Drug Eluting Stents overhyped, overused and overpriced?

Transcription

1 Advanced Angioplasty 2008 BCIS 23 rd Jan 2008 Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst

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 Clinical Failure rate [%] BMS 1 DES 2 DES 1 Lesion / Patient complexity Adapted from E.R. Edelman, C. Rogers, Circ. 1999; 100:896-8

4 Efficacy of Sirolimus- and Paclitaxel-Eluting Coronary Stents SES PES Gradient = 15.8% Gradient = 9.9% Stone GW et al, NEJM 2007;356:

5 Long-Term Outcomes with Drug-Eluting Stents vs Bare-Metal Stents in Sweden Lagerqvist et al, NEJM 2007;356:

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 > US) Per protocol angiography results in ± doubling of TLR rates, even after adjustement for clinically-driven TLR ( oculo-stenotic reflex )

8 Cumulative probability of restenosis 0,10 0,08 0,06 0,04 Clinical restenosis Less well studied BMS Work horse BMS DES SCAAR UCR SWEDEN ,02 0, Years after PCI 2 3

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 2006;27:

11 Ach response 6 m following SES Hofma et al. Eur Heart J 2006;27:

12 After intracoronary nitrates Hofma et al. Eur Heart J 2006;27:

13 Flow-Mediated, Endothelium-Dependent Epicardial Vasomotor Changes Coronary Angiography Pacing Protocol* min Baseline Pacing ISDN IC Nitrates QCA reference vessel, stented vessel (proximal, distal) * Stop vasoactive drugs 24 hours

14 Change in Vessel Diameter (% from Baseline) BMS DES A DES B n = 8 n = 17 n = Pacing ISDN Pacing ISDN Pacing ISDN Reference Vessel Distal segment stented vessel

15 Change in Vessel Diameter (% from Baseline) BMS DES C DES D n = 8 n = 5 n = 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 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

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 I. HTA analyses are necessarily unfavorable given the lack of mortality reduction, as opposed to drugs or other devices II. III. 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-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.

25 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

26 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?

27 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?

28 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?

29 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

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. 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 Cardio 3, biotechnology start-up on Cell Therapy

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33 Which DES should be recommended? predominantly stable CAD de-novo stenosis 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

34 EVALUATION PATHWAYS FOR DES 1 ST GENERATION Preclinical FIM (Dose-response & kinetics) Pivotal RCT Superiority vs BMS Powered for combined clinical / angio endpoint (Lesion / patient subsets) Real life registry 2 ND GENERATION Preclinical FIM (Dose-response & kinetics) Pivotal RCT Non inferiority vs 1 st DES Powered for angiographic efficacy endpoints (Lesion / patient subsets) Real life registry

35 All-cause survival On- vs. Off-label BMS/DES use 100 Overall survival, (%) Log rank p-values On-label use DES vs. BMS: 0.71 Off-label use DES vs. BMS: 0.69 On-label DES use On-label BMS use 93.3% 92.3% 84.8% 84.6% 70 Off-label DES use Off-label BMS use Days

36 Target Lesion Revascularization Diabetic Patients Non-Diabetic Patients 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) Years BMS PES SES 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) Years BMS PES SES

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 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