4 th European Bifurcation Club 26-27 September 2008 - PRAGUE

4th European Bifurcation Club 26-27 September 2008 - PRAGUE

A comprehensive meta-A comprehensive meta-analysis on drug-eluting analysis on drug-eluting stenting for unprotected stenting for unprotected

left main diseaseleft main disease

Background

• Cardiac surgery is the gold standard revascularization means for unprotected left main disease (ULM).

• Percutaneous drug-eluting stent (DES) implantation has been recently reported in patients with ULM, but with unclear results.

• Moreover, predictors of adverse events after DES implantation in ULM are still under investigation.

Aims

• To perform a systematic review of the outcomes of DES implantation in patients with ULM coronary disease.

• To pool major outcomes with meta-analytic techniques.

• To identify predictors of adverse events by means of meta-regression analysis.

Methods• Several databases (BioMedCentral, clinicaltrials.gov, Google

Scholar, and PubMed) were systematically searched for pertinent clinical studies

• Major selection criteria were: enrolment of at least 20 patients, follow-up for at least 6 months, and full text publication (thus excluding abstracts)

• Pre-specified subgroup analyses were performed according to ostial ULM, and non-high-risk features (defined by means of Parsonnet or EuroSCORE systems)

• Generic-inverse-variance random-effect methods were used to pool incidence rates and adjusted risk estimates (odds ratios [OR], with 95% confidence intervals) of death, myocardial infarction (MI), target vessel revascularization (TVR), or their composite, ie major adverse cardiovascular events (MACE)

Methods• Several databases (BioMedCentral, clinicaltrials.gov, Google Scholar,

and PubMed) were systematically searched• Major selection criteria were: enrolment of at least 20 patients, follow-up

for at least 6 months, and full text publication (thus excluding abstracts)• Pre-specified subgroup analyses were performed according to ostial

ULM, and non-high-risk features (defined by means of Parsonnet or EuroSCORE systems)

• Generic-inverse-variance random-effect methods were used to pool incidence rates and adjusted risk estimates (odds ratios [OR], with 95% confidence intervals) of death, myocardial infarction (MI), target vessel revascularization (TVR), or their composite, ie major adverse cardiovascular events (MACE)

• Meta-regression was performed to identify regression coefficients (with 95% confidence intervals) for event predictors

Review profile

17 studies (16 original cohorts) included in the review

774 titles/abstracts excludedbecause non-relevant

32 articles excluded according to selection criteria

7 duplicate publications 4 enrolling <20 patients 9 ongoing 7 unpublished 5 using BMS only

823 hits retrieved from extensive database search

49 articles assessed according to inclusion/exclusion criteria

Included studiesStudy design and ID Country Patients treated with DES

Observational cohorts on DESAgostoni et al (2005) Netherlands 58de Lezo et al (2004) Spain 52Dudek et al (2006) Poland 28KOMATE (2005) Korea 54Lozano et al (2005) Spain 42Migliorini et al (2006) Italy 156Price et al (2006) USA 50Wood et al (2005) USA 100

Non-randomized studies of DES vs BMSCarrié et al (2006) France 120Chieffo et al (2005) Italy 85Christiansen et al (2006) Denmark 46Han et al (2006) China 138Park et al (2005) Korea 102Sheiban et al (2006) Italy 85

Non-randomized studies of PCI vs CABGChieffo et al (2006) Italy 107Lee et al (2006) USA 50Palmerini et al (2006) Italy 94

Major excluded studiesStudy Country Patients Design Reason for exclusionArampatzis et al(2003) Netherlands 31 Observational cohort Duplicate publicationArampatzis et al(2004) Netherlands 16 Observational cohort Duplicate publicationBerenguer et al(2005) Spain 7 Observational cohort Duplicate publicationCARDIA(2006) UK 600 RCT of PCI vs CABG OngoingCOMBAT Worldwide 1800 RCT of PCI vs CABG On holdeCYPHER(2006) Worldwide 171 Observational cohort UnpublishedErglis et al Europe 103 RCT of DES vs BMS UnpublishedEuropean Registry Europe 224 Observational cohort UnpublishedFrench Multicenter Taxus Study France 150 Observational cohort OngoingHerz et al(2005) Israel 4 Non-RCT of PCI vs CABG <20 patients includedKim et al(2006) Korea 116 Observational cohort Duplicate publicationKorean Randomized Study Korea 124 RCT of PCI vs CABG OngoingLE MANS(2005) Poland 37 Observational cohort UnpublishedLefevre et al France 146 Observational cohort UnpublishedLeipzig Study Germany 200 RCT of PCI vs CABG OngoingLopez-Palop et al(2004) Spain 10 Observational cohort <20 patients includedMunich Study Germany 340 RCT of Cypher vs Taxus OngoingPalmerini et al(2005) Italy 42 Observational cohort Duplicate publicationPeszek-Przybyla et al(2006) Poland 62 Observational cohort <20 patients includedPohl et al(2004) Germany 23 RCT of PCI vs CABG BMS use onlyREVASCULARIZE USA NA RCT of PCI vs CABG OngoingSECURE USA 20 Observational cohort UnpublishedSYNTAX Worldwide 1500 RCT of PCI vs CABG OngoingTeplitsky et al(2004) Israel 11 Observational cohort <20 patients includedTRUE Europe 115 Observational cohort UnpublishedValgimigli et al(2005) Netherlands 80 Before-after study Duplicate publicationValgimigli et al(2006) Netherlands 110 Observational cohort Duplicate publication

Characteristics of included studiesStudy

Age (years)

Males (%)

DM (%)

ACS (%)

Non-bifurcational ULM (%)

Surgical high risk

features (%)

LVEF (%)

COPD (%)

RF (%)

Angio follow-up

(%)

Oral antiplatelet

regimen

SES vs PES use

(%)

Agostoni et al(2005) 63±13 69 33 32 45 NA 48±12

NA NA NA A+C, 6 m NA

Carrié et al(2006) 66±12 75 29 63 0 NA 59±11

NA NA 100 A+C, 6m 0/100

Chieffo et al(2005) 63±12 84 21 31 19 45 51±11

NA NA 85 A+C, ≥6 m NA

Chieffo et al(2006) 64±10 NA 19 32 19 32 52±10

NA 6 85 NA 51/49

Christiansen et al(2006)

NA NA NA NA 46 43 NA NA NA NA A+C, ≥3 m NA

de Lezo et al(2004) 63±11 42 35 83 58 NA 57±13

NA NA 67 A+C, 12 m 100/0

Dudek et al(2006) NA NA NA NA NA NA NA NA NA NA A+C, 6-12 m 46/54Han et al(2006)* 62±11 NA 29 45 29 NA NA NA NA 36 A+C, 6-9 m NAKOMATE (2005) 59±9 68 27 65 67 NA 60±1

8NA 4 44 A+C, 6 m 65/35

Lee et al(2006) 72±15 50 36 66 40 64 51±15

NA 16 42 A+C, 6 m 84/16

Lozano et al(2005) 70±11 60 33 17 31 100 37* NA NA 57 A+C, 3-6 m 71/19Migliorini et al(2006) 70±10 80 32 69 15 61 27† NA 27 84 A+C, 6 m 26/74Palmerini et al(2006) 73±11 70 26 63 20 64 52±1

416 20 66 NA 68/32

Park et al(2005) 60±11 75 28 60 29 NA 60±8 NA NA 84 A+C, 6 m 100/0Price et al(2006) 69±13 64 26 34 6 58 24‡ NA 16 98 A+C,

indefinitely100/0

Sheiban et al(2006) 68±10 77 22 67 40 46 55±10

NA 4 61 A+C or A+T, 6 m

100/0

Wood et al(2005) 68±13 64 30 NA 31 NA 47±13

NA NA NA A+C, ≥6 m NA

Unadjusted clinical outcomesStudy N In-hospital

death (%)

In-hospital MI (%)

Follow-up (months)

Follow-up completion

(%)

MACE (%)

MACCE (%)

Death (%) MI (%) Stroke

(%)TVR (%)

ST (%)

Agostoni et al (2005) 58 2 3 14 100 16 NA 5 3 NA 7 NACarrié et al (2006)–BMS arm* 57 0 5 10 100 66 NA 7 5 NA 26 0Carrié et al (2006)–DES arm* 49 4 3 10 100 13 13 10 3 0 2 1Chieffo et al (2005)–BMS arm 64 0 8 12 100 42 NA 14 NA NA 30 0Chieffo et al (2005)–DES arm 85 0 6 12 100 25 NA 4 NA NA 19 1Chieffo et al (2006)–CABG arm 142 2 26 12 100 42 44 8 27 2 6 NA

Chieffo et al (2006)–DES arm 107 0 9 12 100 33 34 3 10 1 20 1

Christiansen et al (2006)–BMS arm*

39 31 3 6 100 44 44 31 5 0 8 NA

Christiansen et al (2006)–DES arm*

42 2 0 6 100 7 7 5 2 0 5 2

de Lezo et al (2004) 52 0 4 12 100 6 NA 0 4 NA 2 0Dudek et al (2006) 36 NA NA 9 NA 14 NA NA NA NA 0 NAHan et al (2006)–BMS arm 34 NA NA 12 NA 27 NA 9 3 NA 15 NAHan et al (2006)–DES arm 138 NA NA 12 NA 11 NA 7 1 NA 10 NA

KOMATE (2005) 54 2 0 6 81 5 NA 2 0 NA 2 0Lee et al (2006)–CABG arm 123 5 2 6 NA 14 17 11 2 8 1 NA

Lee et al (2006)–DES arm 50 2 0 6 NA 11 11 4 4 0 7 0Lozano et al (2005) 42 10 0 10 100 26 NA 20 4 NA 2 1Migliorini et al (2006)* 156 7 1 6 100 24 24 11 1 0 12 0

Palmerini et al (2006)–CABG arm

154 NA NA 6 NA 14 NA 11 13 NA NA NA

Palmerini et al (2006)–DES arm 94 NA NA 6 NA 22 NA 9 13 NA NA NAPark et al (2005)–BMS arm 121 0 8 12 100 25 NA 0 8 NA 17 0

Park et al (2005)–DES arm 102 0 7 12 100 9 NA 0 7 NA 2 0

Price et al (2006) 50 0 8 8 100 54 NA 10 10 NA 44 4Sheiban et al (2006)–BMS arm* 69 10 3 10 99 36 36 20 3 0 13 0Sheiban et al (2006)–DES arm* 77 3 3 10 100 9 10 3 3 1 4 0Wood et al (2005)* 100 2 3 19 100 19 NA 6 3 NA 7 1

Results

• After excluding 806 non-pertinent citations, we finally included 16 original studies (1274 patients, median follow-up 9 months [range 6-24])

• There were 8 uncontrolled reports on DES, 5 non-randomized comparison between DES and bare-metal stents (BMS), and 3 between DES and CABG

• Overall, 31% of patients had non-bifurcational ULM and 59.5% had high-risk features at EuroSCORE or Parsonnet

Results

• Mid-term MACE occurred in 18.2%, mid-term death in 4.4%, and repeat revascularization in 7.4%

• Meta-regression showed that location of disease was the most significant predictor of mid-term MACE (p=0.001) as well as of TVR (p=0.050)

• On the other hand, high-risk features at EuroSCORE or Parsonnet were the most significant predictor of mid-term death (p=0.027)

• Stenting technique was also significantly associated with MACE rate (p=0.050)

Risk of in-hospital death

2,3 (1,1-3,4)

2,02,8

0,0

0,07,1

9,52,0

1,9

0,02,4

0,04,2

1,7

0 3 6 9 12 15

Overall estimate (95%CI)

Wood et al (2006, 100 pts)Sheiban et al (2006, 85 pts)

Price et al (2006, 50 pts)Park et al (2005, 102 pts)

Migliorini et al (2006, 156 pts)

Lozano et al (2005, 42 pts)Lee et al (2006, 50 pts)

KOMATE (2005, 54 pts)de Lezo et al (2004, 52 pts)

Christiansen et al (2006, 42 pts)

Chieffo et al (2005, 85 pts)Carriè et al (2006, 120 pts)

Agostoni et al (2005, 58 pts)

Stud

y

Rate of in-hospital death (%)

Risk of in-hospital MI

3,02,6

8,06,9

0,60,00,00,0

3,90,0

5,92,5

3,5

0 3 6 9 12 15



Migliorini et al (2006, 156 pts)Lozano et al (2005, 42 pts)

Lee et al (2006, 50 pts)KOMATE (2005, 54 pts)

de Lezo et al (2004, 52 pts)Christiansen et al (2006, 42 pts)



Stud

y

2,5 (1,2-3,8)Overall estimate (95%CI)

Rate of in-hospital myocardial infarction (%)

Risk of MACE at follow-up

19,09,1

54,08,8

25,523,7

26,210,6

4,610,9

14,35,8

7,132,7

12.515,5

0 15 30 45 60



Palmerini et al (2006, 94 pts)Migliorini et al (2006, 156 pts)


KOMATE (2005, 54 pts)Han et al (2006, 138 pts)

Dudek et al (2006, 28 pts)de Lezo et al (2004, 52 pts)

Christiansen et al (2006, 42 pts)Chieffo et al (2005, 85 pts)Carriè et al (2006, 120 pts)


Stud

y

Rate of mid-term MACE (%)


Risk of death at follow-up

8,02,6

10,00,0

13,810,9

19,14,0

1,95,1

0,04,8

2,8

5,2

0 15 30 45 60



Palmerini et al (2006, 94 pts)Migliorini et al (2006, 156 pts)


KOMATE (2005, 54 pts)Han et al (2006, 138 pts)

de Lezo et al (2004, 52 pts)Christiansen et al (2006, 42 pts)



Stud

y

Rate of mid-term death (%)


10,0

Risk of TVR at follow-up

8,03,9

44,02,0

12,12,4

6,32,3

7,30,0

1,94,8

18,81,7

6,9

0 15 30 45 60



Migliorini et al (2006, 156 pts)Lozano et al (2005, 42 pts)

Lee et al (2006, 50 pts)KOMATE (2005, 54 pts)Han et al (2006, 138 pts)

Dudek et al (2006, 28 pts)de Lezo et al (2004, 52 pts)

Christiansen et al (2006, 42 pts)Chieffo et al (2005, 85 pts)Carriè et al (2006, 120 pts)


Stud

y

Rate of mid-term TVR (%)


Surgical risk and death rate

Prevalence of high-risk clinical features (%)10090807060504030

Ris

k of

dea

th a

t fol

low

-up

(Log

10 o

f the

act

ual r

ate)

-,6

-,8

-1,0

-1,2

-1,4

-1,6

Christiansen

Lee

Sheiban

Lozano

Palmerini

Chieffo

Migliorini

Price

P=0.027

←Lo

wer

risk

Hig

her r

isk→

Patients at high surgical risk are

significantly more likely to die during follow-up

Stenosis location and MACE rate

Prevalence of non-bifurcational disease (%)706050403020100

-,2

-,4

-,6

-,8

-1,0

-1,2

-1,4Komate

De LezoChristiansen

Agostoni

Lee

Sheiban

Lozano

Wood

Park

Han

Carrié

Palmerini

Chieffo

Migliorini

Price P=0.001R

isk

of M

AC

E a

t fol

low

-up

(Log

10 o

f the

act

ual r

ate)

←Lo

wer

risk

Hig

her r

isk→

Patients with high distal ULM are

significantly more likely to have MACE

Stenting technique and MACE rate

Rate of complex stenting technique (%)10080604020 0

-,2

-,4

-,6

-,8

-1,0

-1,2

-1,4

De Lezo

Christiansen

Agostoni

Lee

SheibanParkHan

Carrié

Palmerini

Chieffo

Migliorini

Price

Dudek

P=0.050R

isk

of M

AC

E a

t fol

low

-up

(Log

10 o

f the

act

ual r

ate)

←Lo

wer

risk

Hig

her r

isk→

Patients treated with 2 stents are

significantly more likely to have MACE

Stenosis location and TVR rate

Prevalence of non-bifurcational disease (%)

706050403020100

-,2

-,4

-,6

-,8

-1,0

-1,2

-1,4

-1,6

-1,8

Komate

De Lezo

Christiansen

AgostoniLee

Sheiban

Lozano

Wood

Park

Han

Carrié

Chieffo

Migliorini

Price P=0.050R

isk

of T

VR

at f

ollo

w-u

p

(Log

10 o

f the

act

ual r

ate)

←Lo

wer

risk

Hig

her r

isk→

Patients with high distal ULM are significantly

more likely to have TVR

Conclusions

• The largest cohort reported to date of patients with ULM treated with DES provides encouraging mid-term follow-up data, at least in selected patients

• Analysis of the largest cohort to date of patients treated with DES for ULM shows that risk-stratification should be based in these patients on location of disease and overall risk features

• Event-free survival is excellent in low-risk patients with non-bifurcational ULM, while a high case fatality can be expected in high-risk subjects, irrespective of disease location

For further slides on these topics please feel free to visit the metcardio.org website:

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4 th European Bifurcation Club 26-27 September 2008 - PRAGUE

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