A Prospective, Randomized Trial of Everolimus-Eluting and Sirolimus-Eluting Stents in Patients with Coronary Artery Disease

The SORT OUT IV Trial

Presentation by-Dr Awadhesh Kr Sharma,DM

cardiology

Authors/Investigators

Lisette Okkels Jensen, Per Thayssen, Henrik Steen Hansen, Evald Hoj Christiansen, Hans Henrik Tilsted, Lars Romer

Krusell, Anton Boel Villadsen, Anders Junker, Knud Norregaard

Hansen, Anne Kaltoft, Michael Maeng, Knud Erik Pedersen, Steen Dalby Kristensen, Hans Erik Botker, Jan Ravkilde,

Richardo Sanchez, Jens Aaroe, Morten Madsen, Henrik Toft Sorensen, Leif Thuesen, Jens Flensted Lassen

Odense University Hospital, Aarhus University Hospital Skejby and Aalborg, Varde

Denmark

Disclosure Statement of Financial Interest

• Lisette Okkels Jensen, MD DMSci, Ph.D. FESC:

• Within the past 12 months, authors had a financial interest/arrangement or affiliation with the organization(s) listed below.

Cordis, Johnson & Johnson: CEC member Abbott: Advisory board member

BACKGROUND Compared with bare metal stents, first-generation drug-eluting stents, such as

sirolimus- and paclitaxel-eluting stents, have shown improved results and reduced the need for repeat revascularization, as assessed in randomized trials

Second-generation drug-eluting stents were designed to improve efficacy, safety, and device performance

The sirolimus-eluting stent has demonstrated the least amount of late lumen loss among previously released first-generation drug-eluting stents, but its efficacy and safety have not been compared head-to-head with the second-generation everolimus-eluting stent

• Debate continues on the safety of first generation drug-eluting stents, given the potential for late stent thrombosis, especially after discontinuation of dual antiplatelet therapy.

• The zotarolimus-eluting Endeavor stent, did not appear superior to the sirolimus-eluting stent in routine practice.

• The next second-generation drug eluting stent, the everolimus-eluting stent, proved superior to the paclitaxel-eluting stent, with a lower rate of stent thrombosis, myocardial infarction, and target vessel revascularization and reduced angiographic late loss.

SORT OUT III:Lancet. 2010;375:1090 –1099

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15

1.2 0.2

20

SORT-OUT III

• MI (p = 0.03), definite stent thrombosis (p = 0.02), target lesion revascularization (p < 0.0001), and clinically significant restenosis (p < 0.0001) were all more frequent with ZES compared with SES

• Overall mortality was similar (p = 0.27)

Trial design: SORT-OUT III was a randomized trial of the Endeavor zotarolimus-eluting stent (ZES) vs. the sirolimus-eluting stent (SES) in patients undergoing PCI. Clinical outcomes were compared at 9 months.

Results

Conclusions

• ZES associated with worse outcomes, including stent thrombosis, compared with SES at 9 months

• Long-term follow-up data are awaited

• Similar to other trials showing higher restenosis with ZES; further investigation is required

Presented by Dr. Jens Flensted Lassen at TCT 2008

ZES(n = 1,162)

SES(n =

1,171)

(p = 0.02)

Stent thrombosis

10

SORT OUT IV - Objective

• To compare the efficacy and safety of the first-generation sirolimus-eluting Cypher Select+ stent and the second-generation everolimus-eluting Xience V/Promus stent in a population-based healthcare setting.

The Scandinavian Organization for Randomized Trials with Clinical Outcome (SORT OUT) IV trial

Methods

• Patients and Study DesignA randomized, multicenter, single-blind, all

comer,2-arm, noninferiority trialThe study period was August 2007 to June

2009

Eligible patients

• Patients were at least 18 years of age• Had chronic stable coronary artery disease or

acute coronary syndromes and at least 1 coronary artery lesion with 50% diameter stenosis requiring treatment with a drug-eluting stent

No restrictions were placed on the number of treated lesions, number of treated vessels, or lesion length

Exclusion criteria

• Life expectancy of 1 year• An allergy to aspirin, clopidogrel, sirolimus, or

everolimus• Participation in another randomized trial• Inability to provide written informed consent

Randomization

• Pts were randomly allocated to treatment groups after diagnostic coronary angiography and before percutaneous coronary intervention.

• Block randomization by center(permuted blocks of random sizes [2/4/6]) was used to assign patients in a 1:1 ratio to receive the everolimus-eluting stent (Xience V, Abbott Vascular, or PROMUS, Abbott’s privately labeled Xience V Everolimus Eluting Coronary Stent System distributed by Boston Scientific Corp) or the sirolimus-eluting stent (Cypher Select, Cordis, Johnson &Johnson)

• Patients were assigned to treatment through an automated telephone allocation service

• Although operators were unblinded, all patients and individuals analyzing data were masked to treatment assignment.

Study Procedures

• Stents were implanted according to standard techniques.

• Direct stenting without prior balloon dilation was allowed.

• Full lesion coverage was attempted by implanting >1 stents.

• Before implantation, patients received at least 75 mg aspirin, a 600-mg loading dose of clopidogrel, and a dose of unfractionated heparin dose (5000 IU or 70–100 IU/kg)

• Recommended postprocedural dual antiplatelet regimens were 75 mg aspirin daily lifelong and 75 mg clopidogrel daily for 1 year

End Points

• The primary end point was a combination of safety (cardiac death,myocardial infarction, definite stent thrombosis) and efficacy (clinically indicated target vessel revascularization) parameters within 9 months of stent implantation

• Intention-to-treat analyses were conducted after 9 and 18 months of follow-up

• Individual components of the primary end point comprised the secondary end points: cardiac death rate; myocardial infarction rate; definite stent thrombosis rate; rate of clinically indicated target vessel revascularization; rate of probable, possible, and overall stent thrombosis; symptom driven target lesion revascularization; and device failure (defined as inability to implant the assigned study stent in >1 target lesions).

Definitions

• Definite stent thrombosis-• Angiographic confirmation of stent thrombosis• The presence of a thrombus that originates in the stent or in the segment 5 mm

proximal or distal to the stent and presence of at least 1 of the following criteria within a 48-hour time window:

Acute onset of ischemic symptoms at rest             New ischemic ECG changes that suggest acute ischemia             Typical rise and fall in cardiac biomarkers

• Definite stent thrombosis is considered to have occurred by either angiographic or pathological confirmation.

• The incidental angiographic documentation of stent occlusion in the absence of clinical signs or symptoms is not considered a confirmed stent thrombosis (silent occlusion).

Consolidated standards of reporting trials(CONSORT) statement

Probable stent thrombosis

• Clinical definition of probable stent thrombosis is considered to have occurred after intracoronary stenting in the following cases:        

Any unexplained death within the first 30 days        Irrespective of the time after the index procedure,

Any MI that is related to documented acute ischemia in the territory of the implanted stent without angiographic confirmation of stent thrombosis and in the absence of any other obvious cause

• For studies with ST-elevation MI population, one may consider the exclusion of unexplained death within 30 days as evidence of probable stent thrombosis

   • Clinical definition of possible stent thrombosis

is considered to have occurred with - any unexplained death from 30 days after

intracoronary stenting until end of trial follow-up.

Possible stent thrombosis 

Cardiac death

• Any death resulting from an evident cardiac cause, any death related to percutaneous coronary intervention, an unwitnesseddeath, or death from unknown causes.

Target vessel revascularization

• Any repeat percutaneous coronary intervention or surgical bypass of any segment within the entire major coronary vessel that was proximal or distal to a target lesion, including upstream and downstream branches, and the target lesion itself.

Target lesion revascularization

• Repeat revascularization caused by a 50% stenosis within the stent or within a 5-mm border proximal or distal to the stent.

Trial flow diagram.

Okkels Jensen L et al. Circulation 2012;125:1246-1255

Copyright © American Heart Association

RESULTS

Time-to-event curves for major adverse cardiac events.

Okkels Jensen L et al. Circulation 2012;125:1246-1255

Copyright © American Heart Association

Discussion

• The first head-to-head comparison of the everolimus-eluting stent and the sirolimus-eluting stent.

• Noninferiority of the everolimus-eluting stent overall, and across a variety of patient and lesion subgroups.

• Rates of cardiac mortality, myocardial infarction, and target vessel revascularization did not differ significantly between the 2 groups.

• Definite stent thrombosis was lower in the everolimus-eluting stent group

• Extensive comparisons of sirolimus-eluting and paclitaxel-eluting stents demonstrated similar safety and probably higher efficacy for the sirolimuseluting stent.

• The Second-Generation Everolimus-Eluting and Paclitaxel-Eluting Stents in Real-Life Practice (COMPARE) trial and the Everolimus-Eluting Versus Paclitaxel-Eluting Stents in Coronary Artery Disease (SPIRIT IV) trial comparing everolimus-eluting and paclitaxel-eluting stents showed a favorable safety and efficacy profile for the everolimus-eluting stent.

• In the SPIRIT V trial, the everolimus-eluting stent demonstrated lower rates of target vessel failure.

• In the COMPARE trial, it demonstrated a reduced rate of combined all-cause mortality, nonfatal myocardial infarction, target vessel revascularization, and early definite stent thrombosis compared with paclitaxel-eluting stents

• A positive safety profile for the everolimus-eluting stent also emerged in long-term registry-based follow-up studies and in the SPIRIT I through III studies

• Surprisingly, present study showed a significant association with less definite stent thrombosis in patients treated with the everolimus-eluting stent

• In the Comparison of Zotarolimus-Eluting and Everolimus-Eluting Coronary Stents (RESOLUTE) trial in which the everolimus-eluting stent was associated with significantly less definite stent thrombosis than the zotarolimus-eluting Endeavor Resolute stent.

• The low rates of definite stent thrombosis observed in the present trial also were comparable to those in the everolimus-eluting groups in 3 large randomized trials: COMPARE, RESOLUTE, and SPIRIT IV, in which the rates after 12 months were 0.4%, 0.3%, and 0.3%,respectively.

• The definite stent thrombosis results were a secondary end point that should be interpreted with caution and need replication to confirm that they are not spurious

• We found a slightly lower reintervention rate in our everolimus-eluting stent group compared with the RESOLUTE trial, most likely because of the 18-month follow-up interval in our study and the 24-month follow-up interval in the RESOLUTE trial.

LIMITATION

• It is important to note that our follow-up period of 18 months may be too short to assess the risk of very late stent thrombosis.

• The SORT OUT II, III, and IV studies relied on registry-based event detection without study-related angiographic or clinical follow-up.

• A single-blind study

SORT OUT IV

• MACE for EES vs. SES: 4.9% vs. 5.2%, p for noninferiority = 0.01

• Target vessel revascularization: 2.8% vs. 3.5%, MI: 1.1% vs. 1.4% (p > 0.05 for all)

• Stent thrombosis: 0.9% vs. 0.9%, p = 0.83

Trial design: Patients with coronary artery disease from Denmark were randomized to receive either everolimus-eluting stents (EES) or sirolimus-eluting stents (SES). Patients were followed for 1 year.

Results

Conclusions

Presented by Dr. Lisette Okkels Jensen at TCT 2010

(p = 0.32)

EES(n = 1,390)

Target vessel revascularization

• EES was noninferior to SES for MACE at 12 months; other outcomes including stent thrombosis were similar

• Adds to recently presented head-to-head data comparing EES with SES; further long-term data are awaited

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5

10

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2.83.5

(p = 0.83)

0.9 0.9

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Stent thrombosis

SES(n = 1,384)

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10

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CONCLUSION

• The everolimus-eluting stent was found to be noninferior to the sirolimus-eluting stent for patients treated with percutaneous coronary intervention.

• 2-Year Patient-Related Versus Stent-Related Outcomes

The SORT OUT IV (Scandinavian Organization for Randomized Trials With Clinical Outcome IV) Trial

• Safety and efficacy outcomes at 2 years were further assessed with specific focus on patient-related composite (all death, all MI, or any revascularization) and stent-related composite outcomes (cardiac death, target vessel MI, or symptom-driven target lesion revascularization).

RESULTS

• At 2 years, the composite primary endpoint occurred in 8.3% in the EES group and in 8.7% in the SES group (hazard ratio [HR]: 0.94, 95% confidence interval [CI]: 0.73 to 1.22).

• The patient-related outcome: 15.0% in the EES group versus 15.6% in the SES group, (HR: 0.95, 95% CI: 0.78 to 1.15).

• The stent-related outcome: 5.2% in the EES group versus 5.3% in the SES group (HR: 0.97, 95% CI: 0.70 to 1.35) did not differ between groups.

• Rate of definite stent thrombosis was lower in the EES group (0.2% vs. 0.9%, (HR: 0.23, 95% CI: 0.07 to 0.80).

Conclusions

• At 2-year follow-up, the EES was found to be noninferior to the SES with regard to both patient-related and stent-related clinical outcomes