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Drug Eluting Stents overhyped, overused and overpriced?

Advanced Angioplasty 2008 BCIS 23 rd Jan 2008. Drug Eluting Stents overhyped, overused and overpriced? . William Wijns MD, PhD Cardiovascular Center Aalst http://www.cardio-aalst.be William.Wijns@village.uunet.be. What did we expect from DES ?. Eliminate restenosis, at last . . .

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Drug Eluting Stents overhyped, overused and overpriced?

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  1. Advanced Angioplasty 2008 BCIS 23rd Jan 2008 Drug Eluting Stents overhyped, overused and overpriced? William Wijns MD, PhD Cardiovascular Center Aalst http://www.cardio-aalst.be William.Wijns@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; 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;356:998-1008

  5. Long-Term Outcomes with Drug-Eluting Stents vs Bare-Metal Stents in Sweden Lagerqvist et al, NEJM 2007;356:1009-1019

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

  8. Clinical restenosis Less well studied BMS 0,10 0,08 Work horse BMS Cumulative probability of restenosis 0,06 0,04 DES 0,02 0,00 0 1 2 3 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 2006;27:166-170

  11. Ach response 6 m following SES Hofma et al. Eur Heart J 2006;27:166-170

  12. After intracoronary nitrates Hofma et al. Eur Heart J 2006;27:166-170

  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 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 • 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 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-yoPW 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 …

  26. The SCAAR registry or the Swedish yo-yoPW 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-yoPW 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-yoPW 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 % 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 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

  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

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