.

Rationale: Drug eluting balloons (DEBs) are currently used for the treatment of flow-limiting in-stent restenosis and de-novo coronary lesions. The use of DEB in non-flow-limiting vulnerable plaques showed promising reduction of the lipid core volume with an overall stabilization of the coronary plaque. The impact of preventive DEB therapy of vulnerable plaques on clinical events remains unsettled.

Aims: The objective of the study is to investigate the impact of DEB treatment of non-flow-limiting vulnerable coronary plaques on MACE in patients following acute coronary syndrome (ACS).

Methodology: This is a prospective randomized open-label, blinded-endpoint (PROBE), investigator-initiated study of roughly 1778 patients with non-flow-limiting vulnerable coronary plaques. Patients with ACS and multivessel coronary disease will be screened for the presence of non-flow-limiting vulnerable plaques within 90 days from index ACS. The non-flow-limiting nature of these lesions is demonstrated by wire-based coronary physiology. Plaque vulnerability is defined by intravascular imaging criteria (IVUS: plaque burden=70%; NIRS: maximal lipid core burden index [MaxLCBI4mm] =325; OCT: thin-capped fibroatheroma [TCFA]) based on established definitions which previously showed association with adverse outcomes. Patients fulfilling the inclusion criteria will be randomized (1:1) to percutaneous coronary intervention with DEB of the vulnerable plaque(s) in addition to guideline-directed medical therapy (GDMT), or to GDMT only.

The primary endpoint is the rate of MACE (cardiac death, any myocardial infarction, any ischemia-driven revascularization or hospitalization for unstable/progressive angina) at the longest available follow-up (with a minimum of 12 months) in the intention-to-treat population. The trial is designed to test the statistical hypothesis that DEB treatment of non-flow-limiting vulnerable coronary plaques in patients with recent ACS is superior to medical therapy alone in terms of MACEs at the longest available follow-up. We expect that the inclusion of 1778 (i.e., 2x889) patients will provide 80% power with a two-tailed 5% alpha to test this hypothesis.

Expected results and impact on the field: This study has high potential for impacting the standard of care and future guidelines. The results of this proposal will inform clinicians on strategies to reduce the ischemic risk following ACS, either by defining non-flow-limiting vulnerable plaques as a target for preventive interventions with DEB or by reinforcing the evidence supporting a purely medical treatment of non-flow-limiting plaques.