Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT05650411 |
| Other study ID # |
2022-1204 |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
July 1, 2024 |
| Est. completion date |
January 1, 2029 |
Study information
| Verified date |
March 2024 |
| Source |
University Hospital, Geneva |
| Contact |
Maëlle Achard, RN |
| Phone |
+41795533553 |
| Email |
maelle.achard[@]hcuge.ch |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The management of patients with unprotected left main coronary artery (LMCA) disease
undergoing percutaneous coronary intervention (PCI) in contemporary interventional cardiology
practice remains matter of intense debate. Particularly, the combination of the optimal
drug-eluting stent (DES) selection and antiplatelet regimen for patients who require LMCA PCI
remains undetermined.
Newest-generation thin-strut polymer-free drug-coated stents have the potential to further
mitigate chronic inflammation and promote faster re-endothelialization. In the LEADERS FREE
randomized trial, PCI with the early-generation BioFreedom (Biosensors International,
Switzerland) thick-strut stainless-steel drug-coated stent group was associated with
significantly lower rates of the primary safety endpoint, defined as a composite of cardiac
death, myocardial infarction, or stent thrombosis at 12 months compared to bare-metal stents
among 2,466 patients at high-risk of bleeding who received one-month dual antiplatelet
therapy (DAPT), a difference driven by a significantly lower risk for clinically driven
target-lesion revascularization. In the ONE-MONTH DAPT randomized study, which enrolled 3,020
patients with coronary artery disease considered for PCI for noncomplex lesions, the rates of
the primary composite endpoint of cardiac death, nonfatal myocardial infarction, target
vessel revascularization, stroke, or major bleeding within 12 months occurred similarly in
patients treated with 1-month DAPT after PCI with early-generation thick-strut
stainless-steel polymer-free drug-coated stent (BioFreedom, Biosensors International,
Switzerland) and those treated with 6- to 12-month DAPT after newer-generation biodegradable
polymer DES (Biomatrix, Biosensors International, Switzerland or Ultimaster, Terumo Corp.,
Japan) implantation. However, no dedicated randomized clinical trial to date has evaluated
the safety and efficacy of newest-generation thinner-strut cobalt-chromium polymer-free
drug-coated stents combined with a P2Y12 inhibitor-based SAPT strategy among patients
undergoing highly complex PCI procedures, such as those treated for LMCA disease.
Recent evidence from a large-scale meta-analysis of several randomized clinical trials
including >32'000 patients indicated that 1-3 months of DAPT followed by P2Y12 inhibitor
single antiplatelet therapy (SAPT) after second-generation DES implantation was associated
with lower risk for major bleeding and similar risk for adverse ischemic outcomes compared
with conventional DAPT. These findings suggest that P2Y12 inhibitor SAPT following a short
DAPT course (1-3 months) may represent a valuable treatment option for patients undergoing
PCI with newer-generation DES compared to standard conventional 12 months DAPT, but this
strategy has never been investigated in dedicated randomized clinical trials focused on
patients at highest-risk for ischaemic events, such as patients undergoing LMCA PCI.
The ULTRA-LM randomized trial aims at filling this current gap of knowledge, which may have
large impact on clinical practice and international guidelines. ULTRA-LM will be the first
randomized clinical trial to investigate the safety and efficacy of a novel thin-strut
cobalt-chromium BioFreedom Ultra polymer-free drug-coated stent (Biosensors International,
Switzerland) combined with P2Y12 inhibitor-based single antiplatelet therapy among patients
undergoing PCI for LMCA disease.
Description:
1. Myocardial revascularization for significant left main coronary artery disease
Significant left main coronary artery disease (LMCA) is observed in 5-7% of patients
undergoing coronary angiography. Coronary revascularization for patients with LMCA
disease with stenosis >50% and documented ischemia or FFR ≤0.80 for diameter stenosis
<90%, is currently recommended with a class of recommendation I and level of evidence
(LOE) A by the 2018 European Society of Cardiology (ESC) guidelines for myocardial
revascularization (8). However, the optimal management of patients with LMCA disease
requiring myocardial revascularization in contemporary clinical practice remains matter
of debate.
2. Coronary artery bypass grafting vs. percutaneous coronary intervention for left main
coronary artery disease
The available evidence from randomized controlled trials (RCTs) and meta-analyses
comparing coronary artery bypass grafting (CABG) with percutaneous coronary intervention
(PCI) using drug-eluting stents (DESs) among patients with LMCA suggests equivalent
results for the safety composite of death, MI, and stroke up to 5 years of follow-up
(9). A significant interaction with time is notable, providing early benefit for PCI in
terms of myocardial infarction (MI) and peri-interventional stroke, which is
subsequently offset by a higher risk of spontaneous MI during long-term follow-up. The
need for repeat revascularization is higher with PCI than with CABG. The EXCEL
(Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left
Main Revascularization) randomized trial compared CABG with PCI using new-generation
DESs among 1,905 patients with significant LMCA (10). At 3 years of follow-up, the
primary endpoint of death, stroke, or MI occurred with similar frequency in the CABG and
PCI group (14.7% vs. 15.4%; HR 1.00, 95% CI 0.79-1.26, p=0.98). The pre-planned landmark
analysis from 30 days to 3 years showed a significant difference for the primary
endpoint in favour of CABG (7.9% vs. 11.5%, p=0.02). The NOBLE (Nordic-Baltic-British
Left Main Revascularization Study) randomized trial compared CABG with PCI using
new-generation biolimus-eluting stents among 1,201 patients with significant LM disease
(mean SYNTAX score of 23) (11). At a median follow-up of 3.1 years, the primary endpoint
of death, non-procedural MI, stroke, and repeat revascularization occurred more
frequently in the PCI than the CABG group (29% vs. 19%; HR 1.48, 95% CI 1.11-1.96,
p=0.007). A recent collaborative individual patient pooled analysis of RCTs including
11,518 patients reviewed the currently available evidence from RCTs comparing CABG with
PCI for LMCA or multivessel disease (12). The primary outcome was all-cause mortality.
In the overall cohort, CABG was associated with a significant survival benefit during a
mean follow-up of 3.8±1.4 years (5-year all-cause mortality 11.2% after PCI vs. 9.2%
after CABG; HR 1.20, 95% CI 1.06-1.37, p=0.0038). There was a linear trend for HRs of
death increasing with increasing SYNTAX tertiles (p=0.0011 for trend). However, among
4,478 patients with LMCA, those randomly assigned to CABG or PCI with a mean follow-up
of 3.4±1.4 years reported similar risks for the primary outcome all-cause mortality
(PCI, 10.7% vs. CABG, 10.5%; HR 1.07, 95% CI 0.87-1.33, p=0.52) at 5 years. There were
no significant differences in mortality between PCI and CABG in subgroup analyses
according to SYNTAX scores. Nevertheless, in patients with a high SYNTAX score, a trend
towards better survival was noted with CABG. The proportion of patients with a high
SYNTAX score was limited in view of the inclusion criteria of the respective studies.
Current evidence indicates that PCI is an appropriate alternative to CABG in LMCA and
low-to-intermediate anatomical complexity (8). Among patients with LMCA and low
anatomical complexity, there is evidence that the outcomes with respect to major
clinical endpoints are similar for PCI and CABG, resulting in a class I recommendation.
Among patients with LMCA and high anatomical complexity, the number of patients studied
in RCTs is low due to exclusion criteria; the risk estimates and CIs are imprecise but
suggest a trend towards better survival with CABG. Therefore, PCI in this setting cannot
be endorsed as reflected by a class III recommendation. For PCI in LMCA with
intermediate anatomical complexity, the previous class IIa recommendation was maintained
in view of the incomplete 5-year follow-up of the two largest RCTs in this setting.
3. Percutaneous coronary intervention with drug-eluting stents for left main coronary
artery disease
The optimal DES therapy for patients with significant LMCA disease undergoing
percutaneous coronary intervention (PCI) in contemporary practice remains undetermined
(8). In the Intracoronary Stenting and Angiographic Results: Drug-Eluting Stents for
Unprotected Coronary Left Main Lesions (ISAR-LEFT MAIN-2) (n=650) trial (13), the
cumulative incidence of the primary endpoint, a composite of all-cause death, myocardial
infarction, or target lesion revascularization was 17.5% in the thin-strut durable
polymer zotarolimus-eluting stent group (Resolute, Medtronic, USA) and 14.3% in the
thin-strut biocompatible durable polymer everolimus-eluting stent group (Xience®, Abbott
Vascular, USA) (relative risk 1.26; 95% CI]: 0.85 to 1.85; p=0.25) at 12 months. In the
EXCEL trial (10), the rates of the primary composite endpoint of all-cause death,
stroke, or myocardial infarction, occurred similarly in patients undergoing PCI with the
newer-generation thin-strut durable polymer everolimus-eluting stent (Xience®) and
coronary artery bypass graft surgery (CABG) (22.0% vs. 19.2%, p=0.13) at 5 years. In the
NOBLE trial (11), the rates of the primary composite endpoint of all-cause death,
non-procedural myocardial infarction, any repeat coronary revascularization, and stroke,
was 29% in patients undergoing PCI with a thick-strut biodegradable polymer
biolimus-eluting stent (Biomatrix Flex®, Biosensors, Switzerland) versus 19% in patients
undergoing CABG (HR 1.48, 95% CI 1.11-1.96, CABG significantly better than PCI,
p=0.0066) at 5 years. In the Improved Drug Eluting stent for All-comers Left Main
(IDEAL-LM) randomized clinical trial (14), the rate of the primary endpoint, a composite
of all-cause death, MI, or clinically indicated target vessel revascularization at 2
years did not differ between patients undergoing PCI with a biodegradable polymer
everolimus-eluting stent (Synergy®, Boston Scientific, USA) combined with 4-month dual
antiplatelet therapy (DAPT) (14.6%) and those undergoing PCI with a durable polymer
everolimus-eluting stent (Xience®, Abbott Vascular, USA) combined with 12-month DAPT
(11.4%) (p=0.17). Newer-generation thin-strut polymer-free drug-coated stents have the
potential to further mitigate chronic inflammation and promote faster
re-endothelialization. No dedicated randomized clinical trial to date has evaluated the
safety and efficacy of newest-generation polymer-free drug-coated stents for PCI in
patients with LMCA disease.
4. Antiplatetelet therapy after percutaneous coronary intervention for left main coronary
artery disease
The 2018 ESC guidelines on myocardial revascularization recommend at least 6 (chronic
coronary syndrome) and 12 (acute coronary syndrome) months of DAPT after PCI with
newer-generation DES among patients with unprotected LMCA stenosis (8). A recent
meta-analysis of five large-scale randomized clinical trials including a total of 32'145
patients, of whom 972 (3%) patients were treated for LMCA disease, indicated that 1-3
months of DAPT followed by P2Y12 inhibitor single antiplatelet therapy (SAPT) after
second-generation DES implantation in patients with chronic and acute coronary syndromes
was associated with lower risk for major bleeding (random-effects model: HR 0.63, 95%
0.45-0.86) and similar risk for stent thrombosis (random-effects model: HR 1.19, 95% CI
0.86-1.65), all-cause death (random-effects model: HR 0.85, 95% CI 0.70-1.03),
myocardial infarction (random-effects model: HR 1.05, 95% CI 0.89-1.23), and stroke
(random-effects model: HR 1.08, 95% CI 0.68-1.74) compared with conventional DAPT (15).
These findings suggest that a P2Y12 inhibitor-based SAPT following a short DAPT course
(1-3 months) may represent a preferable treatment option, which is associated with
similar ischemic, but lower bleeding risk, for patients undergoing PCI with
newer-generation DES compared to standard conventional 12 months DAPT. Importantly,
there was no significant differences between P2Y12 inhibitor SAPT and conventional DAPT
with respect to stent thrombosis (random-effects model: HR 1.19, 95% CI 0.86-1.65;
p=0.302). Overall, the incidences of stent thrombosis with modern DESs used in trials
included in the meta-analysis were low, ranging from 0.2% vs. 0.1% in the SMART-CHOICE
trial (19), to 0.7% vs. 0.5% in the GLOBAL LEADERS (20) trial and 0.4% vs. 0.6% in the
TWILIGHT (21) trial. In addition, there were no significant differences with respect to
other ischemic outcomes such as all-cause death despite a trend towards benefits with
P2Y12 inhibitor SAPT (random-effects model: HR 0.85, 95% CI 0.70-1.03; p=0.091),
myocardial infarction (random-effects model: HR 1.05, 95% CI 0.89-1.23; p=0.567), and
stroke (random-effects model: HR, 1.08; 95% CI 0.68-1.74; p=0.738), while there was a
significant 37% reduction in the risk of major bleeding complications (random-effects
model: HR, 0.63; 95% CI 0.39-1.01; p=0.004) with P2Y12 inhibitor SAPT compared to
conventional DAPT, suggesting a net clinical benefit in favour of P2Y12 inhibitor SAPT.
However, the safety and efficacy of a potent P2Y12 receptor inhibitor-based SAPT after
highly complex PCI, such as PCI for LMCA disease, has not been investigated to date.
5. Newer-generation polymer-free drug-coated stents for percutaneous coronary intervention
The BioFreedom polymer-free drug-coated stent (Biosensors International, Switzerland) has
potential to further mitigate chronic inflammation, promote faster re-endothelialization and
reduce DAPT duration among patients undergoing PCI. In the LEADERS FREE randomized trial
(16), which included 2,466 patients at high-risk of bleeding, the primary safety endpoint,
defined as a composite of cardiac death, myocardial infarction, or stent thrombosis at 12
months, was 9.4% in the early-generation thick-strut stainless-steel drug-coated stent
(BioFreedom, Biosensors International, Switzerland) group and 12.9% in the bare-metal-stent
(BMS) group (risk difference, -3.6 percentage points; 95% CI, -6.1 to -1.0; hazard ratio,
0.71; 95% CI, 0.56-0.91; p<0.001 for noninferiority, p=0.005 for superiority). The rates of
clinically driven target-lesion revascularization were 5.1% in the drug-coated stent group
and 9.8% in the bare-metal stent group (risk difference, -4.8 percentage points; 95% CI, -6.9
to -2.6; hazard ratio, 0.50; 95% CI, 0.37-0.69; p<0.001). In the ONE-MONTH DAPT study (17),
which enrolled 3,020 patients with coronary artery disease considered for PCI for noncomplex
lesions, the rates of the primary composite endpoint of cardiac death, nonfatal myocardial
infarction, target vessel revascularization, stroke, or major bleeding within 12 months
occurred similarly in 5.9% of patients treated with 1-month DAPT after early-generation
thick-strut stainless-steel polymer-free drug-coated stent (BioFreedom, Biosensors
International, Switzerland) implantation and in 6.5% of patients treated with 6- to 12-month
DAPT after biodegradable polymer DES (Biomatrix, Biosensors International, Switzerland or
Ultimaster, Terumo Corp., Japan) implantation (absolute difference -0.7%; upper limit of
one-sided 97.5% CI, 1.33%; p<0.001 for noninferiority). The occurrence of major bleeding was
not different (1.7% vs. 2.5%; p=0.136). There was no difference in the occurrence of stent
thrombosis (0.7% vs 0.8%; p=0.842). These findings confirm the safety and efficacy of a short
one-month DAPT course after PCI of noncomplex lesions with the BioFreedom polymer-free
drug-coated stent (Biosensors International, Switzerland) among all-comer patients, including
high- and non-high-bleeding risk patients. BioFreedom Ultra (Biosensors International,
Switzerland), the latest iteration of the BioFreedom drug-coated stent, is a thin-strut
(84-88 μm) cobalt-chromium polymer-free biolimus-coated stent. In the LEADERS III trial (18),
which included 401 patients at high-risk of bleeding with similar criteria than in the
historical LEADERS-FREE trial and who received one-month DAPT, the BioFreedom Ultra
drug-coated stent with a thin-strut cobalt-chromium stent platform was shown non-inferior to
the original thick-strut stainless-steal BioFreedom drug-coated stent with regards to the
primary safety endpoint, a composite of cardiac death, myocardial infarction, and
definite/probable stent thrombosis, and superior to BMS with respect to the primary efficacy
endpoint of clinically indicated target lesion revascularization at one-year follow-up in a
propensity-matched comparison. The safety and efficacy of the novel thin-strut
cobalt-chromium BioFreedom Ultra polymer-free drug-coated stent (Biosensors International,
Switzerland) combined with a potent P2Y12 inhibitor SAPT among patients undergoing PCI for
complex coronary lesions, such as patients with LMCA stenosis, have however not been
investigated to date.
