Enrico Romagnoli MD, PhDInterventional Cardiology Unit,

San Raffaele Hospital, Milan

Torino14 Novembre 2007

DRUG-ELUTING STENTS: DRUG-ELUTING STENTS: WHICH AND TO WHOM?WHICH AND TO WHOM?

DES & restenosis

Drug-eluting stents represent a major advance Drug-eluting stents represent a major advance for reduction of restenosisfor reduction of restenosis

Drug-eluting stents consistently have been shown Drug-eluting stents consistently have been shown to reduce the amount of to reduce the amount of late lumen loss late lumen loss in months in months following implantation represent a major advance following implantation represent a major advance for reduction of restenosis, compared to bare for reduction of restenosis, compared to bare metal stentmetal stent

This difference translated in a marked reduction This difference translated in a marked reduction in in restenosis rate restenosis rate and need for and need for target vessel target vessel revascularizationrevascularization in randomized controlled trials in randomized controlled trials

DES caveat

Early DES trials were performed in low-risk population

End-points (usually late loss) were considered as the surrogate of clinical events

Routine Angiographic follow-up not clinically driven

DES versus BMS of similar design (not necessarily the best BMS)

DES trials vs. DES registry

LAD location

single lesion treatmentprior restenosis

female genderRCA

<15-20 lesion de novo

small vessel

long lesion

long stent lengthin-stent restenosis

bifurcation

multivessel treatment

advanced atherosclerosis

diabetes

Patient risk

Lesi

on

ris

k

DES caveat

Early DES trials were performed in low-risk population

End-points (usually late loss) were considered as the surrogate of clinical events

Routine Angiographic follow-up not clinically driven

DES versus BMS of similar design (not necessarily the best BMS)

Surrogate end-points: late Surrogate end-points: late lossloss

Camenzind et al. Circulation 2007

Frequency of Frequency of distribution of late distribution of late loss values (%)loss values (%)

Frequency of Frequency of clinical event (%)clinical event (%)

Larger lumenLarger lumen Smaller lumenSmaller lumenLate loss (mm)Late loss (mm)

DES DES

BMSBMS

healedhealedInflammation Inflammation and delayed and delayed

healinghealing

There is no evidence of correlation between angiographic late lumen loss and clinical events

The use of late loss as an end point tended to overestimate the difference in restenosis, and the derived effect seemed to be overemphasized with respect to the real risk.

We don’t know the real clinical effect of late loss and its reliability as an end-point in direct comparative drug-eluting stent trials

Surrogate end-points: late Surrogate end-points: late lossloss

Agostoni et al. Am J Cardiol. 2006

DES caveat

Early DES trials were performed in low-risk population

End-points (usually late loss) were considered as the surrogate of clinical events

Routine Angiographic follow-up not clinically driven

DES versus BMS of similar design (not necessarily the best BMS)

DES caveat

Early DES trials were performed in low-risk population

End-points (usually late loss) were considered as the surrogate of clinical events

Routine Angiographic follow-up not clinically driven

DES versus BMS of similar design (not necessarily the best BMS)

BASKET trialBASKET trialThe primary endpoint was cost-effectiveness after 6 months, with effectiveness defined as reduction of major adverse cardiac events

Total costs at 6 months were higher with DES € 10,544than with BMS € 9,639;

The higher stent costs of DES were not compensated for by lower follow-up costs

Kaiser C. Lancet 2005

p<0.0001

BASKET trial: 18-month analysisIn a real-world setting, use of DES in all patients is less cost effective than in studies with selected patients. Use of these stents could be restricted to patients in high-risk groups

Brunner-La Rocca Lancet 2007

DES off-label spreadingDES off-label spreading

very small vessel/stent !very long lesion !left main diseasebifurcation lesionschronic total occlusion in-stent restenosis !!saphenous vein graft

acute myocardial infarction

multivessel diseasediabetics !!!severe LVEF dysfunctionrenal dysfunction

High risk patient subsetsHigh risk patient subsetsHigh risk lesion subsetsHigh risk lesion subsets

Earlier, DES were used in complex lesions and in lesion with high risk of restenosis, despite the lack of data from RCT

Off-label DES useOff-label DES use~80% ~80% off-label use of these devices in the real world”off-label use of these devices in the real world”

18,295 lesions/15,157 patients

EDITORIAL  S Kaul, GA Diamond. www. cardiosource.com

Are DES adverse event rates Are DES adverse event rates increased with off-label use? increased with off-label use?

EVENT registry EVENT registry N = 3,323 NSTEMI with SES and PES, 55% off-label

Off-label: 1.6%On-label: 0.9%

Off-label: 17.5%On-label: 8.9%

P<0.001

Win HK JAMA 2007

Off-label questionOff-label question

Is there any reason to assume that DES won’t work equally Is there any reason to assume that DES won’t work equally as well in other lesion subsets?as well in other lesion subsets?

Lack of approval is related to many factors: Lack of approval is related to many factors:

already widely used off-label (no commercial reason)already widely used off-label (no commercial reason)

logistically difficult to conduct study (no financial logistically difficult to conduct study (no financial reason)reason)

previous studies conducted did not meet the required previous studies conducted did not meet the required standards for approval standards for approval Off label use is not subject to a rigorous Off label use is not subject to a rigorous pre-market approval processpre-market approval process

TLR: independent of classic risk factors – Taxus VI a 12 Months

P=0.0003 P=0.0050

TL

R (

%)

Control TAXUSTM stent MR

30.6

5.0

19/62 3/60

4.4

27.0

10/37 2/45

25.5

5.1

12/47 2/39

P=0.0002

Small vessels<2.5mm

Long lesions≥26mm

Diabetes

84 % 85 % 80 %

Overlappingstents

14/60 1/63

23.6

1.6

93 %

P=0.0168

Control : bare metal stentControl : bare metal stent

2006 DES storm

SCAAR SCAAR registry registry

Lagerqvist NEJM 2007 356;1009-19Lagerqvist NEJM 2007 356;1009-19

Cum

ula

tive R

isk

Cum

ula

tive R

isk

00 0.5 0.5 1.01.0 1.51.5 2.02.02.52.5

Time (years)Time (years)

RR: 1.32 (1.11-RR: 1.32 (1.11-1.57)1.57)

BMSBMSDESDES

BMSBMS 1288012880 1247312473 1235412354 1221312213 929892985960 5960

DESDES 57705770 56045604 55415541 54685468 3434343417761776

0.00.000

0.00.022

0.00.044

0.00.066

0.00.088

0.10.100

RR: 1.03(0.84-RR: 1.03(0.84-1.26)1.26)

3-year mortality increased 18% with DES

Stent registryStent registry

Wake forest experience

4.9%

7.1%

P = 0.03

Applegate AJC 2007

DES in OntarioDES in Ontario

Tu JV NEJM 2007Western Denmark Western Denmark registryregistry

Jensen LO JACC 2007

Marzocchi et al Circulation 2007

Italian Real prospective registryItalian Real prospective registry

Only in 2007… DES vs. BMS

Definite Stent Thrombosis with DES

Daemen J Lancet 2007

Combined DES Thrombosis

*Taxus-II, Taxus-IV, Taxus.VI (2yr); RAVEL, SIRIUS, E-SIRIUS, C-SIRIUS (3 yrs)** 24-36 months for Cypher data only

DES “a chi”?

• Thesis: Thesis: TLR reduction with no beneficial TLR reduction with no beneficial effect on death and re-infarction was effect on death and re-infarction was observed in RCTobserved in RCT

• AntithesisAntithesis: there are still concerns regarding : there are still concerns regarding generalization of DES to the population-at-generalization of DES to the population-at-large (potentially armful)large (potentially armful)

• Synthesis: do we have to apply evidence based medicine?

DES Evidence based guidelines

DES Evidence based guidelines

DES Evidence based guidelines

What is the Evidence?What is the Evidence?

Randomized controlled trials(selective patients, underpowered)

Observational Cohort registries(different strategies, unblinded, biased)

Meta-analyses (meta-analysis have been proven wrong 35% of the time by large RCT!)

Treatment strategy studies (biased, underpowered)

DES and Lesions/Patients Characteristics: the Fact

DES have been revolutionary in cardiology

Failure rates are increasing with increasing complexity of disease treated

In-stent restenosis – is still In-stent restenosis – is still predictable?predictable?

Reference Table for restenosis riskReference Table for restenosis risk

Serruys JACC 1999Serruys JACC 1999

% stenosis

at end

Vessel Size

2.14 - 2.45

23.5 27.9

39%30% - 49%

% stenosis

at end

Vessel Size

3.07 - 3.38

19.1 23.5

13%10% - 16%

Restenosis Risk

BASKET trial: 18-month analysisUsed in all patients, drug-eluting stents are not good value for money, even if prices were substantially reduced.

Brunner-La Rocca Lancet 2007

High-risk patients

Drug-eluting stents are cost effective in patients needing small vessel or bypass graft stenting, but not in those who require large native vessel stenting

Implantation of DES in large coronary arteries confers no additional benefit compared to BMS

The 2 approaches are associated with equally favorable 1-year outcome

Steinberg JACC 2007Steinberg JACC 2007

233 SVD pts treated with DES compared to 233 propensity-matched pts treated with BMS

Comparison of effectiveness of BMS vs.Comparison of effectiveness of BMS vs. DES in large (≥3.5mm) coronary arteriesDES in large (≥3.5mm) coronary arteries

Cost-effectiveness in subgroups

Steinberg JACC 2007

Adjusted for type of lesion, stent diameter and length

Restenosis is variable

SCAAR annual report 2007SCAAR annual report 2007

Unadjusted

Predictors of stent thrombosis

Moses CIT 2006Moses CIT 2006

DES pending questions

ISR lesion (esp. Diffuse proliferative and s/p VBT)

Bifurcation (ostial side branch)

SVGs

LM disease (esp. Distal bifurcation)

Acute MI and thrombus-containing lesions

Quale DES?Quale DES?

ManifacturerManifacturer NameName DrugDrug Stent Stent MaterialMaterial PolymerPolymer

BiosensorsBiosensors AxxionAxxion PaclitaxelPaclitaxel Stainless SteelStainless Steel NoneNone

BiosensorsBiosensors BioMatrixBioMatrix Biolimus-A-9Biolimus-A-9 Stainless SteelStainless Steel BioabsorbableBioabsorbable

Boston ScientificBoston Scientific Taxus LibertéTaxus Liberté PaclitaxelPaclitaxel Stainless SteelStainless Steel DurableDurable

Boston ScientificBoston Scientific PromusPromus EverolimusEverolimus Cobalt Cobalt ChromiumChromium

DurableDurable

Cordis / J&JCordis / J&J Cypher SelectCypher Select SirolimusSirolimus Stainless SteelStainless Steel DurableDurable

Cordis / J&JCordis / J&J Cypher NeoCypher Neo SirolimusSirolimus Cobalt Cobalt ChromiumChromium

DurableDurable

EurocorEurocor Genius TaxcorGenius Taxcor PaclitaxelPaclitaxel Stainless SteelStainless Steel NoneNone

Guidant/AbbottGuidant/Abbott ChampionChampion EverolimusEverolimus Stainless SteelStainless Steel BioabsorbableBioabsorbable

Guidant/AbbottGuidant/Abbott Xience VXience V EverolimusEverolimus Cobalt Cobalt ChromiumChromium

DurableDurable

MedtronicMedtronic EndeavorEndeavor ZotarolimusZotarolimus Cobalt Cobalt ChromiumChromium

DurableDurable

SorinSorin JanusJanus TacrolimusTacrolimus Stainless SteelStainless Steel NoneNone

SMTSMTTransluminaTranslumina

InfinniumInfinniumYukonYukon

PaclitaxelPaclitaxelSirolimusSirolimus

Stainless SteelStainless SteelStainless stelStainless stel

BioabsorbableBioabsorbableNpneNpne

TerumoTerumo NoboriNobori Biolimus-A-9Biolimus-A-9 Stainless SteelStainless Steel BioabsorbableBioabsorbable

DES Summary - 2007 in Italy: DES Summary - 2007 in Italy: 10 DES With CE Mark in Yellow10 DES With CE Mark in Yellow

DES Strut and Polymer DES Strut and Polymer ThicknessThickness

Cypher® TAXUS® Express

EndeavorTM XIENCETM V

Strut Thickness140 m

Polymer Thickness12.6 m

Total152.6 m

Strut Thickness132 m

Polymer Thickness16.0 m

Total148.0 m

Strut Thickness91 m

Polymer Thickness5.3 m

Total96.3 m

Strut Thickness81 m

Polymer Thickness7.6 m

Total88.6 m

3.0 mm diameter, 500x magnification

Some DES do not workSome DES do not work

Quanam – Taxane (polymer sleeve)Quanam – Taxane (polymer sleeve)

Guidant – Actinomycin D (polymer matrix)Guidant – Actinomycin D (polymer matrix)

Guidant/Cook – Placlitaxel (direct application)Guidant/Cook – Placlitaxel (direct application)

Abbott – Batimastat (PC coating)Abbott – Batimastat (PC coating)

DES future directions

Top factor driving DES brand Top factor driving DES brand selectionselection

In-Stent Late Loss Across Multiple Randomized Olimus Trials

In-Stent Late Loss Across Multiple Randomized Olimus Trials

CYPHER™ StentCYPHER™ Stent

ENDEAVOR™ StentENDEAVOR™ Stent

XIENCE™ V Stent(PROMUS™ Stent)XIENCE™ V Stent(PROMUS™ Stent)

ZoMaxx™

StentZoMaxx™

Stent

8 mos.6 mos.

SPIRIT

I

6 mos.

SPIRIT

II*

FIMRAVEL

SIRIU

S

C-SIR

IUS

E-SIR

IUS

SES SM

ART

REALITY

ENDEAVOR

III ENDEAVOR

IENDEAVOR

II ZOMAXX I

6 mos. 6 mos. 8 mos. 8 mos. 8 mos. 8 mos.ENDEAVOR

III

9 mos.12 mos. 9 mos.9 mos. 9 mos.

Does lesion characteristics Does lesion characteristics dictate stent selection?dictate stent selection?

Any specific Any specific suggestions?suggestions?

A)A)To limit restenosis To limit restenosis

B)B)To limit thrombosisTo limit thrombosis

C) To limit costsC) To limit costs

What have we learned… about DES?

Dual antiplatelet therapy is crucial for a Dual antiplatelet therapy is crucial for a longer duration then for BMS (longer duration then for BMS (how long?how long?))

Risk of complication (death, MI, ST) are Risk of complication (death, MI, ST) are higher for patients receiving DES off-label higher for patients receiving DES off-label vs on-label (vs on-label (is it different for BMS?is it different for BMS?))

Timing and mechanisms of stent Timing and mechanisms of stent thrombosis seem different than for BMS thrombosis seem different than for BMS ((which is the overall incidence?which is the overall incidence?))

““Do the right choice…” Do the right choice…”

DES DES

““Right” stent selectionRight” stent selection

Cath lab Cath lab practicepractice

RCTsRegistriesMeta-analysesExpert opinions

Clinical judgement

Patient and physician expectation

Operator-related issues

Socio-economic factors

Evidence based

medicine

Other factors

Innovative Technology Innovative Technology LifecycleLifecycle

Rapid Adoption

(data > perception)

UnbridledEnthusiasm(perception > dara)

UntowardComplications

(perception > data)

Technology

New technology + new data

Realistic application

(data > perception)

We are here

Variables for DES Variables for DES selectionselectionPPatientatient

ASA intolleranceASA intollerancePlavix resistancePlavix resistanceHypercoaugulabilityHypercoaugulability

PProcedurerocedureOptimize stent Optimize stent implantationimplantationAvoid certain Avoid certain lesionslesionsUtilize IVUSUtilize IVUS

PProviderroviderIncreasing PM surveilance Increasing PM surveilance New formulation New formulation no drug/polymer no drug/polymer New drugsNew drugs

Freedom From Cardiac Death9 Prospective, Double-Blind, Randomized Trials

60

70

80

90

100

60

70

80

90

100

Time after Initial Procedure (years)Time after Initial Procedure (years)

00 11 22 33 44

Time after Initial Procedure (years)Time after Initial Procedure (years)

TAXUS I, II, IV, V, VITAXUS I, II, IV, V, VI(n=3,506)(n=3,506)

RAVEL, SIRIUS, E-SIRIUS, C-SIRIUSRAVEL, SIRIUS, E-SIRIUS, C-SIRIUS(n=1,748)(n=1,748)

P=0.3297.4% (22)96.5% (29)

CYPHER stent (n=870) Bare metal stent (n=878)

00 11 22 33 4460

70

80

90

100

60

70

80

90

100

P=0.5297.0% (42)97.6% (36)

TAXUS stent (n=1,749) Bare metal stent (n=1,757)

60

70

80

90

100

60

70

80

90

100

Time after Initial Procedure (years)Time after Initial Procedure (years)

00 11 22 33 44

Time after Initial Procedure (years)Time after Initial Procedure (years)

TAXUS I, II, IV, V, VITAXUS I, II, IV, V, VI(n=3,506)(n=3,506)

RAVEL, SIRIUS, E-SIRIUS, C-SIRIUSRAVEL, SIRIUS, E-SIRIUS, C-SIRIUS(n=1,748)(n=1,748)

P=0.8693.8% (53)93.6% (55)

CYPHER stent (n=870) Bare metal stent (n=878)

00 11 22 33 4460

70

80

90

100

60

70

80

90

100

P=0.6493.7% (104)93.0% (110)

TAXUS stent (n=1,718) Bare metal stent (n=1,727)

Freedom From Myocardial Infarction9 Prospective, Double-Blind, Randomized Trials

Freedom From ischemic TLR9 Prospective, Double-Blind, Randomized Trials

60

70

80

90

100

60

70

80

90

100

Time after Initial Procedure (years)Time after Initial Procedure (years)

00 11 22 33 44

Time after Initial Procedure (years)Time after Initial Procedure (years)

TAXUS I, II, IV, V, VITAXUS I, II, IV, V, VI(n=3,506)(n=3,506)

RAVEL, SIRIUS, E-SIRIUS, C-SIRIUSRAVEL, SIRIUS, E-SIRIUS, C-SIRIUS(n=1,748)(n=1,748)

P<0.000176.4% (202)92.2% (66)

CYPHER stent (n=870) Bare metal stent (n=878)

00 11 22 33 4460

70

80

90

100

60

70

80

90

100

P<0.000180.0% (337)89.9% (164)

TAXUS stent (n=1,749) Bare metal stent (n=1,757)

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