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Drug Eluting Stents overhyped, overused and overpriced?
William Wijns MD, PhD
Cardiovascular Center Aalst
http://www.cardio-aalst.be
Advanced Angioplasty 2008
BCIS 23rd Jan 2008
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
Adapted from E.R. Edelman, C. Rogers, Circ. 1999; 100:896-8
10
20
30
40
Clin
ica
l Fa
ilure
rat
e [
%]
BMS 1
DES 2
DES 1
FIM Randomized Clinical Trials Registries Real Life
Lesion / Patient complexity
Efficacy of Sirolimus- and Paclitaxel-Eluting Coronary Stents
Stone GW et al, NEJM 2007;356:998-1008
Gradient = 15.8% Gradient = 9.9%
PESSES
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”)
SCAARUCR
SWEDEN2007
Years after PCI
3210
Cu
mu
lati
ve p
rob
abili
ty o
f re
sten
osi
s0,10
0,08
0,06
0,04
0,02
0,00
DES
Work horse BMS
Less well studied BMS
Clinical restenosis
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
Baseline Pacing
1 2 3 4
Flow-Mediated, Endothelium-Dependent Epicardial Vasomotor Changes
Pacing Protocol*
min
ISDNIC
Nitrates
CoronaryAngiography
QCA reference vessel, stented vessel (proximal, distal)
* Stop vasoactive drugs ≥ 24 hours
Change in Vessel Diameter (% from Baseline)
-10
0
10
20
30
BMS
n = 8
Pacing ISDN
-10
0
10
20
30
DES A
n = 17
Pacing ISDN
-10
0
10
20
30
DES B
n = 9
Pacing ISDN
Reference Vessel
Distal segment stented vessel
Change in Vessel Diameter (% from Baseline)
-10
0
10
20
30
BMS
n = 8
Pacing ISDN
-10
0
10
20
30
DES C
n = 5
Pacing ISDN
-10
0
10
20
30
DES D
n = 23
Pacing ISDN
Reference Vessel
Distal segment stented vessel
• Flow-mediated vasodilation is observed 6-9 Flow-mediated vasodilation is observed 6-9 months after bare metal stenting in segments months after bare metal stenting in segments proximal and distal to the stentproximal and distal to the stent• Vasomotor responses to increased flow vary from Vasomotor responses to increased flow vary from vasoconstriction to vasodilatation with different DES vasoconstriction to vasodilatation with different DES brands while non-endothelial dependent dilation to brands while non-endothelial dependent dilation to nitrates is maintainednitrates is maintained• Some drug-polymer-device combinations exert Some drug-polymer-device combinations exert durable “toxic” effects on the endothelium at a durable “toxic” effects on the endothelium at a distance from the implantdistance from the implant
Summary of findings
• 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
Thienopyridines for ever ?
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. HTA analyses are necessarily unfavorable given the lack of mortality reduction, as opposed to drugs or other devices
II. All HTA analyses (NICE, Ontario, Belgian KCE) indicate exceedingly high incremental costs to avoid one TLR event
III. 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 high-risk 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 ?
48 %48 %
22 %22 %
STABLE STABLE Class I AClass I A
If large ischemic areaIf large ischemic area
NSTEMI – ACSNSTEMI – ACSClass I AClass I A
Clinical Indications for PCI Clinical Indications for PCI Euro Heart SurveyEuro Heart Survey
30 %30 %
STEMISTEMIClass I AClass I A
6789 Patients across Europe6789 Patients across Europe
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
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
Disclosures for W. WijnsCardiovascular Center Aalst (B)
19 DES are CE-certified
- most o
f them are commercially available
- more new DES will b
e CE-certified soon
STENT DRUG STUDY
High Level of Evidence, Efficacy proven in a randomized trial
with an adequate primary clinical endpoint:Cypher Sirolimus SIRIUS
Taxus PaclitaxelTAXUS-IV, TAXUS-V,
(TAXUS-VI) Endeavor Zotarolimus 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
Which DES should be recommended ?Which DES should be recommended ?
predominantly stable CAD
de-novo stenosis
1ST GENERATION
• Preclinical
• FIM
• (Dose-response & kinetics)
• Pivotal RCT
Superiority vs BMS
Powered for combinedclinical / angio endpoint
• (Lesion / patient subsets)
• Real life registry
2ND GENERATION
• Preclinical
• FIM
• (Dose-response & kinetics)
• Pivotal RCT
Non inferiority vs 1st DES
Powered for angiographicefficacy endpoints
• (Lesion / patient subsets)
• Real life registry
EVALUATION PATHWAYS FOR DES
All-cause survivalOn- vs. Off-label BMS/DES use
0 365 730 1095 1460
70
75
80
85
90
95
100
Ov
era
ll s
urv
ival
, (%
)
Days
93.3%
84.6%
92.3%
84.8%
On-label BMS use
Off-label BMS use
On-label DES use
Off-label DES use
Log rank p-values
On-label use DES vs. BMS: 0.71
Off-label use DES vs. BMS: 0.69
BMS 1228 1228 667 451 348 3384 3384 2128 1420 1195PES 1161 1161 942 486 146 3466 3466 2776 1477 660 SES 1373 1373 947 606 219 3505 3505 2614 1512 753
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)
05
10
15
20
25
30
0 1 2 3 4Years
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 1 2 3 4Years
BMS
PES
SES
BMS
PES
SES
Target Lesion RevascularizationDiabetic Patients Non-Diabetic Patients
Target lesion revascularisation
Myocardial infarction
Death or myocardial infarction
Definite stent thrombosis
• Mimics physiological changes that occur during Mimics physiological changes that occur during exercise or tachycardia exercise or tachycardia • Technically easier to obtain and to analyze than Technically easier to obtain and to analyze than coronary angiography during physical exercisecoronary angiography during physical exercise• Reference segment available in all cases and Reference segment available in all cases and obtained with the same, simultaneously applied obtained with the same, simultaneously applied stimulusstimulus• Dilation is the unequivocal normal responseDilation is the unequivocal normal response• Patients in whom the reference segment does not Patients in whom the reference segment does not dilate have a diffuse endothelial disorder and should dilate have a diffuse endothelial disorder and should be excludedbe excluded• No need for “baseline” measurements prior to stent No need for “baseline” measurements prior to stent implantationimplantation
Advantages of Atrial Pacing as a means to induce flow-mediated vasomotor changes