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

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  • Drug Eluting Stents overhyped, overused and overpriced?William Wijns MD, PhDCardiovascular Center Aalsthttp://[email protected]

    Advanced Angioplasty 2008BCIS 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 ComplexityAdapted from E.R. Edelman, C. Rogers, Circ. 1999; 100:896-810203040Clinical Failure rate [%]BMS 1DES 2DES 1FIMRandomized Clinical TrialsRegistriesReal LifeLesion / Patient complexity

  • Efficacy of Sirolimus- and Paclitaxel-Eluting Coronary StentsStone GW et al, NEJM 2007;356:998-1008Gradient = 15.8%Gradient = 9.9%PESSES

  • Long-Term Outcomes with Drug-Eluting Stents vs Bare-Metal Stents in SwedenLagerqvist 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 year8.3 % at 2 yearsBMS vs Taxus5.0 % 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 casesThe 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)

    SCAARUCRSWEDEN2007

    Years after PCI3210Cumulative probability of restenosis0,100,080,060,040,020,00DESWork horse BMSLess well studied BMSClinical 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 SESHofma et al. Eur Heart J 2006;27:166-170

  • Ach response 6 m following SESHofma et al. Eur Heart J 2006;27:166-170

  • After intracoronary nitratesHofma et al. Eur Heart J 2006;27:166-170

  • Flow-Mediated, Endothelium-Dependent Epicardial Vasomotor Changes

    Pacing Protocol*BaselinePacing1234minISDNICNitratesCoronaryAngiography QCA reference vessel, stented vessel (proximal, distal)

    * Stop vasoactive drugs 24 hours

  • Change in Vessel Diameter (% from Baseline)BMS n = 8PacingISDNDES An = 17PacingISDNDES Bn = 9PacingISDNReference VesselDistal segment stented vessel

  • Change in Vessel Diameter (% from Baseline)BMSn = 8PacingISDNDES Cn = 5PacingISDNDES Dn = 23PacingISDNReference VesselDistal 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 implantSummary of findings

  • 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

  • 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 AssessmentHTA analyses are necessarily unfavorable given the lack of mortality reduction, as opposed to drugs or other devicesAll HTA analyses (NICE, Ontario, Belgian KCE) indicate exceedingly high incremental costs to avoid one TLR eventNNT 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-yoPW Serruys, J Daemen, EuroIntervention 2007;3:297The 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-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

  • 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 ?

  • 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 ?

  • 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 ?

  • 48 %22 %STABLE Class I AIf large ischemic areaNSTEMI ACSClass I AClinical Indications for PCI Euro Heart Survey30 %STEMIClass I A6789 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

  • 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) companiesAll Consulting Fees, Honoraria and Research Grants go to the Cardiovascular Research Aalst Foundation (non profit organisation)Speakers Bureau: NONEEquity Interests/Stock Options/Major-Minor Stock Shareholder: NONERoyalty Income: NONEOwnership/Founder/Co-Founder: Cardiovascular Research Aalst Foundation co-founder of Cardio3, biotechnology start-up on Cell Therapy

  • 19 DES are CE-certified- most of them are commercially available- more new DES will be CE-certified soon

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

    STENTDRUGSTUDYHigh Level of Evidence, Efficacy proven in a randomized trial with an adequate primary clinical endpoint:CypherSirolimusSIRIUSTaxusPaclitaxelTAXUS-IV, TAXUS-V, (TAXUS-VI) EndeavorZotarolimusENDEAVOR-II Medium Level of Evidence, Efficacy proven in a randomized trial with a primary surrogate endpoint:Xience-V / PromusEverolimusSPIRIT-I, -II, -IIIYukonSirolimusISAR-Test

  • EVALUATION PATHWAYS FOR DES

    1ST GENERATIONPreclinicalFIM(Dose-response & kinetics)Pivotal RCTSuperiority vs BMSPowered for combinedclinical / angio endpoint(Lesion / patient subsets)Real life registry2ND GENERATIONPreclinicalFIM(Dose-response & kinetics)Pivotal RCTNon inferiority vs 1st DESPowered for angiographicefficacy endpoints(Lesion / patient subsets)Real life registry

  • All-cause survivalOn- vs. Off-label BMS/DES use036573010951460707580859095100Overall survival, (%)Days93.3%84.6%92.3%84.8%On-label BMS useOff-label BMS useOn-label DES useOff-label DES useLog 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 1195PES 1161 1161 942 486 146 3466 3466 2776 1477 660 SES 1373 1373 947 606 219 3505 3505 2614 1512 753SES 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)05101520253001234YearsSES 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)01234YearsBMSPESSESBMSPESSESTarget Lesion RevascularizationDiabetic PatientsNon-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 implantationAdvantages of Atrial Pacing as a means to induce flow-mediated vasomotor changes

    Figur 74. Justerad risk fr restenos vid stentning med olika stent.When used in the expression Provisional stenting the term provisional express a condition on which stenting actually depends. It might be replaced by conditional stenting. FFR is useless in these situation. In contrast, FFR is very usefull to decide whether or not a lesion should be treated at all. These are data from 1993, showing that less than 30% of patients undergoing PCI ever had some kind of non-invasive testing beforehand. This was 12 years ago, When used in the expression Provisional stenting the term provisional express a condition on which stenting actually depends. It might be replaced by conditional stenting. FFR is useless in these situation. In contrast, FFR is very usefull to decide whether or not a lesion should be treated at all.