SORT OUT IV TRIAL

1. 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

2. 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

3. 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

4. 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

5. • 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

6. SORT-OUT III
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
(p = 0.02) • MI (p = 0.03), definite stent thrombosis (p =
0.02), target lesion revascularization (p <
20 0.0001), and clinically significant restenosis (p <
0.0001) were all more frequent with ZES
compared with SES
15 • Overall mortality was similar (p = 0.27)
%
10 Conclusions
5 • ZES associated with worse outcomes, including
stent thrombosis, compared with SES at 9 months
1.2 0.2
0 • Long-term follow-up data are awaited
• Similar to other trials showing higher restenosis
Stent thrombosis with ZES; further investigation is required
ZES SES
(n = 1,162) (n = Presented by Dr. Jens Flensted Lassen at
1,171) TCT 2008

8. 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

9. Methods
• Patients and Study Design
A randomized, multicenter, single-blind, all
comer,2-arm, noninferiority trial
The study period was August 2007 to June
2009

10. 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

11. 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

12. 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)

13. • 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.

14. 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.

15. • 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

16. 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

17. • 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).

18. 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

19. 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

20. Possible 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.

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

22. 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.

23. 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.

24. Trial flow diagram.
Okkels Jensen L et al. Circulation 2012;125:1246-1255
Copyright © American Heart Association

27. RESULTS

29. Time-to-event curves for major adverse cardiac events.
Okkels Jensen L et al. Circulation 2012;125:1246-1255
Copyright © American Heart Association

30. 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.

31. • 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.

32. • 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.

33. • 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

34. • 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.

35. • 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.

36. • 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.

37. 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

38. SORT OUT IV
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.
(p = 0.32) (p = 0.83) Results
• MACE for EES vs. SES: 4.9% vs. 5.2%, p for
noninferiority = 0.01
10 10
• 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
% 5 % 5
3.5
2.8 Conclusions
0.9 0.9 • EES was noninferior to SES for MACE at 12 months;
0 0 other outcomes including stent thrombosis were similar
Target vessel Stent thrombosis • Adds to recently presented head-to-head data
revascularization comparing EES with SES; further long-term data are
awaited
EES SES
(n = 1,390) (n = 1,384)
Presented by Dr. Lisette Okkels Jensen at
TCT 2010

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

40. • 2-Year Patient-Related Versus Stent-Related
Outcomes
The SORT OUT IV (Scandinavian Organization for Randomized Trials With
Clinical Outcome IV) Trial

41. • 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).

42. 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).

43. 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