Clinical trial NCT01347554: Efficacy of Everolimus-Eluting Versus Zotarolimus-Eluting Sten for Coronary Lesions in Acute Myocardial Infarction
Official title: Comparison of the Efficacy of Everolimus-Eluting Versus Zotarolimus-Eluting Stent for Coronary Lesions in Acute Myocardial Infarction
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Myocardial Infarction
Keywords: drug-eluting stent
everolimus
zotarolimus
myocardial ischemia
cardiovascular diseases
MACE
safety
Lead sponsor: Yonsei University
Sponsor class: OTHER
Collaborators: name: Medtronic
First posted: 2011-05-04
Enrollment: 461
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Most of the previous data regarding the efficacy of the everolimus-eluting stent (EES) was derived from studies comparing EES with bare metal stent (BMS) or EES with paclitaxel-eluting (PES). Although sirolimus-eluting stents (SES) have been shown to be the most efficacious drug regarding inhibition of neointima and late loss, there have been no previous head to head comparisons between EES and zotarolimus-eluting stent (ZES). Both everolimus and sirolimus are macrocyclic lactones that target the mTOR (mammalian target of rapamycin) to reduce vascular smooth muscle proliferation after vessel injury and therefore in principle may show similar results after stenting in humans. Data pooled from the EES arm that received follow up angiography in the SPIRIT III trial and the SES arm in the SIRIUS trial show similar rates of binary restenosis and late loss. However, the stent and polymer platform is not the same between the EES and ZES and it is reported that the EES system has the thinnest stent + polymer thickness (88.6um) of all of the previously KFDA-approved drug-eluting stent (DES). In addition, there are no data available on the efficacy of the EES and ZES in "real world" lesions other than the selected lesions studied in the previous trials, such as acute myocardial infarction.

Detailed description: Previous randomized trials have shown the efficacy of a slow-release polymeric sirolimus-eluting stent (CYPHER, Cordis, Warren, NJ, USA), paclitaxel-eluting stent (TAXUS, Boston Scientific, Natick, MA, USA), and zotarolimus-eluting stent (Endeavor, Medtronic, Minneapolis, MN, USA) over bare metal stents in reducing neointimal hyperplasia, late luminal loss, and angiographic restenosis leading to decreased target lesion revascularization. The everolimus-eluting stent (XIENCE V, Abott Vascular, Santa Clara, CA, USA, PROMUS, Boston Scientific, Natick, MA, USA) is a newly developed drug eluting stent using the MULTILINK VISION® stent platform combined with the drug everolimus contained in a polymer coating.

In the first-in-man SPIRIT First clinical trial, XIENCE V showed a significant benefit over the bare metal VISION stent. Compared with late loss of 0.85 ± 0.36mm in the VISION arm, XIENCE V reduced late loss by 88% (0.10 ± 0.23mm). Also the clinical safety of XIENCE V was confirmed with a 6-month MACE rate of 7.7%. In the SPIRIT II clinical trial, which compared the efficacy and safety of the XIENCE V stent versus the TAXUS PECSS stent, the primary endpoint was met showing a non-inferiority of the XIENCE V compared with the TAXUS regarding in-stent late loss at 180 days. Actually, XIENCE V was superior to TAXUS and reduced in-stent late loss by 72% from a mean of 0.36 mm to 0.11 mm. In addition, analysis of other key clinical endpoints showed a lower rate of ischemia driven MACE (2.7% vs. 6.5% for XIENCE V vs. TAXUS) and protocol-defined stent thrombosis (0.5% vs. 1.3% for XIENCE V vs. TAXUS). The lower rate of ischemia driven MACE at 180 days was sustained through 1 year and there were no new instances of late stent thrombosis in either group up to 1 year.

The SPIRIT III RCT was a prospective, 2:1 randomized, active-controlled, single blinded, parallel, multi-center clinical evaluation of the XIENCE V Everolimus Eluting Coronary Stent System (XIENCE V EECSS) compared to TAXUS Paclitaxel Eluting Coronary Stent System (TAXUS PECSS) in the treatment of up to two de novo lesions. This pivotal clinical trial was designed to demonstrate the non-inferiority of the XIENCE V EECSS to the TAXUS PECSS. Patients were randomized 2:1 to XIENCE V or TAXUS and the primary endpoint was in-segment late loss at 240 days. The results showed a mean in-segment late loss of 0.14mm for XIENCE V and 0.28 mm for TAXUS (p\<0.001 for non-inferiority, p=0.0037 for superiority). The secondary endpoint, which was ischemia-driven target vessel failure (TVF), was 7.6% for XIENCE V and 9.7% for TAXUS, confirming the non-inferiority of XIENCE V. Furthermore, the rate of definite and probable stent thrombosis was 1.1% and 0.6% for XIENCE V and TAXUS, respectively.

With a recent approval of new DES, zotarolimus-eluting stent (Endeavor, Medtronic, Minneapolis, MN), other comparison studies have been conducted to compare Endeavor zotarolimus-eluting stent with the sirolimus-eluting stent and paclitaxel-eluting stent. zotarolimus and sirolimus share some common structural and biological properties. In vitro data suggest that sirolimus and tetrazole containing rapamycin analogs have similar inhibitory effects in a mixed lymphocyte reaction assay. The ENDEAVOR clinical trials are currently in progress to evaluate a phosphoryl choline (PC)-coated zotarolimus-eluting stent(ZES) for the prevention of restenosis. The Endeavor zotarolimus-eluting stent utilizes a cobalt alloy balloon-expandable stent (Driver; Medtronic) with a geometry similar to the stainless steel stent used in this preliminary study (S7; Medtronic). The Endeavor ZES also employees a PC strut surface coating as the drug delivery reservoir with a dose of 10 g/mm of ABT-578. The Endeavor (ZES), however, differs from the stent used in this experimental study by the addition of a drug-free PC topcoat to serve as a diffusion barrier to retard drug release from the polymer reservoir. Angiographic analysis at 4 months in the 100-patient focal de novo lesion ENDEAVOR I feasibility study demonstrated a mean in-stent percent diameter stenosis of approximately 14% and a late lumen loss of 0.3 mm with a low frequency of target lesion revascularization (1%). The clinical outcomes from the ENDEAVOR II (1,500 patients randomized to ABT-578 or bare metal stent) and the ENDEAVOR III (436 patients randomized 3:1 to ABT-578 or Cypher) trials as well as other ongoing studies showed efficacy of the PC-coated ABT-578-eluting stent. In ENDEAVOR III study, the Endeavor stent had larger late loss and higher binary restenosis in both the analysis segment and stented segment.

Most of the previous data regarding the efficacy of the EES was derived from studies comparing EES with BMS or EES with PES. Although sirolimus eluting stents (SES) have been shown to be the most efficacious drug eluting stent regarding inhibition of neointima and late loss, there have been no previous head to head comparisons between EES and ZES. Both everolimus and sirolimus are macrocyclic lactones that target the mTOR (mammalian target of rapamycin) to reduce vascular smooth muscle proliferation after vessel injury and therefore in principle may show similar results after stenting in humans. Data pooled from the EES arm that received follow up angiography in the SPIRIT III trial and the SES arm in the SIRIUS trial show similar rates of binary restenosis and late loss. However, the stent and polymer platform is not the same between the EES and ZES and it is reported that the EES system has the thinnest stent + polymer thickness (88.6um) of all of the previously KFDA-approved DES. In addition, there are no data available on the efficacy of the EES and ZES in "real world" lesions other than the selected lesions studied in the previous trials, such as acute myocardial infarction.

Eligibility criteria: Inclusion Criteria:

* Age \> 18 years
* Chest pain duration more than 10 minutes
* At least on of the following criteria
* A. ECG change (T inversion, ST depression or ST elevation)
* B. Cardiac enzyme elevation more than upper normal limit
* Significant coronary artery stenosis (\>50% by visual estimate)
* The patient or guardian agrees to the study

Exclusion Criteria:

* Stent thrombosis
* Left main disease
* Cardiogenic shock
* Cronic kidney disease or renal failure requiring hemodialysis
* History of bleeding diathesis or known coagulopathy
* Gastrointestinal or genitourinary bleeding within the prior 3 months
* History of major surgery within 2 months
* Planned surgery requiring cessation of clopidogrel within 12 months of percutaneous coronary intervention (PCI)
* Serious patients whose life expectancy \<1 year or severe infectious status

Primary outcomes:
measure: Device-oriented Composite Outcome
timeFrame: Two year
Secondary outcomes:
measure: Device-oriented Composite Outcome
timeFrame: Two years
measure: Stent Thrombosis
timeFrame: Two years
measure: Any Bleeding
timeFrame: Two year
Other outcomes:
Locations:
city: Wonju
country: Korea, Republic of
facility: Yonsei University Wonju College of Medicine; Wonju Severance Christian Hospital
Study officials:
affiliation: Division of Cardiology, Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju Severance Christian Hospital
name: Seung-Hwan Lee, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ahn SG, Choi HH, Lee JH, Lee JW, Youn YJ, Yoo SY, Cho BR, Lee SH, Yoon J. The impact of initial and residual thrombus burden on the no-reflow phenomenon in patients with ST-segment elevation myocardial infarction. Coron Artery Dis. 2015 May;26(3):245-53. doi: 10.1097/MCA.0000000000000197.