Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center...

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Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst http://www.cardio-aalst.be [email protected] Advanced Angioplasty 2008 BCIS 23 rd Jan 2008

Transcript of Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center...

Page 1: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

Drug Eluting Stents overhyped, overused and overpriced?

William Wijns MD, PhD

Cardiovascular Center Aalst

http://www.cardio-aalst.be

[email protected]

Advanced Angioplasty 2008

BCIS 23rd Jan 2008

Page 2: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

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 . . .

Page 3: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

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

Page 4: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

Efficacy of Sirolimus- and Paclitaxel-Eluting Coronary Stents

Stone GW et al, NEJM 2007;356:998-1008

Gradient = 15.8% Gradient = 9.9%

PESSES

Page 5: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

Long-Term Outcomes with Drug-Eluting Stents vs Bare-Metal Stents in Sweden

Lagerqvist et al, NEJM 2007;356:1009-1019

Page 6: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

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

Page 7: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

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”)

Page 8: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

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

Page 9: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

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 . . .

Page 10: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

LAD 6 months following SES

Hofma et al. Eur Heart J 2006;27:166-170

Page 11: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

Ach response 6 m following SES

Hofma et al. Eur Heart J 2006;27:166-170

Page 12: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

After intracoronary nitrates

Hofma et al. Eur Heart J 2006;27:166-170

Page 13: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

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

Page 14: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

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

Page 15: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

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

Page 16: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

• 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

Page 17: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

• 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 ?

Page 18: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

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 . . .

Page 19: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

Overall mortality

Page 20: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

Cardiac death

Page 21: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

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 ...

Page 22: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

Drug Eluting Stents overhyped, overused and overpriced?

Are these the real issues ?

Page 23: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

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

Page 24: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

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.

Page 25: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

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 …

Page 26: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

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 ?

Page 27: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

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 ?

Page 28: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

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 ?

Page 29: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

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

Page 30: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

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

Page 31: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

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)

Page 32: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

19 DES are CE-certified

- most o

f them are commercially available

- more new DES will b

e CE-certified soon

Page 33: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

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

Page 34: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

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

Page 35: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

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

Page 36: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

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

Page 37: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

Target lesion revascularisation

Page 38: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

Myocardial infarction

Page 39: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

Death or myocardial infarction

Page 40: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

Definite stent thrombosis

Page 41: Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst  William.Wijns@village.uunet.be.

• 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