TicIn for the Treatment of coronAry lesioNs – PlAque Regression AnD stabilIsation with Sirolimus Elution (TITAN-PARADISE)

Background and rationale: Acute coronary syndromes (ACS) frequently arise from intraluminal thrombosis on the basis of a ruptured or eroded atherosclerotic plaque. Plaques causing ACS express a vulnerable phenotype consisting of a large necrotic lipid core separated from the lumen by a thin fibrous cap, which can be detected by intravascular imaging such as intravascular ultrasound (IVUS), near-infrared spectroscopy (NIRS) or optical coherence tomography (OCT). A growing body of evidence shows an association between the presence of vulnerable plaques and major adverse cardiac events (MACE).Importantly, most vulnerable plaques are non-flow-limiting and appear angiographically mild, and are therefore currently treated solely with a pharmacological approach. Guidelines-directed medical therapy (GDMT), and in particular lipid lowering therapy, is able to stabilize vulnerable plaque, but does not completely mitigate the MACE risk. Additional interventional treatment of non-flow-limiting NCLs has been explored as a modality to stabilize vulnerable plaques. Recently, the PROSPECT-ABSORB trial showed safety of the implantation of bioresorbable coronary scaffolds in vulnerable NCLs, with a signal towards a reduction in MACE. Similarly, the PREVENT trial showed that preventive percutaneous coronary intervention reduced major adverse cardiac events arising from vulnerable plaques, compared with optimal medical therapy alone.Within this framework, drug eluting balloons (DEB) represent a promising solution for pre-emptive treatment of coronary vulnerable plaque. DEBs are currently used with good results and excellent safety in the treatment of coronary small vessels (diameter <2.5 mm) and in-stent restenosis, and a growing body of evidence is suggesting that DEBs are also effective in treating de-novo stenoses of larger coronary vessels. Preliminary data show that DEBs are associated with a significant plaque stabilization. The impact of a preventive treaAims: The planned study aims to investigate the clinical effects of a preventive treatment of vulnerable, non-flow limiting non-culprit lesions (NCLs) with sirolimus-eluting balloons additionally to GDMT in patients following a prior ACS.Methodology: Patients with multivessel coronary artery disease and ACS can be screened following successful PCI of the culprit lesion(s). NCLs will be assessed functionally by means of wire-based or angiography-based coronary physiology, and morphologically by means of 3-vessel IVUS-NIRS. A NCL is defined vulnerable when it presents simultaneously a plaque burden=70% and a maximal lipid core burden index=325. A patient can be included if presenting at least one non-flow-limiting and vulnerable NCL. Included patients will be randomized 1:1 to GDMT only (control arm) or to GDMT plus DEB treatment of all non-flow-limiting, vulnerable NCLs (experimental arm). Randomization will be stratified for number of eligible NCLs and diabetes status.Patients randomized in the GDMT arm will receive standard medical treatment, optimized through a predefined protocol and supervised by a secondary prevention specialist. No local interventional therapy of the vulnerable NCL(s) will be performed.Patients randomized in the experimental (DEB+GDMT) arm will undergo PCI of all NCLs fulfilling the vulnerability criteria with a sirolimus-eluting balloon additional to GDMT.Primary endpoint is MACE (cardiac death, any myocardial infarction, any ischemia-driven revascularization or hospitalization for unstable/progressive angina) rate at longest available follow-up (with a minimum of 12 months). Key secondary endpoints will include the individual components of the composite MACE endpoint, as well as target lesion revascularization, target vessel failure (TVF), stroke and bleeding.