The Black Back Yard of D.E.S[D.ES Pitfalls)

Ehud Grenadier M.DH.M.C, Assuta , Rambam Med. Ctrs.Israel

DrugElutingStent

In the first year after coronary stents insertions, clinical failures are driven mainly by procedural complications and restenosisHowever: 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 trialyearsEvent rate46.4%37.9%20.3%CompositeNo restenosisRestenosisCutlip et al, Circulation 2004

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Questions that need to be askedAre 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 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 thrombosis is probably D.E.S related and is due to ..

Sub acute-Late Stent ThrombosisDelayed EndothelializationDiscontinuation of anti-platelet therapyLate incomplete Stent appositionPolymer [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

n=1147n=1317n=1317In Hospitalto 30 days9-12 months>30 days to 9 monthsDischargeCumulative Total= 1.2%= 0.8%SourcesTaxus clinical trial and registry summary, BSX,NEJM Vol. 349, No. 14J. Moses presentation ACC04,Cordis analyst meeting March 6, 2005 at ACC05 LANCET Vol 362, Oct 4, 2003,NEJM Vol 346 No. 23Leon 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.S9 months F.U

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

Stent Thrombosis in Cypher Trials1.0%n=90.6%n=5%Stent thrombosis 1-3 years Cypher 4 pts (0.4%) Control 0

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

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

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

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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 CONCLUSIONM.A.C.E vs. M.I.C.E

Incidence of Stent ThrombosisTaxus II, IV, VILate Stent thrombosis is more prevalentNEJM 2004

TAXUS THROMBOGENICITY

Stent Thrombosis Acute & SubacuteACC 2005. Mary-Claude Morice

Thrombosis Rates Accordingto Selected Patient Characteristics

(N=2,000)*Antiplatelet Therapy DiscontinuationDiabetesPrior BrachyRenal FailureBifurcationsULMUAThere 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 ThrombosisDelayed EndothelializationDiscontinuation of anti-platelet therapyLate incomplete Stent appositionPolymer [sensitivity/inflammation]Late Stent Thrombosis

Premature Discontinuation of Antiplatelet TherapyNon complianceDue to procedures: Surgery, dental, biopsyASA or Clopidogrel [ plavix ] resistance

Are the most important predictors of stent thrombosis29 pts at 9 months F.U (1.3%)13/29 (45%) died. Fatality rate - 45%Common reasonsIakovov 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 availableLate Stent Thrombosis

Late Stent ThrombosisDelayed EndothelializationDiscontinuation of anti-platelet therapyLate incomplete Stent appositionPolymer [sensitivity/inflammation]Late Stent Thrombosis

Late Stent MalapositionPost stent insertionPositive remodelingBlack holeF.U

Sub acute-Late Stent ThrombosisDelayed EndothelializationDiscontinuation of anti-platelet therapyLate formationOf aneurysm

Polymer [sensitivity/inflammation]Late Stent Thrombosis

Late [ 3 YEARS ] aneurysm formation

Late aneurysm formation

Late formation [ 3 years ] of LAD aneurysmPost Cypher stent insertion

Late LAD aneurysm formation

Late Stent ThrombosisDelayed EndothelializationDiscontinuation of anti-platelet therapyLate incomplete appositionPolymer [sensitivity/inflammation]Late Stent Thrombosis

Inflammation In D.E.S there is a further delay arterial wall healing process and increased inflammationCompared to B.E.S , D.E.S induce greater:Fibrin depositionMedial cell lossWBC infiltrationLess Late neointimal hyperplasia

Sub acute-Late Stent ThrombosisDelayed EndothelializationDiscontinuation of anti-platelet therapyLate incomplete appositionPolymer [sensitivity/inflammation]Late Stent Thrombosis

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

Basel Stent Cost-effectiveness Trial-Late Thrombotic Events (BASKET LATE) Trial

Presented atThe American College of Cardiology Scientific Session 2006Presented by Dr. Matthias E. Pfisterer

BASKET LATE Trial

BASKET LATE Trial: Background

In the original BASKET trial, a rather complex patient population was enrolled and randomized to receive one of the following: a bare metal stent, paclitaxel-eluting stent, or sirolimus-eluting stent and the cost effectiveness of drug-eluting stents vs. bare metal stents was evaluated.In the BASKET LATE trial, the 743 patients from the BASKET trial who were MACE free at six months were followed for an additional 12 months after the cessation of clopidogrel treatment.The BASKET LATE trial pooled the paclitaxel- and sirolimus-eluting stent groups into one drug eluting stent group for analysis. The goal of BASKET LATE was to evaluate late thrombotic events among patients treated with drug eluting stents vs. bare metal stents after clopidogrel discontinuation.

Presented at ACC 2006

Basket - Late - StudyBMS244 pts.S.e.s/p.e.s499 pts.1/1 ratio

746 ptsPlavixASAASA onlyF.U6 months mace free12 months(no clopidogrel [plavix])Pfisterer ACC 2006

BASKET LATE Trial: Study Design

Primary Endpoint: Composite cardiac death or nonfatal MI.Other Endpoints: - Thrombosis-related events:- angiographically documented stent thrombosis- cardiac death/ target vessel MI- Target vessel revascularization (TVR)

743 patients all undergoing PCI irrespective of indication for PCI and without target vessel diameter 4mm, restenotic lesions, or an event during the on-clopidogrel phase.Original BASKET study randomized patients in 1:1:1 strategy. Present study pooled DES patients into one group.21% female, 21% ST-elevation MI, 37% unstable angina, 42% stable angina, 67% with multivessel disease, 51% with LAD culprit lesions, average 1.9 stents per patient, mean age 63 years, mean follow-up 18 months.Concomitant medications: aspirin indefinitely.

Presented at ACC 2006

Bare metal stents (BMS)

n=244

Drug-eluting stents (DES)(pooled paclitaxel and sirolimus DES groups) n=499

Cardiac Death or M.I [ Composite endpoint]

BASKET LATE Trial: Primary Composite Endpoint

In the year following clopidogrel discontinuation, the primary composite endpoint of cardiac death or MI occurred significantly more frequently in the DES group than in the BMS group (4.9% vs. 1.3%, p=0.01).

Composite of Cardiac death or nonfatal MI (%)

p=0.01

% patients

Presented at ACC 2006

Cardiac Death or M.i

BASKET LATE Trial: Primary Endpoint

Non-fatal MI was higher in the DES group compared with the BMS group (4.1% vs. 1.3%, p=0.04).

Also, cardiac death trended higher in the DES group than in the BMS group (1.2% vs. 0%, p=0.09).

% patients

Components of primary composite endpoint: nonfatal MI/cardiac death (%)

p=0.04

p=0.09

Presented at ACC 2006

Summary

BASKET LATE Trial: Summary

Among patients with coronary artery disease treated with PCI, use of a drug-eluting stent was associated with significantly higher rates of cardiac death or MI compared with a bare metal stent in the year following clopidogrel discontinuation.Many trials have demonstrated a reduction in target lesion revascularization with DES compared with BMS in recent years, but none has ever demonstrated an effect on the hard endpoints of death or MI.Restenosis, while not desirable, is not an independent correlate of subsequent mortality. The present study showed a more than three-fold increase in death or MI with DES in the year after clopidogrel discontinuation. Late stent thrombosis is a serious and often fatal complication.

Presented at ACC 2006

Basket Late TrialConclusionIndependent predictors of late cardiac death/M.IPrior M.IThe need for IIb IIIa inhibitorsThe use of D.E.S

BASKET LATE Trial: Summary cont.

Clopidogrel is generally prescribed for the first 6 months following stent placement, along with aspirin indefinitely. These data suggest the 6 month anti-platelet regimen of clopidogrel may not be long enough to provide adequate protection from late thrombosis with DES.It is unknown if a better strategy would be a longer duration of clopidogrel, a more potent anti-platelet drug, or a different drug-elution kinetic pattern.The authors noted that for every 100 patients treated with a DES, 3.3 cases of cardiac death or MI are induced for a reduction of 5 cases of target lesion revascularization. Further study on late thrombotic events with DES is strongly warranted given these findings.

Presented at ACC 2006

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

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

TLR: Comparative rates

ConclusionD.E.S have major beneficial impact on restenosis reductionImportant 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

The incidence of stent thrombosis according to selected patient characteristics was 29% in pts with premature antiplatelet therapy discontinuation, 8.7% in prior brachytherapy at the target vessel, 5.5% with renal failure, 3.5% in bifurcations, 3.2% in unprotected left main treated, 2.6% in diabetes, and 1.3% in unstable angina