Drug Eluting Stents overhyped, overused and overpriced?

1
Drug Eluting Stents overhyped, overused and
overpriced?
Advanced Angioplasty 2008 BCIS 23rd Jan 2008

• William Wijns MD, PhD
• Cardiovascular Center Aalst
• http//www.cardio-aalst.be
• William.Wijns_at_village.uunet.be

2
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 . . .

3
Expected Gradient in Clinical Outcome as a
function of Lesion / Patient Complexity
FIM
Randomized Clinical Trials
Registries
Real Life
40
BMS 1
30
Clinical Failure rate
20
DES 2
DES 1
10
Lesion / Patient complexity
Adapted from E.R. Edelman, C. Rogers, Circ. 1999
100896-8
4
Efficacy of Sirolimus- and Paclitaxel-Eluting
Coronary Stents
PES
SES
Gradient 15.8
Gradient 9.9
Stone GW et al, NEJM 2007356998-1008
5
Long-Term Outcomes with Drug-Eluting Stents vs
Bare-Metal Stents in Sweden
Lagerqvist et al, NEJM 20073561009-1019
6
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
7
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 gt US)
• Per protocol angiography results in doubling of
  TLR rates, even after adjustement for
  clinically-driven TLR (oculo-stenotic reflex)

8
Less well studied BMS
Clinical restenosis
0,10
0,08
Work horse BMS
Cumulative probability of restenosis
0,06
0,04
DES
0,02
0,00
3
2
1
0
Years after PCI
9
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 . . .

10
LAD 6 months following SES
Hofma et al. Eur Heart J 200627166-170
11
Ach response 6 m following SES
Hofma et al. Eur Heart J 200627166-170
12
After intracoronary nitrates
Hofma et al. Eur Heart J 200627166-170
13
Flow-Mediated, Endothelium-Dependent Epicardial
Vasomotor ChangesPacing Protocol
Coronary Angiography
min
Baseline
Pacing
ISDN IC
Nitrates
1
2
3
4

• QCA reference vessel, stented vessel (proximal,
  distal)
• Stop vasoactive drugs 24 hours

14
Change in Vessel Diameter ( from Baseline)
BMS n 8
DES A n 17
DES B n 9
Pacing
ISDN
Pacing
ISDN
Pacing
ISDN
Reference Vessel Distal segment stented vessel
15
Change in Vessel Diameter ( from Baseline)
BMS n 8
DES C n 5
DES D n 23
Pacing
ISDN
Pacing
ISDN
Pacing
ISDN
Reference Vessel Distal segment stented vessel
16
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

17
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 2007297159-68), 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

18
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 . . .

19
Overall mortality
20
Cardiac death
21
Health Technology Assessment

• 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 ...

22
Drug Eluting Stents overhyped, overused and
overpriced?

• Are these the real issues ?

23
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

24
The SCAAR registry or the Swedish yo-yoPW
Serruys, J Daemen, EuroIntervention 20073297
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.
25
The SCAAR registry or the Swedish yo-yoPW
Serruys, J Daemen, EuroIntervention 20073297

• 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

26
The SCAAR registry or the Swedish yo-yoPW
Serruys, J Daemen, EuroIntervention 20073297

• What about the data yo-yo ?
• Why do we seem to care more about devices and
  technicalities than about patients ?

27
The SCAAR registry or the Swedish yo-yoPW
Serruys, J Daemen, EuroIntervention 20073297

• 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 ?

28
The SCAAR registry or the Swedish yo-yoPW
Serruys, J Daemen, EuroIntervention 20073297

• 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 ?

29
Clinical Indications for PCI Euro Heart Survey
STABLE Class I A If large ischemic area
48
STEMI Class I A
22
30
NSTEMI ACS Class I A
6789 Patients across Europe
30
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

31
Disclosures for W. WijnsCardiovascular Center
Aalst (B)

• Grants/Research
• Investigator, co-PI or PI in trials for several
  device (Abbott, Biosensors, Biotronik, Boston
  Scientific, Cappella, Conor, Cordis JJ, 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)
• Speakers 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

32
19 DES are CE-certified - most of them are
commercially available - more new DES will be
CE-certified soon
33
Which DES should be recommended ?
predominantly stable CAD de-novo stenosis
34
EVALUATION PATHWAYS FOR DES

• 1ST GENERATION
• Preclinical
• FIM
• (Dose-response kinetics)
• Pivotal RCT
• Superiority vs BMS
• Powered for combined
• clinical / angio endpoint
• (Lesion / patient subsets)
• Real life registry

• 2ND GENERATION
• Preclinical
• FIM
• (Dose-response kinetics)
• Pivotal RCT
• Non inferiority vs 1st DES
• Powered for angiographic
• efficacy endpoints
• (Lesion / patient subsets)
• Real life registry

35
All-cause survival On- vs. Off-label BMS/DES use
100
95
93.3
92.3
90
84.8
85
Overall survival, ()
Log rank p-values On-label use DES vs. BMS
0.71 Off-label use DES vs. BMS 0.69
84.6
80
75
On-label BMS use
On-label DES use
Off-label BMS use
Off-label DES use
70
0
365
730
1095
1460
Days
36
Target Lesion Revascularization
Non-Diabetic Patients
Diabetic Patients
BMS PES SES
BMS PES 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)
30
25
20
15
10
5
0
0
1
2
3
4
0
1
2
3
4
Years
Years
BMS 1228 1228 667 451
348 3384 3384 2128 1420
1195 PES 1161 1161 942
486 146 3466 3466 2776
1477 660 SES 1373 1373
947 606 219 3505 3505
2614 1512 753
37
Target lesion revascularisation
38
Myocardial infarction
39
Death or myocardial infarction
40
Definite stent thrombosis
41
Advantages of Atrial Pacing as a means to induce
flow-mediated 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