September 26, 2008

Title: Potential NCD for Off-Label Use of Drug-
eluting Coronary Stents
(As posted to the CMS website July 30, 2008)

Cordis Corporation appreciates the effort CMS has
taken to make available the list of potential
National Coverage Determination (NCD) topics and
to elicit public comment, prior to opening an
NCD. The topic, off-label use of drug-eluting
coronary stents, raises the question of whether
adequate evidence is available to determine which
patient groups benefit from treatment with
coronary stents. We have thoughtfully reviewed
the off-label use of drug-eluting coronary stents
and find the evidence strongly supports continued
coverage for both on-label and off-label use.

Drug-eluting stents approved for use in the
United States have similar, although not
identical, labeling. The CYPHERâ sirolimus-
eluting coronary stent (SES) is indicated for
improving coronary luminal diameter with
symptomatic ischemic disease due to de novo
lesions of length £ 30mm in native coronary
arteries with a reference vessel diameter of ³
2.50 to £ 3.50 mm.

Based on an extensive body of evidence,
interventional cardiologists around the world
have realized the clinical impact and patient
benefits of drug-eluting stents (DES) and as a
result, have proactively chosen to treat 3
million patients with SES. Outcomes data has
been collected through more than 70 studies
conducted since launch in on-label and in many
off-label patient populations, such as diabetic
patients, patients with small vessels, patients
who suffer an acute myocardial infarction with an
emergent need for immediate revascularization,
patients who experience in-stent restenotic
lesions, and patients with multi- vessel disease,
lesions longer than 30mm, ostial lesions or
lesions that are located in saphenous vein
grafts, bifurcations, or in an unprotected left
main coronary artery.
From launch in March 2003 to current date, the
CYPHERâ sirolimus-eluting coronary stent has been
the most studied DES in the United States and
abroad. Below is an overview of the vast array
of randomized controlled trials (RCTs) and non-
RCTs that have evaluated the safety and efficacy
of on-label and off-label use of DES. It is
important to mention that of the 46 RCTs, 8
represent mostly on-label use while the remaining
38 represent off-label use of DES. All of these
studies provide important data on the safety and
efficacy outcomes for varying patient and lesions
types. This extensive body of evidence
illustrates that “off-label” does not mean “not
studied.” While the FDA has not made a final
determination of DES safety and efficacy in these
populations, substantial clinical data exists in
these patient and lesion types to allow
physicians to make informed medical judgments
regarding the appropriateness of DES treatment
for their individual patients.

SLIDE ON FILE WITH CMS

Cordis will provide details on the specifics of
each study upon request.

Several meta-analyses of these RCTs comparing DES
and bare metal stents (BMS) were published in
peer review journals in 2007. 1,2,3,4 Of note,
the ACC/AHA/SCAI Practice Guidelines 2006
(http://circ.ahajournals.org) state meta-analysis
of multiple RCTs is the highest level of
evidence.

In the RCT meta-analysis comparing CYPHERâ to
BMS, there was a significant reduction in the
combined risk of death, myocardial infarction, or
re-intervention (hazard ratio, 0.43; 95%
confidence interval [CI], 0.34 to 0.54)
associated with the use of SES. There was a
slight increase (not statistically significant)
in the risk of stent thrombosis associated with
SES after the first year. However, there was no
significant difference in the overall risk of
stent thrombosis at 12 to 59 months of follow-up
with SES vs. BMS (hazard ratio, 1.09; 95% CI,
0.64 to 1.86). The overall risk of death (hazard
ratio, 1.03; 95% CI, 0.80 to 1.30) and the
combined risk of death or myocardial infarction
(hazard ratio, 0.97; 95% CI, 0.81 to 1.16) were
not significantly different for patients
receiving SES vs. BMS at 12 to 59 months follow-
up. Of note, the authors also reported outcomes
by on- and off-label RCTs in a follow-up meta-
analysis of 17 RCTs. In this analysis, there was
no evidence that off-label use of SES was
associated with compromised safety compared to
BMS .1,2
Additional safety and efficacy evidence of DES
use was found in a more comprehensive network
meta-analysis of 38 RCTs (18,023 patients) with a
follow-up to 4 years, comparing either CYPHERâ
vs. BMS, Taxus (paclitaxel-eluting coronary
stent) vs. BMS, or CYPHERâ vs. Taxus, published
in the Lancet 2007. In this study, Stettler et
al. noted that mortality was similar in the three
groups: hazard ratios (HR) were 1.00 (95%
credibility interval 0.82-1.25) for SES vs. BMS,
1.03 (0.84-1.22) for paclitaxel-eluting (PES)
versus BMS, and 0.96 (0.83-1.24) for SES vs.
PES. Other key findings noted that SES were
associated with the lowest risk of myocardial
infarction (HR 0.81, 95% credibility interval
0.66-0.97, p=0.030 vs BMS; 0.83, 0.71-1.00,
p=0.045 vs. PES) and that there were no
significant differences in the risk of definite
stent thrombosis (0 days to 4 years). However,
the risk of late definite stent thrombosis (>30
days) was increased with PES (HR 2.11, 95%
credibility interval 1.19-4.23, p=0.017 vs. BMS;
1.85, 1.02-3.85, p=0.041 vs. SES). In addition,
the reduction in target lesion revascularization
seen with DES compared with BMS was more
pronounced with SES than with PES (0.70, 0.56-
0.84; p=0.0021). Overall, the authors indicated
the risks of mortality associated with DES and
BMS were similar and noted that SES seemed to be
clinically better than BMS and PES in this
analysis.2

Database and registry data also contribute to a
better understanding of the safety and efficacy
of DES use in all-comer populations. Patient
level data from 3 Medicare beneficiary database
analyses comparing 2-year patient outcomes among
>50,000 DES and BMS recipients, found that the
widespread adoption of DES into routine practice
was associated with a significant survival
benefit among the elderly, a decline in the need
for repeat revascularization procedures and a
similar risk for death or ST-elevation myocardial
infarction when compared to BMS.35,36,37
Furthermore, studies from the National Heart,
Lung and Blood Institute Dynamic Registry and the
Wake Forest Registry have had similar findings
relevant to the widespread use of DES.38,39

Among the many RCT analyses, real world registry
data and non-randomized studies that are noted in
peer reviewed journal publications, there is a
consistent body of evidence indicating the use of
DES in on-label and many off-label settings is
associated with a sustained reduction in the need
for reintervention and that the safety is
comparable to that seen with BMS. 1,2, 3

Cordis encourages CMS to explore the extensive
body of evidence related to the long-term safety
and efficacy in off-label use of the CYPHERâ
sirolimus-eluting stent and other drug-eluting
stents, and welcomes the opportunity to work with
CMS in this regard.

Sincerely,




Ryan H. Saadi, M.D., M.P.H.
Vice President, Health Economics and Reimbursement
Cordis Corporation




References:

Meta-Analyses
1) Kastrati A, Mehili J, Pache J., et al.
Analysis of 14 trials comparing sirolimus-eluting
stents with bare-metal stents. N Engl J Med. 2007
Mar 8;356(10):1030-9. Epub 2007 Feb 12.)
2) Stettler C, Wandel S, Allemann S., et al.
Outcomes associated with drug-eluting and bare-
metal stents: a collaborative network meta-
analysis. Lancet 2007 Sep 15;370(9591):937-48
3) Schomig A, Dibra A, Windecker S., et al. A
meta-analysis of 16 randomized trials of
sirolimus-eluting stents versus paclitaxel-
eluting stents in patients with coronary artery
disease. J Am Coll Cardiol. 2007 Oct 2;50
(14):1373-80.
4) Kastrati A. Schomig A. Drug-eluting stents is
their future as bright as their past? J Am Coll
Cardiol. 50(2):146-8, 2007 Jul 10.

SES SMART
5) Ardissino D, Cavalli C, Bramucci E, et al.
Sirolimus-eluting vs uncoated stents for
prevention of restenosis in small coronary
arteries: a randomized trial. JAMA. 2004 Dec 8;292
(22):2727-34
6) Ortolani P, Ardissino D, Cavallini C, et al.
Effect of sirolimus-eluting stent in diabetic
patients with small coronary arteries (a SES-
SMART substudy). Am J Cardiol. 2005 Nov 15;96
(10):1393-8. Epub 2005 Sep 27

ISAR SMART
7) Mehilli J, Dibra A, Kastrati A, et al.
Randomized trial of paclitaxel- and sirolimus-
eluting stents in small coronary vessels. Eur
Heart J. 2006 Feb;27(3):260-6. Epub 2006 Jan 9.

PARK Long Lesion II
8) Kim YH, Park SW, Park DW., et al. Sirolimus-
eluting stent versus paclitaxel-eluting stent for
patients with long coronary artery disease.
Circulation. 2006 Nov 14;114(20):2148-53. Epub
2006 Oct 23

DIABETES TRIAL
9) Jimenez-Quevedo P, Sabate M, Angiolillo DJ.,
et al. Long-term clinical benefit of sirolimus-
eluting stent implantation in diabetic patients
with de novo coronary stenoses: long-term results
of the DIABETES trial. European Heart Journal. 28
(16):1946-52, 2007 Aug.
10) Sabate M, Jimenez-Quevedo P, Angiolillo DJ.,
et al. Randomized comparison of sirolimus-eluting
stent versus standard stent for percutaneous
coronary revascularization in diabetic patients:
the diabetes and sirolimus-eluting stent
(DIABETES) trial. Circulation. 112(14):2175-83,
2005
Oct 4.

DECODE
11) Charles Chan, MD, Robaayah Zambahari, MD,
Upendra Kaul, MD DM., et al. A randomized study
with sirolimus-eluting BX velocity balloon-
expandable stent in the treatment of diabetic
patients with native coronary artery lesions. AHA
Oral Presentation 2005

SCORPIUS
12) Baumgart D, Klauss V, Baer F., et al. One-
year results of the SCORPIUS study: a German
multicenter investigation on the effectiveness of
sirolimus-eluting stents in diabetic patients.
Journal of the American College of Cardiology,
Volume 50 , Issue 17 , Pages 1627 – 1634

CARDIA
13)Coronary Artery Revascularization in Diabetes
Trial. The Heart.org and Oral presentation ESC
2008

DESSERT
14) Maresta A, Varani E, Balducelli M., et al
Comparison of effectiveness and safety of
sirolimus-eluting stents versus bare-metal stents
in patients with diabetes mellitus (from the
Italian Multicenter Randomized DESSERT Study). Am
J Cardiol. 2008 Jun 1;101(11):1560-6. Epub 2008
Apr 11

ISAR DIABETES
15) Dibra A, Kastrati A, Mehilli J., et al.
Paclitaxel-eluting or sirolimus-eluting stents to
prevent restenosis in diabetic patients. N Engl
J Med. 2005 Aug 18;353(7):663-70. Epub 2005 Aug
16.

KOREAN Study
16) Kim MH, Hong SJ, Cha KS., et al. Effect of
Paclitaxel-eluting versus sirolimus-eluting
stents on coronary restenosis in Korean diabetic
patients. J Interv Cardiol. 2008 Jun;21(3):225-
31. Epub 2008 Mar 13.

DECLARE
17) Lee SW, Park SW, Kim YH., et al. Drug-eluting
stenting followed by cilostazol treatment reduces
late restenosis in patients with diabetes
mellitus the DECLARE-DIABETES Trial (A Randomized
Comparison of Triple Antiplatelet Therapy with
Dual Antiplatelet Therapy After Drug-Eluting
Stent Implantation in Diabetic Patients). J Am
Coll Cardiol. 2008 Mar 25;51(12):1181-7.

SWEDISH RTC
18) Jensen, L, Maeng M, Thayssen P., et al.
Extent and patterns of neointimal hyperplasia
distribution after drug-eluting stent
implantation in diabetic patients assessed by
intravascular ultrasound. WCC 2008; Circ 2008
Buenos Airies

ITALIAN RCT
19) Tomai F, Reimers B, De Luca L., et al. Head-
to-head comparison of sirolimus- and paclitaxel-
eluting stent in the same diabetic patient with
multiple coronary artery lesions: a prospective,
randomized, multicenter study. Diabetes Care.
2008 Jan;31(1):15-9. Epub 2007 Oct 1.

PRISON II
20) Suttorp MJ, Laarman GJ, Rahelll BM., et al.
Primary Stenting of Totally Occluded Native
Coronary Arteries II (PRISON II): a randomized
comparison of bare metal stent implantation with
sirolimus-eluting stent implantation for the
treatment of total coronary occlusions.
Circulation. 2006 Aug 29;114(9):921-8. Epub 2006
Aug 14.

SISR
21) Holmes DR Jr., Terstein P, Statler L., et
al. Sirolimus-eluting stents vs vascular
brachytherapy for in-stent restenosis within bare-
metal stents: the SISR randomized trial. JAMA.
2006 Mar 15;295(11):1264-73. Epub 2006 Mar 12.


RIBS II
22) Alfonso F, Perez-Vizcayno MJ, Hernandez R.,
et al. A randomized comparison of sirolimus-
eluting stent with balloon angioplasty in
patients with in-stent restenosis: results of the
Restenosis Intrastent: Balloon Angioplasty Versus
Elective Sirolimus-Eluting Stenting (RIBS-II)
trial. J Am Coll Cardiol. 2006 Jun 6;47(11):2152-
60.

INDEED
23) Park SW, Lee SW, Koo BK., et al. Treatment
of diffuse IN-stent restenosis with Drug-Eluting
stents vs. intracoronary bEta-raDiation therapy:
INDEED Study. Int J Cardiol. 2008 Jan 9.

TYPHOON
24) Spaulding C, Henry P, Teiger E., et al.
Sirolimus-eluting versus uncoated stents in acute
myocardial infarction. N Engl J Med. 2006 Sep
14;355(11):1093-104.

SESAMI
25) Menichelli M, Parma A, Pucci E., et al.
Randomized trial of Sirolimus-Eluting Stent
Versus Bare-Metal Stent in Acute Myocardial
Infarction (SESAMI). J Am Coll Cardiol. 2007 May
15;49(19):1924-30. Epub 2007 Apr 30.

MISSION,
26) van der Hoeven BL, Liem SS, Jukema JW., et
al. Sirolimus-eluting stents versus bare-metal
stents in patients with ST-segment elevation
myocardial infarction: 9-month angiographic and
intravascular ultrasound results and 12-month
clinical outcome results from the MISSION!
Intervention Study. J Am Coll Cardiol. 2008 Feb
12;51(6):618-26.

STRATEGY
27) DeLuca L, Sardella G., et al. Tirofiban plus
sirolimus-eluting stent vs abciximab plus bare-
metal stent.
JAMA. 2005 Oct 5;294(13):1617; author reply 1617-
8.


STRATEGY II
28)Valgimigli M, Campo G, Arcozzi C., et al. Two-
year clinical follow-up after sirolimus-eluting
versus bare-metal stent implantation assisted by
systematic glycoprotein IIb/IIIa Inhibitor
Infusion in patients with myocardial infarction:
results from the STRATEGY study. J Am Coll
Cardiol. 2007 Jul 10;50(2):138-45. Epub 2007 May
22

DIAZ
29) Diaz de la Llena LS, Ballesteros S, Nevado
J., et al Sirolimus-eluting stents compared with
standard stents in the treatment of patients with
primary angioplasty. Am Heart J. 2007 Jul;154
(1):164.e1-6
DiLorenzo
30) DiLorenzo E, Varricchio A, Lanzillo T., et
al. Paclitaxel and Sirolimus Stent Implantation
in Patients with Acute Myocardial Infarction.
Scientific Sessions 2005

pROSIT
31) Lee JH, Kim HS, Lee SW., et al. Prospective
randomized comparison of sirolimus- versus
paclitaxel-eluting stents for the treatment of
acute ST-elevation myocardial infarction: pROSIT
trial.
Catheter Cardiovasc Interv. 2008 Jul 1;72(1):25-32

SCANDSTENT
32) Kelbaek H, Kløvgaard L, Helqvist S., et al.
Long-term outcome in patients treated with
sirolimus-eluting stents in complex coronary
artery lesions: 3-year results of the SCANDSTENT
(Stenting Coronary Arteries in Non-
Stress/Benestent Disease) trial. J Am Coll
Cardiol. 2008 May 27;51(21):2011-6.

PRISC
33) Vermeersch P, Agostoni P, Verheye S., et al.
Randomized Double-Blind Comparison of Sirolimus-
Eluting Stent Versus Bare-Metal Stent
Implantation in Diseased Saphenous Vein Grafts.
American College of Cardiology. 48(12):2423-31,
2006 Dec 19.

34) Agostoni P, Vermeersch P, Semeraro O., et al.
Intravascular ultrasound comparison of sirolimus-
eluting stent versus bare metal stent
implantation in diseased saphenous vein grafts
(from the RRISC [Reduction of Restenosis In
Saphenous Vein Grafts With Cypher Sirolimus-
Eluting Stent] trial). American Journal of
Cardiology. 100(1):52-8, 2007 Jul

Medicare Database Studies
35) Groeneveld PW, Matta MA, Greenhut AP., et
al. Drug-eluting compared with bare-metal
coronary stents among elderly patients. J Am Coll
Cardiol. 51(21):2017-24, 2008 May

36) Malenka DJ, Kaplan AV, Lucas FL., et al.
Outcomes following coronary stenting in the era
of bare-metal vs the era of drug-eluting stents.
JAMA. 299(24):2868-76, 2008 Jun 25.

37) Wang F, Uretsky B, Freeman J., et al.
Survival advantage in Medicare patients receiving
drug-eluting stents compared with bare metal
stents: Real or artefactual? Catheterization and
Cardiovascular Interventions 71:636–643 (2008)

NHLB Institute
38) Marroquin O, Selzer F, Mulukutla S., et al.
A Comparison of Bare-Metal and Drug-Eluting
Stents for Off-Label Indications. NEJM. 358:331-
341

Wake Forest
39) Applegate RJ, Sacrinty MT, Kutcher MA., et
al. "Off-label" stent therapy 2-year comparison
of drug-eluting versus bare-metal stents. J Am
Coll Cardiol. 51(6):607-14, 2008 Feb 12.