1. Journal Club Presentation
First-in-Human Evaluation of a Bioabsorbable Polymer-Coated Sirolimus-
Eluting Stent Imaging and Clinical Results of the DESSOLVE I Trial (DES With
Sirolimus and a Bioabsorbable Polymer for the Treatment of Patients With
De Novo Lesion in the Native Coronary Arteries)
by
ORMISTON, J., WEBSTER, M., STEWART, J., VROLIX, M., WHITBOURN, R., DONOHOE, D., KNAPE, C.,
LANSKY, A., ATTIZZANI, G. F., FITZGERALD, P., KANDZARI, D. E. & WIJNS, W.
Jacc-Cardiovascular Interventions. 2013;6(10):1026-1034.
CDL402 Assignment
Registration number 150118756

2. • Coronary artery disease is the leading cause of mortality and morbidity
in the world. Its pathogenesis is the development of atherosclerotic
lesions in coronary arteries
• Coronary stents have substantially evolved since their first therapeutic
use in 1986
• First drug eluting stent (DES) containing sirolimus, was implanted in
coronary artery in 1999
• In 2011, European Medicines Agency approved the use of bioabsorbable
vascular scaffold in Europe
Iqbal J, Gunn J, Serruys PW. Coronary stents: historical development, current status and future directions. British Medical Bulletin. 2013

3. Stents1st generation
2nd generation
3rd generation
Stainless steel
Cobalt Chromium
Platinum Chromium
Figure: Typical DES, cross-section
Figure: Vascular changes after implantation of DES in a coronary vessel after atherosclerosis formation
Figure collected from, Nakano M, Otsuka F, Yahagi K, et al. Human autopsy study of drug-eluting stents
restenosis: histomorphological predictors and neointimal characteristics. European Heart Journal. 2013

4. Dual antiplatelet therapy (DAPT):
• Due to the risk of stent thrombosis, all patients undergoing percutaneous
coronary intervention (PCI) and stenting, receive DAPT, unless there is a
contraindication
• Duration and choice of anti-platelet agents are controversial and mostly
depend on the patient presentation
• Usually after PCI, aspirin with either clopidogrel or ticlopidine or prasugrel
are advised for 6-12 months. After that, aspirin is advised for lifetime
Iqbal J, Gunn J, Serruys PW. Coronary stents: historical development, current status and future directions. British Medical Bulletin. 2013

5. Complications of using durable polymer
coating antiproliferative DES
• Complications from delayed wound healing
• Hypersensitivity reaction
• Neoatheroma formation
• Restenosis, with the potential for repeat intervention
• Stent thrombosis (ST)
• Acute MI (Myocardial Infarction)
• Sudden death

6. What was the need to look for DES with
biodegradable source?
• Potential link between the permanent polymer and late adverse
effects has prompted the use of biodegradable sources of drug
delivery to the stent vessel
• Additionally,
• Absorbable polymer eluting antiproliferative drug may lower the rate of
stent thrombosis, especially beyond 1 year after stent implantation
• Stents with absorbable polymers may allow shorter duration of DAPT
than currently recommended1
1. Valgimigli M, Borghesi M, Tebaldi M, Vranckx P, Parrinello G, Ferrari R. Should duration of dual antiplatelet therapy depend on the type and/or potency of implanted stent? A pre-specified analysis from the
PROlonging Dual antiplatelet treatment after Grading stent-induced Intimal hyperplasia studY (PRODIGY). European Heart Journal. 2013;34(12):909-919.

7. • Laser cut
• Thin cobalt-chromium alloy tube
• Electro-polished
• Coated with fully absorbable, biocompatible and biodegradable polymer of poly lactide-co-glycolic acid
• Polymer contains antiproliferative crystalline sirolimus
• 5 µm thick on luminal and 15 µm thick on abluminal side
• Dose of sirolimus 9-11 µg/mm
• Stents were 15 or 23 mm in length and 2.5, 3.0 or 3.5 mm in diameter, implanted on a rapid exchange balloon
delivery system
MiStent (Micell Technologies, Durham, North Carolina) sirolimus-eluting stent (SES)

8. Advantages expected from the new stent
• The combination of crystalline sirolimus and absorbable polymer enables the
deposition of drug into the surrounding tissue
• Prolonged elution at a controlled rate provides therapeutic tissue concentration of
sirolimus through 6 month post-implantation
• No initial burst of drug release
• Coating cleared from the stent in 45 and 60 days and absorbed into tissue within 90
days, leaving an inert bare metal stent (BMS) in pre-clinical animal testing2
2. Carlyle WC, McClain JB, Tzafriri AR, et al. Enhanced drug delivery capabilities from stents coated with absorbable polymer and crystalline drug. Journal of Controlled Release. 2012;162(3):561-567.

9. Methods
• DESSOLVE I study was a Phase 2 interventional study which was titled
as “Efficacy Study” according to endpoint classification
• The interventional model was “Single Group Assignment” where the
study was done in 30 non-randomized patients
• Primary purpose of the study was the treatment
The information on DESSOLVE I study is available in clinicaltrials.gov
and it was approved by local ethical committee

10. Inclusion criteria
• Non-pregnant women on birth control or men, 18 year ≤ n ≤ 85 year,
eligible to undergo PCI and, if necessary, coronary artery bypass graft
surgery (CABG)
• Class I, II, III or IV stable or unstable angina pectoris or silent ischemia
• Single, de novo, types A, B1 or B2, >50% coronary stenosis in a native
coronary artery
• Target lesion in vessel 2.5-3.5 mm in diameter, coverable with ≤23mm long
stent
• Presence of one other non-target lesion, successfully treated before the
target lesion and not part of the study

11. Exclusion criteria
General condition covering all internal
systems
Angiographic criteria
• Left ventricular ejection fraction <30%
• History of cardiogenic shock
• ≤6 month old stroke or transient ischemic attack
• Serum creatinine >2.0 mg/dl
• Contraindication to dual antiplatelet therapy
including GIT hemorrhage in past 3 months and
platelet count <100,000/mm3 or >700,000/mm3
• Prior treatment of target vessel intervention
within 10 mm of target lesion
• Coronary intervention <30 days before trial
enrollment and coronary brachytherapy
• In-stent restenosis, totally occluded or ostial
target lesion
• Presence of >50% diameter stenosis proximal or
distal to the target lesion
• >50% unprotected coronary artery branch
lesion

12. End points
Primary end point
• Angiographic in-stent late lumen loss (LLL)
• LLL was measured by the difference between post-procedural minimal
lumen diameter (MLD) in the stented segment and MLD in same
segment at follow up

13. End points
Secondary end points
• Device success: <50% final in-stent residual diameter stenosis by
quantitative coronary angiography after MiStent SES
• Lesion success: <50% final in-stent residual diameter stenosis by
quantitative coronary angiography using the assigned and any other
device without cardiac death, MI or target lesion revascularization
before discharge from the hospital
Clinical secondary end points
• Major adverse cardiac events (MACE) defined as deaths, Q and non Q-
wave MI, target lesion revascularization and rates of stent thrombosis

14. • The enrollment of patients in this study was
prospective and non-randomized
• Informed written consent was taken from each
patient
• Enrolled between November 2010 and March 2011
at 5 centers in New Zealand, Belgium and Australia
• American College of Cardiology/American Heart
association classification of coronary lesion3
Type A coronary lesion: Discrete (<10mm),
concentric, readily accessible, nonangulated
segment (<45O) with smooth contour
Type B coronary lesion: Tubular lesion (10-20mm
length), eccentric, moderate tortuosity of
proximal segment, moderately angulated
segment (>45O, <90O) with irregular contour.
Includes B1 (one-type characteristic) and B2
(≤two-type characteristic) lesions.
3. Ellis SG, Vandormael MG, Cowley MJ, et al. Coronary morphologic and clinical determinants of
procedural outcome with angioplasty for multivessel coronary disease. Implications for patient
selection. Multivessel Angioplasty Prognosis Study Group. Circulation. 1990;82(4):1193-1202.

15. Ethical consideration
• The major ethical issue to consider for this study was to ensure safety
of the patients while studying the efficacy of the MiStent SES
• The exclusion criteria were strictly maintained to screen out the high
risk patients from this study
• The patients were carefully selected with the coronary artery lesions
having the indication to implant coronary stent
• Follow up was maintained
• Patients were given the full authority to exclude themselves from the
trial at any point

16. Result
• Polymer coating was absorbed at approximately 3 month. First
assessment point was selected at 4 month keeping that on mind
• Repeated assessment at 6, 8 and 18 months allowed detailed
assessment of tissue strut coverage, strut malposition, positive
remodeling and other changes associated with durable polymer DES
• Baseline data and interventional follow up was done by clinical
assessment, quantitative coronary angiography (QCA), intravascular
ultrasound (IVUS) and optical coherence tomography (OCT

17. • Up to 18 months, the preliminary safety and efficacy of MiStent
SES was observed
• Crystalline sirolimus is delivered locally in sustained, therapeutic
concentrations up to 6 months, without initial burst
• The LLL at each time point (including the low neointimal volume
obstruction) indicates stent efficacy
• In contrast to other SES, there was no evidence of late “catch-up”

18. Result : Summery
Procedural outcome
 Post-procedural in-stent MLD 2.8 ± 0.3 mm
 Residual percentage of diameter stenosis 2.3 ± 7.4%
Long term angiographic results
 Compared with post-procedural MLD, in-stent MLD in 30 patient, up to 8 months was 2.7 ± 0.4 mm
 It corresponds to mean ± SD in-stent LLL of 0.1 ± 0.2 mm
 18-month cumulative in-stent and in-lesion binary restenosis rates were both 0%
IVUS data
 Increase in neointimal obstruction was observed up to 8 months post-procedure. No further
progression up to 18 months
 Observation is consistent with significant neointimal suppression
 Favorable persistent arterial response at 18 month post-procedure, without late “catch-up”
phenomenon
OCT data
 Median percentage of stent struts malposition at 4, 6, 8 and 18 months were 0.4% (0-23%), 0.7%
(0-19%), 0.3% (0-2%) and 0% (0-1%)
 Neointimal tissue volume increased (median) of 6 mm3 to 15 mm3 between 4 to 6 months of follow
up and remained numerically similar between 6 to 18 months of follow up
DAPT
 At the time of discharge, all patients were on DAPT, including aspirin and either clopidogrel,
ticlopidine or prasugrel
 73% continued on DAPT for 12 months
 Decrease in DAPT duration was associated with no thrombotic event
Clinical events up to 18 months
 No patient died or experienced TLR, TVR, ST during 18 months post-procedure
 One patient had a non-Q-wave MI at 44 days
 Cumulative 18 month MACE rate was 3.3%
From the results,
• The LLL was very minimal
which was the primary end point of the study.
Considering the secondary end points
• Device and lesion success were proved as the
residual diameter stenosis is very low
• Only 1 non-Q-wave MI
• Low MACE rate in 18 months of post-procedural
follow up
DAPT
• Reduced DAPT duration with no thrombotic event
Complications
• No death from Target Lesion Revascularization
(TLR), Target Vessel Revascularization (TVR), Stent
thrombosis (ST) in 18 months post-procedure
• No thrombotic complication
• No complication regarding DAPT

19. Discussion
• 1 year post-implantation stent thrombosis has been a major concern for
first generation DES. It was regarded as the most feared long term
complication of DES implantation4 as it
– leads to death
– correlates with incomplete endothelialization
– correlates with under-expansion of the stent
• Durable polymer coating DES has been identified as a factor associated
with stent thrombosis4,5
4. Mauri L, Hsieh W-h, Massaro JM, Ho KKL, D'Agostino R, Cutlip DE. Stent Thrombosis in Randomized Clinical Trials of Drug-Eluting Stents. New England Journal of Medicine. 2007;356(10):1020-1029
5. Lüscher TF, Steffel J, Eberli FR, et al. Drug-Eluting Stent and Coronary Thrombosis: Biological Mechanisms and Clinical Implications. Circulation. 2007;115(8):1051-1058

20. • DES with more biocompatible polymers are associated with
suppression of the neointimal response with more rapid neo-
endothelialization6
• Use of current generation DES has lower rate of stent thrombosis at
even 2 years after implantation comparing to BMS7
• Although neoatheroma formation is common after any DES
implantation, but it continues to occur with bare metal stents
6. Finn AV, Joner M, Nakazawa G, et al. Pathological Correlates of Late Drug-Eluting Stent Thrombosis: Strut Coverage as a Marker of Endothelialization. Circulation. 2007;115(18):2435-2441.
7. Palmerini T, Biondi-Zoccai G, Della Riva D, et al. Stent thrombosis with drug-eluting and bare-metal stents: evidence from a comprehensive network meta-analysis. Lancet. 2012;379(9824):1393-1402.

21. DES with absorbable polymer: Advantages
• The rate of TLR and ST was lower in antiproliferative DES with absorbable
polymer coating than antiproliferative DES with permanent polymer8
• There is less ongoing inflammation with absorbable polymer containing DES
than with permanent polymer containing ones. And inflammatory response is
a major contributor to the processes leading to late adverse events
• So the chance of long term adverse events from MiStent SES with
biodegradable polymer was likely to be lower
• DES coated with bio-absorbable polymers remain very effective for a longer
time. They eliminate risks of stent thrombosis as well as decreasing the need
for prolonged DAPT
8. Stefanini GG, Byrne RA, Serruys PW, et al. Biodegradable polymer drug-eluting stents reduce the risk of stent thrombosis at 4 years in patients undergoing percutaneous coronary intervention: a pooled analysis of
individual patient data from the ISAR-TEST 3, ISAR-TEST 4, and LEADERS randomized trials. European Heart Journal. 2012;33(10):1214-1222

22. Conclusion
• It is established that there is “indeed” a relation between
permanent polymers and adverse vascular reactions
• Most of the studies proved that the stents coated with
biodegradable polymers lower the risk of adverse cardiac events
related with stent thrombosis through 5 year follow up. ie.
LEADERS (Limus Eluted from A Durable versus ERodeble Stent)
• However, SORT OUT (Scandinavian Organization for Randomized
Trials with Clinical Outcomes) V study at 1 year follow up suggest
that there maybe no additional clinical benefit between a
biodegradable polymer DES and durable polymer DES

23. Conclusion: Using MiStent SES
• The study of MiStent SES in simple coronary artery lesion showed
>95% median strut coverage at 6 and 8 months after implantation
• Small and minimally progressive in-stent LLL and no stent related
MACE up to 18 months of MiStent SES implantation
• MiStent SES is concluded to be at least as effective as the durable-
polymer based SES or newer generation bioabsorbable polymers
and stent platforms

24. However
• It is a small, non randomized, hypothesis generating, first-in-man
study
• Anti-proliferative efficacy and the safety of the stent require
confirmation in a large randomized trial
• The stability of intimal hyperplasia and the absence of late “catch-
up” phenomenon need further studies with randomized large
trials with MiStent SES

25. Further steps
• The DESSOLVE I study was successful in the sense that MiStent SES
was proved to be safe and efficacious in the non-randomized trial of
30 patients
• Clinical trial phase 3 should be conducted after this to gather more
information on safety and effectiveness of biodegradable polymer
coated DES
• Different dosage of antiplatelet agents in larger population with other
cardiac drugs should be included in future studies