Download Club des Chirurgiens Cardiaques 20

Advanced Angioplasty 2008
BCIS 23rd Jan 2008
Drug Eluting Stents
overhyped, overused and overpriced?
William Wijns MD, PhD
Cardiovascular Center Aalst
http://www.cardio-aalst.be
[email protected]
What did we expect from DES ?
• Eliminate restenosis, at last . . .
• Improve durability of the results of PCI thereby
justifying expanding indications
• Allow vessel healing and endothelialisation, without
interfering with normal vessel biology
• Avoid any systemic side effects
• Be affordable . . .
Expected Gradient in Clinical Outcome as
a function of Lesion / Patient Complexity
Clinical Failure rate [%]
FIM
Randomized Clinical Trials
Registries
Real Life
40
BMS 1
30
20
DES 2
DES 1
10
Lesion / Patient complexity
Adapted from E.R. Edelman, C. Rogers, Circ. 1999; 100:896-8
Efficacy of Sirolimus- and Paclitaxel-Eluting
Coronary Stents
SES
PES
Gradient = 15.8%
Gradient = 9.9%
Stone GW et al, NEJM 2007;356:998-1008
Long-Term Outcomes with Drug-Eluting Stents
vs Bare-Metal Stents in Sweden
Lagerqvist et al, NEJM 2007;356:1009-1019
The Rotterdam experience with 100% DES use
- Sequential monocentric registry
- Systematic use of one DES brand
- Comparison with historical* controls
► Revascularisation GRADIENT
BMS vs Cypher
6.7 % at 1 year
8.3 % at 2 years
BMS vs Taxus
5.0 % at 1 year
* Worse patient / lesion characteristics in DES era
Why did the Edelman-Rogers
model not work?
•
•
•
Randomised clinical trials were designed to maximise
the outcome gradient between DES and BMS, in order
to provide the evidence that DES should replace BMS
and be used in all cases
The performance of BMS used in DES trials is
perceived by many as exceedingly poor compared to
their experience (EU > US)
Per protocol angiography results in ± doubling of
TLR rates, even after adjustement for clinically-driven
TLR (“oculo-stenotic reflex”)
Clinical
restenosis
Cumulative probability of restenosis
0,10
Less well
studied
BMS
SCAAR
UCR
SWEDEN
2007
0,08
Work horse
BMS
0,06
0,04
DES
0,02
0,00
0
1
2
Years after PCI
3
What did we expect from DES ?
• Eliminate restenosis, at last . . .
• Improve durability of the results of PCI thereby
justifying expanding indications
• Allow vessel healing and endothelialisation, without
interfering with normal vessel biology
• Avoid any systemic side effects
• Be affordable . . .
LAD 6 months following SES
Hofma et al. Eur Heart J 2006;27:166-170
Ach response 6 m following SES
Hofma et al. Eur Heart J 2006;27:166-170
After intracoronary nitrates
Hofma et al. Eur Heart J 2006;27:166-170
Flow-Mediated, Endothelium-Dependent
Epicardial Vasomotor Changes
Pacing Protocol*
Coronary
Angiography
min
Baseline
Pacing
1
2
3
4
ISDN
IC
Nitrates
QCA reference vessel, stented vessel (proximal, distal)
* Stop vasoactive drugs ≥ 24 hours
Change in Vessel Diameter (% from Baseline)
BMS
DES A
DES B
n=8
n = 17
n=9
30
30
30
20
20
20
10
10
10
0
0
0
-10
-10
-10
Pacing ISDN
Pacing ISDN
Reference Vessel
Distal segment stented vessel
Pacing ISDN
Change in Vessel Diameter (% from Baseline)
BMS
DES C
DES D
n=8
n=5
n = 23
30
30
30
20
20
20
10
10
10
0
0
0
-10
-10
-10
Pacing ISDN
Pacing ISDN
Reference Vessel
Distal segment stented vessel
Pacing ISDN
Summary of findings
• Flow-mediated vasodilation is observed 6-9
months after bare metal stenting in segments
proximal and distal to the stent
• Vasomotor responses to increased flow vary from
vasoconstriction to vasodilatation with different DES
brands while non-endothelial dependent dilation to
nitrates is maintained
• Some drug-polymer-device combinations exert
durable “toxic” effects on the endothelium at a
distance from the implant
Thienopyridines for ever ?
• Maintaining patients at higher risk of thrombosis on dual antiplatelet
therapy (DAPT) forever has no scientific foundation yet
• There is some benefit associated with the extension of DAPT from 6
months up to 1 year (Eisenstein et al. JAMA 2007;297:159-68), a
practice now endorsed by FDA and by the ESC PCI Guidelines (in the
absence of increased risk for bleeding)
• Outcomes may improve with better patient compliance, from a better
understanding and identification of non-responders and with the
availability of more potent antiplatelet agents. However, at the
expense of excess bleeding (Triton)
• Maintaining
patients on long term DAPT is disruptive of other
medical and surgical practices, as readily apparent in elderly patients
with multiple co-morbidities
• Solving the late thrombosis issue will be mandatory because trying
to mask it will not be sustainable for the long term
What did we expect from DES ?
• Eliminate restenosis, at last . . .
• Improve durability of the results of PCI thereby
justifying expanding indications
• Allow vessel healing and endothelialisation, without
interfering with vessel biology
• Avoid any systemic side effects
• Be affordable . . .
Overall mortality
Cardiac death
Health Technology
Assessment
I.
II.
III.
HTA analyses are necessarily unfavorable
given the lack of mortality reduction, as
opposed to drugs or other devices
All HTA analyses (NICE, Ontario, Belgian
KCE) indicate exceedingly high incremental
costs to avoid one TLR event
NNT to avoid restenosis events depend on
the background risk of recurrence with BMS.
Absolute risk reduction is what matters ...
Drug Eluting Stents
overhyped, overused and overpriced?
Are these the real issues ?
Drug Eluting Stents
overhyped, overused and overpriced?
The real challenges are …
• to recover our credibiliy
• to restore professional leadership
• to protect our freedom to operate
The SCAAR registry or the
Swedish yo-yo
PW Serruys, J Daemen, EuroIntervention 2007;3:297
…
The impact of the NEJM on the Swedish medical
practice resulted in a drop of the DES use to less
than 20%,a phenomenon which has been
sarcastically coined the Swedish yo-yo. It is a heavy
responsability for our Swedish colleagues to assess
the result of this drop in DES-use.
…
The SCAAR registry or the
Swedish yo-yo
PW Serruys, J Daemen, EuroIntervention 2007;3:297
• What about the data yo-yo ?
- September 2006, Barcelona: safety concern ?
- New analyses up to Stettler, 2007: no fire, neutral effect of
DES on death and infarction rates up to 4 years, even in highrisk such as diabetes (!) and off label indications
- September 2007, Vienna: 6-fold increase in adjusted OR for
out of hospital mortality in STEMI patients treated with DES
- October 2007, TCT: DES are saving lives …
The SCAAR registry or the
Swedish yo-yo
PW Serruys, J Daemen, EuroIntervention 2007;3:297
• What about the data yo-yo ?
• Why do we seem to care more about devices and
technicalities than about patients ?
The SCAAR registry or the
Swedish yo-yo
PW Serruys, J Daemen, EuroIntervention 2007;3:297
• What about the data yo-yo ?
• Why do we seem to care more about devices and
technicalities than about patients ?
• Despite the plethora of trials and registries,
essential patient-oriented questions remain
unanswered. Why so few patient-oriented trials ?
The SCAAR registry or the
Swedish yo-yo
PW Serruys, J Daemen, EuroIntervention 2007;3:297
•
•
•
•
What about the data yo-yo ?
Why do we seem to care more about devices
and technicalities than about patients ?
Despite the plethora of trials and registries,
essential patient-oriented questions remain
unanswered. Why so few patient-oriented trials ?
Why do we not focus on the life-saving
indications of PCI that represent most of our
activity ?
Clinical Indications for PCI
Euro Heart Survey
STABLE
Class I A
If large ischemic area
48 %
22 %
STEMI
Class I A
30 %
6789 Patients across Europe
NSTEMI – ACS
Class I A
Drug Eluting Stents
overhyped, overused and overpriced?
The real challenges are …
• to recover our credibiliy
• to restore professional leadership
• to protect our freedom to operate
Disclosures for W. Wijns
Cardiovascular Center Aalst (B)
Grants/Research:
Investigator, co-PI or PI in trials for several device (Abbott, Biosensors,
Biotronik, Boston Scientific, Cappella, Conor, Cordis J&J, Devax,
Medtronic, Orbus Neich, Sorin, Terumo, Topspin, Volcano) and
pharmaceutical (BMS, GSK, Therabel) companies
All Consulting Fees, Honoraria and Research Grants go to the
“Cardiovascular Research Aalst Foundation” (non profit organisation)
Speaker’s Bureau: NONE
Equity Interests/Stock Options/Major-Minor Stock
Shareholder: NONE
Royalty Income: NONE
Ownership/Founder/Co-Founder: “Cardiovascular Research
Aalst Foundation” co-founder of Cardio3, biotechnology start-up on
Cell Therapy
Which DES should be recommended ?
STENT
DRUG
STUDY
High Level of Evidence, Efficacy proven in a randomized trial
with an adequate primary clinical endpoint:
Cypher
Sirolimus
Taxus
Paclitaxel
Endeavor
Zotarolimus
SIRIUS
TAXUS-IV, TAXUS-V,
(TAXUS-VI)
ENDEAVOR-II
Medium Level of Evidence, Efficacy proven in a randomized trial
with a primary surrogate endpoint:
Xience-V / Promus
Everolimus
SPIRIT-I, -II, -III
Yukon
Sirolimus
ISAR-Test
EVALUATION PATHWAYS FOR DES
1ST GENERATION
2ND GENERATION
• Preclinical
• Preclinical
• FIM
• FIM
• (Dose-response & kinetics)
• (Dose-response & kinetics)
• Pivotal RCT
• Pivotal RCT
Superiority vs BMS
Non inferiority vs 1st DES
Powered for combined
clinical / angio endpoint
Powered for angiographic
efficacy endpoints
• (Lesion / patient subsets)
• (Lesion / patient subsets)
• Real life registry
• Real life registry
All-cause survival
On- vs. Off-label BMS/DES use
100
Overall survival, (%)
95
93.3%
92.3%
90
85
84.8%
84.6%
Log rank p-values
On-label use DES vs. BMS: 0.71
80
Off-label use DES vs. BMS: 0.69
75
70
0
On-label DES use
On-label BMS use
Off-label DES use
Off-label BMS use
365
730
Days
1095
1460
Target Lesion Revascularization
Non-Diabetic Patients
BMS
BMS
PES
PES
SES
SES
SES vs BMS: 0.31 (0.21,0.41)
PES vs BMS: 0.42 (0.25,0.54)
SES vs PES: 0.74 (0.51,1.19)
SES vs BMS: 0.29 (0.21,0.38)
PES vs BMS: 0.47 (0.34,0.61)
SES vs PES: 0.62 (0.46,0.83)
0
5
10
15
20
25
30
Diabetic Patients
0
BMS 1228
PES 1161
SES 1373
1
2
Years
3
4
0
1
1228
1161
1373
667
942
947
451
486
606
348
146
219
3384
3466
3505
3384
3466
3505
2
Years
2128
2776
2614
3
4
1420
1477
1512
1195
660
753
Target lesion revascularisation
Myocardial infarction
Death or myocardial infarction
Definite stent thrombosis
Advantages of Atrial Pacing as a means to induce flowmediated vasomotor changes
• Mimics physiological changes that occur during
exercise or tachycardia
• Technically easier to obtain and to analyze than
coronary angiography during physical exercise
• Reference segment available in all cases and
obtained with the same, simultaneously applied
stimulus
• Dilation is the unequivocal normal response
• Patients in whom the reference segment does not
dilate have a diffuse endothelial disorder and should
be excluded
• No need for “baseline” measurements prior to
stent implantation