The Black Back Yard of D.E.S [D.ES Pitfalls) Ehud Grenadier M.D H.M.C, Assuta, Rambam Med. Ctrs. Israel The Black Back Yard of D.E.S [D.ES Pitfalls) Ehud Grenadier M.D H.M.C, Assuta, Rambam Med. Ctrs. Israel

D eliverable E ffective S afe D rug E luting S tent

 In the first year after coronary stents insertions, clinical failures are driven mainly by procedural complications and restenosis  However: The subsequent relative contributions of restenosis and the disease progression to late failures states are less clear

5-years clinical outcomes from second generation coronary stent trial years Event rate 46.4% 37.9% 20.3% Composite No restenosis Restenosis Cutlip et al, Circulation 2004

Questions that need to be asked  Are D.E.S effective in prevention of restenosis?  Is there an increased survival by using D.E.S compare to B.M.S ?  Is an acute, subacute or late stent thrombosis events still a continuous risk ?  What are the additional risks of D.E.S therapy ?  What is the appropriate treatment and its duration that should be applied for risks reductions?  Is the risk of side-effect or complications of the applied therapy worth it ?

Are we going in the right direction ? Or to make a long story short

One of the most dreadful complication of P.C.I is : Acute stent thrombosis, it has claimed to be of more relevancy in the long term to : D.E.S treatment.

It is frequently presented clinically as : ACUTE M.I or DEATH

Acute stent : When it occurs ’Days from the procedure’ is frequently a procedural related complication. Not a D.E.S related. Acute stent thrombosis : When it occurs ’Days from the procedure’ is frequently a procedural related complication. Not a D.E.S related.

But : Sub Acute or late acute stent But : Sub Acute or late acute stent thrombosis is probably D.E.S related and is due to..

Sub acute-Late Stent Thrombosis Delayed Endothelialization Discontinuation of anti- platelet therapy Late incomplete Stent apposition Polymer[sensitivity/inflammation] Late Stent Thrombosis

It is angiographycaly detected as :

Acute thrombosis, 7 months F.U

POST 15 MONTHS

Acute stent thrombosis: kills ! Restenosis : does not !

STENT THROMBOSIS RATES TAXUS II, IV, VI n=1147 CYPHER SIRIUS, e-SIRIUS, c-SIRIUS, Direct SVELTE, RAVEL, EIII n=1317 ENDEAVOR I, II, II CA, III n=1317 In Hospital to 30 days 9-12 months >30 days to 9 months Discharge Cumulative Total = 1.2% = 0.8% = 0.3% Sources Taxus clinical trial and registry summary, BSX,NEJM Vol. 349, No. 14 J. Moses presentation ACC04,Cordis analyst meeting March 6, 2005 at ACC05 LANCET Vol 362, Oct 4, 2003,NEJM Vol 346 No. 23 Leon SIRIUS 3-year update ACC05,ESC Congress 2005 – Drug-eluting stents bare metal stents: still an issue in 2005 ? (4/1317) (14/1147) (11/1317) Note: > 12 month follow-up on 679/1317 patients enrolled in Endeavor trials Note: > 12 month follow-up max of 928/1147 patients enrolled in Taxus trials Note: > 12 month follow-up max of 708/1317 patients enrolled in Cypher trials

Clinical events of the 3 major D.E.S 9 months F.U

Stent thrombosis in Cypher studies - F.U 12 months Urban P et al. ESC 2005 The Risk of Thrombosis

Stent Thrombosis in Cypher Trials 1.0% n=9 0.6% n=5 % Stent thrombosis 1-3 years Cypher 4 pts (0.4%) Control 0

+ 43% 5% 3,5% Cypher increases AMI by 43% versus BMS CYPHER RAVEL AMI AT 4 YEARS

+ 80% 11% 6,1% CYPHER RAVEL DEATH AT 4 YEARS

+66% 16% 9,6% CYPHER RAVEL AMI + DEATH AT 4 YEARS

A detailed analysis of the Ravel at 4 years show that DES restrictly improve TLR, while other critical components of MACE such as MI and DEATH are significantly increased. DES BENEFIT IN THE LONG TERM Ravel Trial

CYPHER RAVEL MACE AT 4 YEARS CONCLUSION M.A.C.E vs. M.I.C.E

Incidence of Stent Thrombosis Taxus II, IV, VI Control % N= 1110 Taxus % N= [0.6%]4 [0.4%] Acute and subacute 1-30 days 1 [0.1%]10 [1.3%] Late 31 days-2 years 8 [0.7%]14 [1.3%]Total Late Stent thrombosis is more prevalent NEJM 2004

TAXUS THROMBOGENICITY

Stent Thrombosis Acute & Subacute 0.6% 1.6% 0.4% 1.7% 0.4% 1.8% P=0.07 p=0.03 p=0.02 ACC Mary-Claude Morice

Thrombosis Rates According to Selected Patient Characteristics (N=2,000) *Antiplatelet Therapy Discontinuation Diabetes Prior Brachy Renal Failure BifurcationsULMUA There are several patient and lesion subgroups with an unacceptably high stent thrombosis rate! *Premature discontinuation, From Milan/Sieburg Experience ACC 05/ JAMA-05

Late Stent Thrombosis Delayed Endothelialization Discontinuation of anti- platelet therapy Late incomplete Stent apposition Polymer[sensitivity/inflammation] Late Stent Thrombosis

Premature Discontinuation of Antiplatelet Therapy  Non compliance  Due to procedures: Surgery, dental, biopsy  ASA or Clopidogrel [ plavix ] resistance  Are the most important predictors of stent thrombosis  29 pts at 9 months F.U (1.3%)  13/29 (45%) died. Fatality rate - 45% Common reasons Iakovov et al JAMA 2005

On the other hand… With The long need of antiplatelets therapy  There is a risk of bleeding from continuation of ASA and or Plavix during surgical procedures. It must be taken in consideration and weighed against the risk of fatal late stent thrombosis.  The requirement of extended (> 1 year?) dual antiplatelets regimen remains uncertain until more data are available Late Stent Thrombosis

Delayed Endothelialization Discontinuation of anti- platelet therapy Late incomplete Stent apposition Polymer[sensitivity/inflammation] Late Stent Thrombosis

Late Stent Malaposition Post stent insertion Positive remodeling Black hole F.U

Sub acute-Late Stent Thrombosis Delayed Endothelialization Discontinuation of anti- platelet therapy Late formation Of aneurysm Polymer[sensitivity/inflammation] Late Stent Thrombosis

Late [ 3 YEARS ] aneurysm formation

Late aneurysm formation

Late formation [ 3 years ] of LAD aneurysm Post Cypher stent insertion

Late LAD aneurysm formation

Late Stent Thrombosis Delayed Endothelialization Discontinuation of anti- platelet therapy Late incomplete apposition Polymer[sensitivity/inflammation] Late Stent Thrombosis

Inflammation  In D.E.S there is a further delay arterial wall healing process and increased inflammation  Compared to B.E.S, D.E.S induce greater: Fibrin deposition Medial cell loss WBC infiltration Less Late neointimal hyperplasia

Sub acute-Late Stent Thrombosis Delayed Endothelialization Discontinuation of anti- platelet therapy Late incomplete apposition Polymer[sensitivity/inflammation] Late Stent Thrombosis

Delayed Endothelialization  D.M.S have a decreased endothelialization process compared to D.E.S  Lack of cells coverage in areas of stents overlaps

Basket - Late - Study BMS 244 pts. S.e.s/p.e.s 499 pts. 1/1 ratio 746 pts Plavix ASA ASA only F.U 6 months mace free 12 months (no clopidogrel [plavix]) Pfisterer ACC 2006

Cardiac Death or M.I [ Composite endpoint]

Cardiac Death or M.i

Summary

 Independent predictors of late cardiac death/M.I Prior M.I The need for IIb IIIa inhibitors The use of D.E.S Basket Late Trial Conclusion

In 100 pts treated with D.E.S : Cypher or Taxus Basket Late Trial Final Remark :

A Trade off with 5 pts for T.L.R Reduction A Trade off with 5 pts for T.L.R Reduction There is a…

...For 3.3 pts with : late M.I or Death between … 7-18 Months

So, is it a good bargain.???

Binary restenosis: Comparative rates P<0.05

TLR: Comparative rates

Conclusion  D.E.S have major beneficial impact on restenosis reduction  Important safety issues need to be clarified like stent thrombosis events (M.I and cardiac mortality)  Antiplatelet therapy increased duration carries increased risk for bleeding, its extended duration is to be determined. But Its premature discontinuation might be fatal.  The risk/benefit aspect of D.E.S vs B.M.S should be taken in consideration in any interventional procedure