Drug Eluting Stents overhyped, overused and overpriced?

William Wijns MD, PhD

Cardiovascular Center Aalst

http://www.cardio-aalst.be

William.Wijns@village.uunet.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

ical

Fai

lure

rate

[%]

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%

PES SES

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”)

SCAAR UCR

SWEDEN 2007

Years after PCI 3 2 1 0

Cum

ulat

ive

prob

abili

ty o

f res

teno

sis

0,10

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

ISDN IC

Nitrates

Coronary Angiography

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 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

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 %

22 %

STABLE Class I A

If large ischemic area

NSTEMI – ACS Class I A

Clinical Indications for PCI Euro Heart Survey

30 %

STEMI Class I A

6789 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. Wijns Cardiovascular Center Aalst (B)

STENT DRUG STUDY

High Level of Evidence, Efficacy proven in a randomized trial with an adequate primary clinical endpoint:

Cypher Sirolimus SIRIUS

Taxus Paclitaxel TAXUS-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 ?

predominantly

stable CAD

de-novo ste

nosis

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

EVALUATION PATHWAYS FOR DES

All-cause survival On- vs. Off-label BMS/DES use

0 365 730 1095 1460

70

75

80

85

90

95

100 O

vera

ll su

rviv

al, (

%)

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 1195 PES 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)

0 5

10

15

20

25

30

0 1 2 3 4 Years

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 4 Years

BMS

PES

SES

BMS

PES

SES

Target Lesion Revascularization Diabetic Patients Non-Diabetic Patients

Target lesion revascularisation

Myocardial infarction

Death or myocardial infarction

Definite stent thrombosis

•  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

Advantages of Atrial Pacing as a means to induce flow-mediated vasomotor changes