A randomized controlled trial to compare the safety and efficacy of siroliMUs-eLuTIng biodegradable polymer ulTrA-thin stent (SUPRAFLEXTM Cruz) and everolimus-eLuting biodegradable polymer stent (SYNERGYTM) in treatmENT for three-vessel coronary artery disease

Stents:
At the Trans-Catheter Cardiovascular Therapeutics (TCT) Conference 2018,
results of the TALENT study were presented in a Late-Breaking session, and
these results were also published in The Lancet in 2019. The TALENT trial
demonstrated non-inferiority of a biodegradable polymer coating and ultra-thin
struts sirolimus-eluting SUPRAFLEXTM stent when compared to a durable polymer
coating everolimus-eluting XIENCETM stent in terms of occurrence of the
device-oriented composite endpoint (cardiac death, target-vessel myocardial
infarction, or clinically indicated target lesion revascularisation) (4.9% in
SUPRAFLEXTM arm vs 5.3% in XIENCETM arm, absolute difference -0.3% [one-sided
95% upper confidence bound 1.6%], non-inferiority margin of 4.0%,
Pnon-inferiority<0.0001).
In the per-protocol analysis of the TALENT study, a 61% relative reduction of
ischemia-driven TLR was found in the SUPRAFLEXTM arm compared to the XIENCETM
arm (1.2% in SUPRAFLEXTM arm vs 3.1% in XIENCETM arm, absolute difference
-1.9%, 95% CI -5.3 to -0.3%, p = 0.021). To amplify that signal, we designed a
new randomised controlled trial with the novel SUPRAFLEXTM Cruz stent in
patients with three-vessel disease.
The SUPRAFLEXTM Cruz stent is the next generation SUPRAFLEXTM DES ultrathin
with a strut thickness of 60µm across all diameters of the device. Instead of a
short S-connectors from *peak to peak* between the strut rings, the new design
of SUPRAFLEXTM Cruz has unique long dual Z connectors from *valley to valley*
between the strut rings which confer to the stent a superior pushability and
flexibility without trade-off in radial strength). This device has been
extensively used in India over the last 3 years in >250,000 implants.

Best Practice PCI:
On the other hand, the most recent trial in patients with multi-vessel disease
applied five treatment principles described as *best practice* in the field of
Multivessel PCI. First, patient selection is based on SYNTAX Score II which
allows to enrol patients with an anatomic score between 22-32 or >33 provided
they have a four years vital prognosis equipoise with the one obtained with
surgical revascularisation; secondly, physiological assessment of stenotic
lesion and treatment targeting the functionally significant lesion; thirdly,
IVUS/OCT for post-stent optimisation since the benefit in outcome has been
demonstrated in the ULTIMATE and IVUS-XPL trials; fourthly, PCI of chronic
total occlusion (CTO) has to be performed by locally accredited experts in CTO,
and lastly, optimal medical treatment before, during and after PCI.
The physiological assessment, iFR for all vessels has however been perceived as
time consuming, expensive and cumbersome. Therefore, the investigators have
decided to replace a pressure wire derived physiological assessment by QFR
(quantitative flow ratio) as a validated angiography derived physiological
assessment.
QFR has been validated as an accurate alternative for iFR and FFR in several
reports and has obtained Conformité Européenne (CE) mark. In the FAVOR I study,
the diagnostic accuracy of QFR has been demonstrated without the need for
pharmacologic hyperemia. Thereafter, the FAVOR II China and the FAVOR II
Europe-Japan study demonstrated the diagnostic accuracy of QFR for detection of
functional significant lesions in comparison with 2D-QCA using FFR as reference
standard In a systematic review and Bayesian meta-analysis, Collet et al
confirmed the high sensitivity and specificity of QFR against pressure wire
derived physiological assessment. Both FAVOR III China and Europe-Japan are
ongoing randomised controlled trials and expected to be completed in 2022.
FAVOR III China study aims to demonstrate the superiority of QFR-guided PCI in
terms of the clinical outcome and cost-effectiveness compared to
angiography-guided PCI. On the other hand, the objective of the FAVOR III
Europe-Japan study is to investigate whether a QFR-based diagnostic strategy
will result in non-inferior clinical outcome after 12 months compared to a
standard pressure-wire guided strategy.
The objective of the Multivessel Talent study is to elucidate the efficacy and
safety of the novel SUPRAFLEXTM Cruz stent in comparison with the SYNERGYTM
stent applying the five treatment principles of the *best practice* PCI and to
use QFR guidance instead of iFR among in these patients with 3-vessel coronary
disease.

Optimal medical therapy:
Recently the sub analysis of the Global Leaders trial demonstrated that in
3-vessel disease Ticagrelor monotherapy following one-month DAPT with aspirin
reduced the occurrence of all-cause death and new Q-wave MI as well as
POCE/NACE without difference in BARC3/5 bleeding, when compared with standard
1-year DAPT followed by aspirin monotherapy. Therefore, one-month DAPT followed
by Ticagrelor monotherapy could be encouraged. On the other hand, the
ISAR-REACT 5 trial demonstrated that, in patients who presented with acute
coronary syndromes, the incidence of death, myocardial infarction, or stroke
was significantly lower among those who received Prasugrel than among those who
received Ticagrelor, and the incidence of major bleeding was not significantly
different between the two groups. Considering altogether, one-month DAPT
followed by Prasugrel monotherapy will be encouraged. In addition, the landmark
analysis in the Global Leaders trial at 1 year, did not demonstrate any
difference between Ticagrelor monotherapy and aspirin monotherapy in clinical
outcomes during the second year. Therefore, at one year, Prasugrel monotherapy
could be replaced by aspirin monotherapy.

Primary Objective:
To compare the SUPRAFLEX Cruz sirolimus-eluting stent (SES) with the SYNERGY
everolimus-eluting stent (EES) with respect to Patient-oriented Composite
Endpoint (PoCE: composite of all-cause death, any stroke, any MI, and any
clinically and physiologically-indicated revascularization) at 12 months in a
3-vessel disease population (non-inferiority);

Secondary objectives:
To compare the SUPRAFLEX Cruz SES with the SYNERGY EES with respect to
Vessel-oriented Composite Endpoint (VoCE, composite of vessel-related
cardiovascular death, vessel-related MI, clinically and
physiologically-indicated-Target vessel revascularization) per vessel at 24
months in a 3-vessel disease population (superiority);

This is a prospective, randomized, 1:1, controlled, multi-center,
angiographically documented three-vessel disease (3VD) open-label study
comparing clinical outcomes between SUPRAFLEX Cruz and SYNERGY in approximately
1550 (2*775 patients). The trial will be sponsored by the National University
of Ireland (NUI) Galway and the sponsorship role coordinated by the
HRB-Clinical Research facility Galway (CRFG).

There will be approximately 50 sites in Europe. University Hospital Galway,
Galway will also be a site. The site activities will also be coordinated by the
CRFG.

Patients with de-novo 3VD will be treated according to *state of art PCI*
including :
1) SYNTAX Score II recommendation (i.e., PCI only or equipoise CABG/PCI);
2) Heart Team discussion (ESC guidelines: Ia );
3) Functional evaluation for diagnosis in absence of objective evidence of
ischemia (ESC guidelines: Ia) (i.e., QFR*); Post-procedure IVUS/OCT
optimization (ESC guidelines: IIa);
4) Contemporary CTO techniques
5) Optimal medical therapy (P2Y12 inhibitor, statin, etc).

*QFR on diagnostic angiography will be analysed in a stand-by central academic
Core Lab and the results will be disclosed to the site after randomization
before treatment.

The only study intervention is randomization between the SUPRAFLEX Cruz stent
and the SYNERGY stent.

Non-Investigational Medical Therapy:
All patients must receive dual anti-platelet therapy, being aspirin (ASA) and
Prasugrel for 1 month, followed by 11 months of Prasugrel only (i.e.
monotherapy).
Prasugrel therapy should be used since this regimen showed to have the best
safety to efficacy ratio in this 3-vessel disease population3. After that,
Prasugrel monotherapy is replaced by aspirin monotherapy at 1 year.
Anticoagulation during the procedure is mandatory, type/dose left to the
operator*s discretion

Percutaneous coronary intervention (PCI) and intravascular stenting may offer
certain advantages as compared to conventional surgical techniques. In
addition, coronary stenting with both BMS and DES has been performed
successfully for several decades and is considered a standard treatment for
coronary artery disease. Furthermore, there is extensive clinical and
commercial experience worldwide with cardiac catheterisation and interventional
procedures and it is expected that the procedural risks in this study and
existing stenting procedure will not be significantly different. Possible
benefits may be found for future patients treated with SUPRAFLEXTM Cruz PCI and
functional guidance (QFR) and IVUS/OCT stent optimisation based upon results of
this study.

The SUPRAFLEXTM Cruz (Sahajanand Medical Technologies, Surat, India) stent
platform is made of an L605 cobalt-chromium alloy. SUPRAFLEXTM Cruz has
ultrathin strut (60 µm) across all stent diameters, with highly flexible long
dual Z connectors from *valley to valley* between the strut rings. Compared
with other available stents, SUPRAFLEXTM Cruz has the thinnest strut to date.
The stent diameters are from 2.25 mm to 4.0 mm, and the lengths are from 8mm to
48mm (8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48mm). Another feature of
SUPRAFLEXTM Cruz is the biodegradable polymeric matrix coating, consists of a
poly L-lactide, 50:50 mixed with poly D-L-lactideco-glycolide and polyvinyl
pyrrolidone. Sirolimus with a concentration of 1.4 µg/mm² is coated on the
conformal surface of the stent together with the polymeric matrix. The polymer
will gradually degrade over 9-12 months. The average thickness of the coating
ranges from 4 µm to 5 µm. Further, since the drug-polymer coating on the
SUPRAFLEXTM Cruz is gone within 9 months, leaving a bare metal stent, this may
diminish the potential concerns regarding long-term effect on vessel healing,
late and very late thrombosis, and hypersensitivity.
Aside from the potential direct benefits to the participant resulting from this
study, there may be benefits to future participants based upon the results of
the study.