Clinical trial NCT01443104: Sirolimus-eluting Stents With Biodegradable Polymer Versus an Everolimus-eluting Stents
Official title: A Randomized Comparison of a Sirolimus-eluting Stent With Biodegradable Polymer Versus an Everolimus-eluting Stent With a Durable Polymer for Percutaneous Coronary Revascularization
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Coronary Artery Disease
Angina Pectoris
Myocardial Infarction
Keywords: coronary artery disease
drug-eluting stents
polymers
Lead sponsor: Insel Gruppe AG, University Hospital Bern
Sponsor class: OTHER
Collaborators: name: Biotronik AG
name: University of Bern
First posted: 2011-09-29
Enrollment: 2119
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: Coronary artery stents have improved the safety and efficacy of percutaneous coronary intervention for coronary artery disease. Drug-eluting stents have been shown to decrease neointimal hyperplasia and to reduce the rate of restenosis and target-lesion revascularization as compared to bare-metal stents. Drug-eluting stents consist of a metallic platform and a therapeutic substance that is usually released from a polymer matrix. A previous study utilizing a bioresorbable polymer has demonstrated a favorable safety and efficacy profile in a large-scale clinical trial as compared to a first-generation druf-eluting stent (LEADERS trial).

The objective of the study is to compare the safety and efficacy of a sirolimus-eluting stent with a biodegradable polymer with an everolimus-eluting stent with a durable polymer in a prospective multicenter randomized controlled non-inferiority trial in patients undergoing percutaneous coronary intervention in routine clinical practice.

Detailed description: Background

Coronary artery stents have improved the safety and efficacy of percutaneous coronary interventions compared with balloon angioplasty alone (New Engl J Med 1994; 331:489-495). Notwithstanding, restenosis is still encountered in 20 to 30% of lesions after implantation of bare metal stents (JAMA 2000; 284:1828-36) and may require repeat revascularization procedures with a negative impact on quality of life and health care expenditures. Drug-eluting stents with local, controlled release of therapeutic agents have addressed this problem successfully (Circulation 2003; 107:3003-7). Current drug-eluting stents consist of a metallic stent platform and a therapeutic agent, which is either directly immobilized on the stent surface or released from a polymer matrix. Polymers currently utilized for drug-eluting stents are either biodegradable or non-biodegradable. While biodegradable polymers are released together with the drug and dissolve after a certain period of time, non-biodegradable polymers reside permanently on the stent surface.

First-generation drug-eluting stents utilized sirolimus and paclitaxel for prevention of restenosis. Both drugs are highly lipophilic and show rapid and strong uptake in arterial wall tissue. In addition, Sirolimus (Circulation 2001; 104:852-5) and paclitaxel (Circulation 1997; 96:636-45) have been shown to reduce smooth muscle cell proliferation and neointimal hyperplasia, the principal cause of restenosis after coronary stenting in experimental models. A polymer-encapsulated stent releasing Sirolimus has been compared with the respective bare metal stent in several randomized clinical trials, demonstrating a consistent reduction in angiographic and clinical restenosis (N Engl J Med 2002; 346:1773-80). Similarly, a polymer-based, paclitaxel-eluting stent consistently reduced restenosis and the need for repeated revascularization procedures compared with the respective bare metal stent (N Engl J Med 2004; 350:221-31). A meta-analysis of drug-eluting stent trials confirmed the reduction in restenosis and repeat revascularization procedures for polymer-based, drug-eluting stents (Lancet 2004; 364:583-91). Moreover, the rates of death and myocardial infarction were comparable to those with bare metal stents, attesting to the safety of these devices, which have been approved by the US Food and Drug Administration.

Newer generation drug-eluting stents with durable polymer coating utilize Limus analogues such as everolimus, zotarolimus or novolimus. Everolimus-eluting stents have been compared to first-generation drug-eluting stents in several randomized clinical trials. A pooled analysis of the four largest randomized trials to date comparing everolimus-eluting stents with paclitaxel-eluting stents demonstrated a lower rate of MACE (4.4% versus 7.6%), myocardial infarction (2.1% vs. 4.0%, p\<0.001), ischemic TLR (2.3% vs. 4.7%, p\<0.001), and definite stent thrombosis (0.4% vs. 1.2%, p\<0.001) in favor of EES, whereas there was no difference with regard to overall and cardiac mortality (Stone GW. The XIENCE V - PROMUS Everolimus-Eluting Stent: New Insights from the SPIRIT/COMPARE Meta-analysis and other randomized trials. Presentation at Transcatheter Cardiovascular Therapeutics, September 22nd 2010). At the same time several trials comparing everolimus-eluting stents with sirolimus-eluting stents reported favorable performance of everolimus-eluting stents. In a randomized trial enrolling 2'774 patients everolimus-eluting stents were non-inferior compared with sirolimus-eluting stents at nine months with regard to MACE (4.9% vs. 5.2%, HR 0.94, 0.67-1.31) and TLR (1.4% vs. 1.7%, HR 0.87, 0.48-1.58) (N Engl J Med 2010;362(28):1663-74). Likewise, event rates at two years were similar for everolimus-eluting stents and sirolimus-eluting stents (3.7% versus 4.3%, p=0.85) in a randomized controlled trial comparing EES, SES, and BMS in large vessels (stent diameter \>3.0 mm), whereas TVR was lower with both EES (3.7%) and SES (4.3%) as compared with bare-metal stents (10.3%, P=0.005 vs SES, P=0.002 vs EES) (N Engl J Med 2010;363(24):2310-9). A propensity-score matched comparison of EES and SES reported lower event rates of myocardial infarction (3.3% versus 5.0%, HR 0.62, 95% CI 0.42-0.92, P=0.017) in part due to a lower risk of stent thrombosis (definite or probable 2.5% versus 4.0%, HR 0.64, 95% CI 0.41-0.98, P=0.041), as well as a lower rate of target vessel revascularization (7.0% versus 9.6%, HR 0.75, 95% CI 0.57-0.99, P=0.039) for EES at three years while mortality was similar (Windecker S. Long-term comparison of Everolimus-eluting and Sirolimus-eluting Stents for coronary revascularization 1 (LESSON1) study. Presentation at the European Society of Cardiology meeting, Stockholm, Sweden, 31st August 2010. 2010).

A previous study utilizing a bioresorbable polymer has demonstrated a favorable safety and efficacy profile in a large-scale clinical trial as compared to a first-generation drug-eluting stent. Among 1,707 patients randomized to either a biolimus-eluting stent with a bioresorbable polymer or a sirolimus-eluting stent with a durable polymer no significant differences with regard to the primary endpoint of cardiac death, myocardial infarction or target-vessel revascularization were observed (9.2% versus 10.5%, HR 0.88, 95% CI 0.64-1.19;: p=0.39)(Lancet 2008;372:1163-73.)

Objective

The objective of the study is to compare the safety and efficacy of a sirolimus-eluting stent with a biodegradable polymer with an everolimus-eluting stent with a durable polymer in a prospective multicenter randomized controlled non-inferiority trial in patients undergoing percutaneous coronary intervention in routine clinical practice.

Methods

Design: Prospective, multi-center, randomized, non-inferiority trial. Patients will be randomized in a single-blind fashion (1:1 randomization) to either the Orsiro® Stent system (Sirolimus-eluting stent with a biodegradable polymer) with the Xience PRIME® stent system (Everolimus-eluting stent with a durable polymer).

Primary endpoint: Target lesion failure (TLF), defined as the composite of cardiac death, target vessel myocardial infarction (MI), and clinically driven target-lesion revascularization (TLR).

Inclusion Criteria: "Real world, all comer" patients with symptomatic coronary artery disease including patients with chronic stable angina, silent ischemia, and acute coronary syndromes including NSTE-ACS and STE-ACS, and presence of one or more coronary artery stenoses \>50% in a native coronary artery or a saphenous bypass graft which can be treated with a stent ranging in diameter from 2.25 to 4.0 mm and can be covered with one or multiple stents.

Eligibility criteria: Inclusion Criteria:

* Age ≥18 years
* Symptomatic coronary artery disease including patients with chronic stable angina, silent ischemia, and acute coronary syndromes including NSTE-ACS and STE-ACS
* Presence of one or more coronary artery stenoses \>50% in a native coronary artery or a saphenous bypass graft which can be treated with a stent ranging in diameter from 2.25 to 4.0 mm and can be covered with one or multiple stents
* No limitation on the number of treated lesions, and vessels, and lesion length

Exclusion Criteria

* Pregnancy
* Known intolerance to aspirin, clopidogrel, heparin, stainless steel, Sirolimus, Everolimus or contrast material
* Inability to provide informed consent
* Currently participating in another trial before reaching first endpoint
* Planned surgery within 6 months of PCI unless dual antiplatelet therapy is maintained throughout the peri-surgical period

Primary outcomes:
measure: Target lesion failure (TLF), defined as the composite of cardiac death, target vessel Q-wave or non-Q wave myocardial infarction (MI), and clinically driven target lesion revascularization (TLR) and emergent coronary artery bypass grafting (CABG)
timeFrame: 12 months
Secondary outcomes:
measure: Number of patients with target lesion revascularization (TLR)
timeFrame: 30 days
measure: Number of patients with target lesion revascularization (TLR)
timeFrame: 1 year
measure: Number of patients with target lesion revascularization (TLR)
timeFrame: 2 years
measure: Number of patients with target lesion revascularization (TLR)
timeFrame: 5 years
measure: Clinically indicated and not clinically indicated target vessel revascularization (TVR)
timeFrame: 30 days
measure: Clinically indicated and not clinically indicated target vessel revascularization (TVR)
timeFrame: 1 year
measure: Clinically indicated and not clinically indicated target vessel revascularization (TVR)
timeFrame: 2 years
measure: Clinically indicated and not clinically indicated target vessel revascularization (TVR)
timeFrame: 5 years
measure: TLF composite of cardiac death, target vessel Q-wave or non-Q wave myocardial infarction (MI)
timeFrame: 30 days
measure: TLF composite of cardiac death, target vessel Q-wave or non-Q wave myocardial infarction (MI)
timeFrame: 2 years
measure: TLF composite of cardiac death, target vessel Q-wave or non-Q wave myocardial infarction (MI)
timeFrame: 5 years
measure: All-cause mortality
timeFrame: 30 days
measure: All-cause mortality
timeFrame: 1 year
measure: All-cause mortality
timeFrame: 2 years
measure: All-cause mortality
timeFrame: 5 years
measure: Definite stent thrombosis
timeFrame: 30 days
measure: Definite stent thrombosis
timeFrame: 1 year
measure: Definite stent thrombosis
timeFrame: 2 years
measure: Definite stent thrombosis
timeFrame: 3 years
measure: Definite stent thrombosis
timeFrame: 5 years
measure: Myocardial infarction (Q-wave and NQWMI)
timeFrame: 30 days
measure: Myocardial infarction (Q-wave and NQWMI)
timeFrame: 1 year
measure: Myocardial infarction (Q-wave and NQWMI)
timeFrame: 2 years
measure: Myocardial infarction (Q-wave and NQWMI)
timeFrame: 3 years
measure: Myocardial infarction (Q-wave and NQWMI)
timeFrame: 5 years
Other outcomes:
Locations:
city: Aarau
country: Switzerland
facility: Kantonsspital Aarau
city: Basel
country: Switzerland
facility: Universitätsklinik Basel
city: Bern
country: Switzerland
facility: Department of Cardiology, Bern University Hospital
city: Freiburg
country: Switzerland
facility: HFR Freiburg
city: Genève
country: Switzerland
facility: Hôpitaux Universitaires de Genève
city: Lausanne
country: Switzerland
facility: Service de cardiologie CHUV
city: Luzern
country: Switzerland
facility: Luzerner Kantonsspital
city: St. Gallen
country: Switzerland
facility: Kantonsspital St. Gallen
city: Zürich
country: Switzerland
facility: Stadtspital Triemli
Study officials:
affiliation: Department of Cardiology, Bern University Hospital, Switzerland
name: Stephan Windecker
role: PRINCIPAL_INVESTIGATOR
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