comprehensive meta-analysis of des vs. bms randomized trials and registries

Columbia University Medical CenterColumbia University Medical CenterThe Cardiovascular Research FoundationThe Cardiovascular Research Foundation

Comprehensive Meta-Analysis Comprehensive Meta-Analysis of DES vs. BMS Randomized of DES vs. BMS Randomized

Trials and RegistriesTrials and RegistriesAjay J. Kirtane, M.D., S.M.Ajay J. Kirtane, M.D., S.M.

Gregg W. Stone, M.D.Gregg W. Stone, M.D.

Conflict of Interest Disclosure

• Ajay J. Kirtane Past honorarium from Boston Scientific

Corporation (modest) Consultant/Speaker: Medtronic Vascular,

Abbott Vascular (modest)• Gregg W. StoneGregg W. Stone

Research grants from Boston Scientific Research grants from Boston Scientific and Abbott Vascularand Abbott Vascular

Background: DES vs. BMS RCTs• In most individual RCTs, DES have reduced the rates of TLR

and TVR compared to BMS, with no significant differences in death or MI

• However, individual RCTs are underpowered to assess low frequency endpoints

• RCTs, particularly the pivotal RCTs leading to regulatory approval, have been criticized for not reflecting “real-world” DES use

• RCT outcomes may vary based upon differences in enrollment criteria (e.g. “on-label” vs. “off-label”), the amount of routine angiographic FU, and with the duration of clinical FU

Background: DES vs. BMS Registries• In order to address issues of both sample size as

well as generalizability to the “real-world”, numerous observational and registry comparisons of DES vs. BMS have been undertaken

• The outcomes from these studies have varied• While more generalizable than RCTs, the DES vs.

BMS registries are heterogeneous, with differences in design and analysis methodology (e.g. adjusted vs. unadjusted, type of adjustment)

• Registry outcomes may also vary based upon the types of patients enrolled (e.g. all comers vs. just ACS or high risk), and the duration of clinical FU

Persistent Questions: DES vs. BMS• While some of the alarm generated after ESC 2006 has

been mitigated by analyses of patient-level data from the “on-label” RCTs*, there remains concern regarding DES outcomes in “off-label” patients and lesions, and with uncontrolled use Are DES safe in higher risk off-label pts and in the

unregulated environment of real-world use? Are the benefits of DES in reducing TVR as robust in the

real-world as in the RCTs, given the impact of routine angio FU and the oculostenotic reflex in many RCTs?

*Stone et al, Kastrati et al, Spaulding et al, Mauri et alN Engl J Med 2007; 356(10).

Methods: Goals and Objectives (1)

• We therefore sought to perform a systematic review and meta-analysis of DES vs. BMS studies To derive summary estimates of all-cause

mortality, MI, and TVR in studies with ≥1 year of follow-up

To specifically assess differences between RCT and registry safety and effiacy with regard to these endpoints

Methods: Goals and Objectives (2)• Randomized Trials

To assess differences between RCTs according to “on-label” vs. “off-label” use, duration of FU, and baseline risk

• Registries / Observational AnalysesTo assess differences in the estimates derived

from registries using unadjusted and adjusted analyses (and according to the types of adjustment)

To assess differences between registries according to duration of FU, and baseline risk

• To assess differences in effect size estimates between the RCTs and registries for each endpoint

Methods: Inclusion Criteria• English language RCTs or registries which English language RCTs or registries which

reported a reported a direct comparison direct comparison of DES of DES (commercialized formulations of SES and PES (commercialized formulations of SES and PES only) vs. BMS. only) vs. BMS.

• Criteria for each study: Criteria for each study: ≥≥100 patients total100 patients totalMortality reported (± MI and/or TVR)Mortality reported (± MI and/or TVR)≥≥1 year of 1 year of cumulativecumulative follow-up reported, with the follow-up reported, with the

outcome assessed at the same time point in both outcome assessed at the same time point in both comparator armscomparator arms

Methods: Exclusion Criteria

• ““DES era” vs. pure “BMS era” studies in which DES era” vs. pure “BMS era” studies in which the DES era group did not exclude BMS ptsthe DES era group did not exclude BMS pts Excepting intent-to-treat RCTsExcepting intent-to-treat RCTs

• Study used a control group from another study Study used a control group from another study already in the meta-analysisalready in the meta-analysis

• Study was itself a meta-analysis (although data Study was itself a meta-analysis (although data abstracted from individual studies in a abstracted from individual studies in a published meta-analysis could be used)published meta-analysis could be used)

Methods: Search Strategy (1)• 2 PUBMED searches2 PUBMED searches

Focused: Focused: (eluting stent OR DES OR drug-eluting stent) AND (eluting stent OR DES OR drug-eluting stent) AND (bare OR uncoated OR standard OR BMS) AND (("2002"[PDat] (bare OR uncoated OR standard OR BMS) AND (("2002"[PDat] : "2008"[PDat]) AND (Humans[Mesh]) AND (English[lang])) : "2008"[PDat]) AND (Humans[Mesh]) AND (English[lang])) AND (coronary) NOT (cost-effectiveness) NOT review[pt] NOT AND (coronary) NOT (cost-effectiveness) NOT review[pt] NOT case reports[pt] NOT editorial[pt] NOT comment[pt]case reports[pt] NOT editorial[pt] NOT comment[pt]

Broad: Broad: stent AND bare AND (eluting OR sirolimus OR stent AND bare AND (eluting OR sirolimus OR paclitaxel)paclitaxel)

• Cochrane databaseCochrane database• Eurointervention journalEurointervention journal

Methods: Search Strategy (2)• Abstracts/presentations from 2007 meetings:Abstracts/presentations from 2007 meetings:

ACC SCAI/I2 SummitACC SCAI/I2 Summit ESCESC TCTTCT AHAAHA

• Data requested from study PI’s for large registriesData requested from study PI’s for large registries For most updated dataFor most updated data Where not publicly available or to clarify methodologyWhere not publicly available or to clarify methodology

Methods: Analysis• Pre-specified separate analysis of RCTs and Pre-specified separate analysis of RCTs and

Registries performed given clinical heterogeneityRegistries performed given clinical heterogeneity• RCTs: Direct randomization to DES vs. BMSRCTs: Direct randomization to DES vs. BMS• Registries: Non-rand comparison of DES vs. BMS Registries: Non-rand comparison of DES vs. BMS

(including non-rand comparisons within a RCT)(including non-rand comparisons within a RCT)• All analyses cumulativeAll analyses cumulative

• No landmarksNo landmarks• Single time point estimate for each study assuming Single time point estimate for each study assuming

constant hazard of DES vs. BMS through study period constant hazard of DES vs. BMS through study period (hence use of HR or RR as the estimate)(hence use of HR or RR as the estimate)

• Higher quality estimate picked for primary analyses Higher quality estimate picked for primary analyses (adjusted > unadjusted)(adjusted > unadjusted)

Methods: Statistical Analysis• All analyses were performed at The Cardiovascular All analyses were performed at The Cardiovascular

Research Foundation/Columbia UniversityResearch Foundation/Columbia University• Models (both reported):Models (both reported):

• Fixed effects (Inverse-Variance weighted)Fixed effects (Inverse-Variance weighted)• Random effects (DerSimonian and Laird)*Random effects (DerSimonian and Laird)*• Fixed effects model was considered the primary Fixed effects model was considered the primary

model if significant heterogeneity was not model if significant heterogeneity was not present; otherwise random effects was present; otherwise random effects was considered primaryconsidered primary

• Formal heterogeneity testing was performed using Formal heterogeneity testing was performed using the Ithe I22 statistic; heterogeneity was defined as I statistic; heterogeneity was defined as I22 ≥ 25% ≥ 25%

*Weights displayed in figures are based upon the primary model used

• GRACEGRACE Non-landmark data not available (PI contacted as well)Non-landmark data not available (PI contacted as well) Unequal follow-up in comparator arms (data not Unequal follow-up in comparator arms (data not

presented at fixed timepoint)presented at fixed timepoint)• RRISCRRISC

Less than 100 patientsLess than 100 patients• Medicare DataMedicare Data

Comparison of pre-DES era with post-DES rather Comparison of pre-DES era with post-DES rather than DES vs. BMSthan DES vs. BMS

Selected Excluded StudiesSelected Excluded Studies

All-Cause Mortality: All RCTsAll-Cause Mortality: All RCTs

I-V Overall (I-squared = 0.0%, p = 0.918)

BASKET (SES only)

TAXUS II

HAAMU-STENTSeville

Ortolani et al

TAXUS IV

E-SIRIUS

Study ID

DIABETES

PRISON II

STRATEGY

RAVEL

SES-SMART

TAXUS V

Typhoon

MISSION!

SCORPIUSSESAMI

D+L Overall

Passion

C-SIRIUS

Pache et al

SIRIUS

0.97 (0.81, 1.15)

0.82 (0.37, 1.84)

1.61 (0.57, 4.53)

2.00 (0.63, 6.38)1.35 (0.23, 7.78)

2.00 (0.19, 21.38)

0.89 (0.63, 1.25)

1.08 (0.25, 2.24)

ES (95% CI)

1.44 (0.48, 4.33)

0.50 (0.09, 2.67)

0.84 (0.36, 1.96)

1.75 (0.73, 4.16)

0.21 (0.02, 1.71)

0.97 (0.57, 1.65)

1.01 (0.38, 2.65)

0.48 (0.09, 2.59)

1.28 (0.35, 4.61)0.43 (0.11, 1.63)

0.97 (0.81, 1.15)

0.70 (0.36, 1.36)

0.68 (0.11, 4.04)

1.40 (0.45, 4.35)

1.02 (0.67, 1.54)

100.00

4.80

2.87

2.301.00

0.55

26.29

2.57

(I-V)

2.55

1.07

4.30

4.08

0.62

10.92

3.27

1.09

Weight

1.861.70

6.99

0.95

2.40

17.82

%

0.97 (0.81, 1.15)

0.82 (0.37, 1.84)

1.61 (0.57, 4.53)

2.00 (0.63, 6.38)1.35 (0.23, 7.78)

2.00 (0.19, 21.38)

0.89 (0.63, 1.25)

1.08 (0.25, 2.24)

ES (95% CI)

1.44 (0.48, 4.33)

0.50 (0.09, 2.67)

0.84 (0.36, 1.96)

1.75 (0.73, 4.16)

0.21 (0.02, 1.71)

0.97 (0.57, 1.65)

1.01 (0.38, 2.65)

0.48 (0.09, 2.59)

1.28 (0.35, 4.61)0.43 (0.11, 1.63)

0.97 (0.81, 1.15)

0.70 (0.36, 1.36)

0.68 (0.11, 4.04)

1.40 (0.45, 4.35)

1.02 (0.67, 1.54)

100.00

4.80

2.87

2.301.00

0.55

26.29

2.57

(I-V)

2.55

1.07

4.30

4.08

0.62

10.92

3.27

1.09

Weight

1.861.70

6.99

0.95

2.40

17.82

%

1.1 1 10

8,867 patients, 21 trials8,867 patients, 21 trials

Favors BMS

Estimate (95% CI) Weight (%)

0.97 (0.81,1.15)0.97 (0.81,1.15), p=0.72

Random Effects*Fixed Effects (I2=0.0%)

Favors DES

Mean f/u 2.9 yrsAjay J. Kirtane and Gregg W. Stone, 2008

All-Cause Mortality: RCTs (On-Label)All-Cause Mortality: RCTs (On-Label)


Ortolani et al

TAXUS V - Simple

D+L Overall

TAXUS IV

Pache et al

C-SIRIUS

E-SIRIUS

SIRIUS

TAXUS II

Study ID

RAVEL

SCORPIUS

1.05 (0.84, 1.30)

2.00 (0.19, 21.38)

1.09 (0.53, 2.22)

1.05 (0.84, 1.30)

0.89 (0.63, 1.25)

1.40 (0.45, 4.35)

0.68 (0.11, 4.04)

1.08 (0.25, 2.24)

1.02 (0.67, 1.54)

1.61 (0.57, 4.53)

ES (95% CI)

1.75 (0.73, 4.16)

1.28 (0.35, 4.61)

100.00

0.85

9.20

40.20

3.67

%

1.45

3.93

27.25

4.39

(I-V)

6.23

2.84

Weight

1.1 1 10


Favors DES Favors BMS


1.05 (0.84,1.30)1.05 (0.84,1.30), p=0.69


Mean f/u 4.0 yrs

Ajay J. Kirtane and Gregg W. Stone, 2008

All-Cause Mortality: RCT’s (Off-Label)All-Cause Mortality: RCT’s (Off-Label)


HAAMU-STENT

Passion

PRISON IIMISSION!

DIABETES

BASKET (SES only)

Seville

D+L Overall

SES-SMARTSTRATEGY

TAXUS V - complex

Study ID

SESAMITyphoon

0.84 (0.62, 1.13)

2.00 (0.63, 6.38)

0.70 (0.36, 1.36)

0.50 (0.09, 2.67)0.48 (0.09, 2.59)

1.44 (0.48, 4.33)

0.82 (0.37, 1.84)

1.35 (0.23, 7.78)

0.84 (0.62, 1.13)

0.21 (0.02, 1.71)0.84 (0.36, 1.96)

0.84 (0.38, 1.84)

ES (95% CI)

0.43 (0.11, 1.63)1.01 (0.38, 2.65)

100.00

6.64

20.16

Weight

3.103.16

7.36

13.84

%

2.871.8012.40

14.32

(I-V)

4.909.44

1.1 1 10




0.84 (0.62,1.13)0.84 (0.62,1.13), p=0.24


Mean f/u 1.5 yrs


All-Cause Mortality: All RegistriesAll-Cause Mortality: All Registries

NOTE: Weights are from random effects analysis

D+L Overall (I-squared = 70.1%, p = 0.000)

Ontario (matched)Germany Metabolic Syndrome

GHOST (adjusted)

RESTEMARTS II (from RCT)

ACUITY (from RCT)

Western Denmark (adjusted)

STENT (adjusted)Massachusetts (matched)

Cedars Acute MI

I-V Overall

NHLBI (on label, adjusted)

Wake Forest (adjusted)

DEScover (unadjusted)

Multicenter SVG (adjusted)

MIDAS (adjusted)

Liverpool (matched)

ERACI III (from RCT)

SCAAR (adjusted)Asan Korea (adjusted)

Study ID

Melbourne

McMaster STEMI (adjusted)

REAL (adjusted)

Mayo FFR SubstudyItalian Diabetic Multivessel (adjusted)

Washington Hosp Center (matched)Rotterdam Off-Label

NHLBI (off label, adjusted)

NY State (adjusted, unmatched)

0.80 (0.72, 0.88)

0.71 (0.59, 0.84) 1.47 (0.65, 3.35)

0.55 (0.36, 0.83)

0.73 (0.51, 1.05) 0.74 (0.41, 1.35)

0.63 (0.49, 0.82)

1.00 (0.86, 1.17)

0.69 (0.55, 0.87) 0.79 (0.71, 0.89)

0.82 (0.37, 1.83)

0.83 (0.79, 0.86)

1.47 (0.87, 2.48)

0.72 (0.55, 0.95)

0.53 (0.35, 0.80)

1.33 (0.47, 3.76)

0.66 (0.59, 0.74)

0.45 (0.24, 0.84)

1.18 (0.54, 2.58)

1.03 (0.94, 1.14) 0.60 (0.46, 0.79)

ES (95% CI)

0.67 (0.23, 1.94)

0.17 (0.03, 0.97)

0.83 (0.70, 0.98)

1.00 (0.21, 4.75) 1.22 (0.36, 4.10)

1.16 (0.78, 1.75) 0.98 (0.85, 1.13)

0.94 (0.64, 1.38)

0.84 (0.72, 0.97)

100.00

5.981.15

3.09

3.631.92

Weight

4.87

6.29

5.256.80

1.20

2.31

4.66

3.13

0.76

6.80

1.78

%

1.25

6.984.70

(D+L)

0.73

0.29

6.10

0.360.57

3.216.44

3.40

6.35

1.1 1 10

161,232 patients, 28 registries161,232 patients, 28 registries

Favors BMS


0.80 (0.72,0.88), p<0.0010.83 (0.79,0.86)

Favors DES

*Random Effects (I2=70.1%)Fixed Effects


All-Cause Mortality: Unadjusted RegistriesAll-Cause Mortality: Unadjusted Registries



Study ID


Western Denmark (unadjusted)

STENT (unadjusted)

NY State (unadjusted, unmatched)

Asan Korea (unadjusted)

Melbourne

I-V Overall

Rotterdam Off-Label

ARTS II (from RCT)

Liverpool (unadjusted)

Massachusetts (unadjusted)

Mayo FFR Substudy

MIDAS (unadjusted)

Germany Metabolic Syndrome


McMaster STEMI (unadjusted)

ACUITY (from RCT)

NHLBI (on label, unadjusted)

REAL (unadjusted)

Wake Forest (unadjusted)

Cedars Acute MI

RESTEM

NHLBI (off label, unadjusted)

0.70 (0.63, 0.78)

ES (95% CI)

0.53 (0.35, 0.80)

0.81 (0.70, 0.94)

0.52 (0.43, 0.62)

0.79 (0.69, 0.92)

0.71 (0.58, 0.87)

0.67 (0.23, 1.94)

0.69 (0.66, 0.72)

0.98 (0.85, 1.13)

0.74 (0.41, 1.35)

0.49 (0.30, 0.80)

0.54 (0.49, 0.59)

1.00 (0.21, 4.75)

0.67 (0.60, 0.75)

1.47 (0.65, 3.35)

1.18 (0.54, 2.58)

0.27 (0.06, 1.24)

0.63 (0.49, 0.82)

1.04 (0.68, 1.58)

0.74 (0.66, 0.82)

0.71 (0.54, 0.92)

0.82 (0.37, 1.83)

0.73 (0.51, 1.05)

0.58 (0.42, 0.80)

100.00

(D+L)

3.79

7.46

6.93

7.51

6.63

0.90

7.53

2.35

Weight

3.08

8.16

0.45

7.94

1.43

1.54

0.47

5.78

3.70

7.98

5.65

1.49

4.37

%

4.86

1.1 1 10


Favors BMS


0.70 (0.63,0.78), p<0.0010.69 (0.66,0.72)

Favors DES


Mean f/u 2.1 yrs


All-Cause Mortality: Adjusted RegistriesAll-Cause Mortality: Adjusted Registries



MIDAS (adjusted)

Washington Hosp Center (matched)




I-V Overall

Study ID

Ontario (matched)

Asan Korea (adjusted)



STENT (adjusted)

REAL (adjusted)

Liverpool (matched)

GHOST (adjusted)



Massachusetts (matched)

Italian Diabetic Multivessel (adjusted)

SCAAR (adjusted)

0.80 (0.72, 0.90)

0.66 (0.59, 0.74)

1.16 (0.78, 1.75)

0.84 (0.72, 0.97)

0.94 (0.64, 1.38)

1.00 (0.86, 1.17)

0.82 (0.79, 0.86)

ES (95% CI)

0.71 (0.59, 0.84)

0.60 (0.46, 0.79)

0.72 (0.55, 0.95)

1.33 (0.47, 3.76)

0.69 (0.55, 0.87)

0.83 (0.70, 0.98)

0.45 (0.24, 0.84)

0.55 (0.36, 0.83)

0.17 (0.03, 0.97)

1.47 (0.87, 2.48)

0.79 (0.71, 0.89)

1.22 (0.36, 4.10)

1.03 (0.94, 1.14)

100.00

8.92

4.34

8.37

4.59

8.29

(D+L)

7.90

6.27

6.22

1.05

6.98

Weight

8.05

2.44

4.18

0.40

3.15

8.92

0.79

9.14

%

1.1 1 10


Favors BMS


0.80 (0.72,0.90), p<0.0010.82 (0.79,0.86)

Favors DES


Mean f/u 2.7 yrs


All-Cause Mortality: RegistriesAll-Cause Mortality: Registries

0 .5 1

-2

-1

0

1

2 p=0.92

log(

Haz

ard

Rat

io)

Standard Error of log(Hazard Ratio)

Begg’s Funnel PlotBegg’s Funnel Plot


MI: All RCTsMI: All RCTs8,850 patients, 20 trials8,850 patients, 20 trials

D+L Overall (I-squared = 3.0%, p = 0.420)I-V Overall

SCORPIUS

TAXUS II

PRISON II

TAXUS V

Passion

STRATEGY

MISSION!

Typhoon

SIRIUS

TAXUS IV

BASKET (All)

RAVEL

Ortolani et alDIABETES

HAAMU-STENT

Study ID

E-SIRIUS

SES-SMART

SCANDSTENT

SESAMI

C-SIRIUS

1.1 1 10


SESAMI

Passion

C-SIRIUS

RAVEL

TAXUS IVTAXUS V

SCORPIUS

SIRIUS

DIABETES

MISSION!

E-SIRIUS

SCANDSTENT

Study ID

Ortolani et al

SES-SMARTSTRATEGY

HAAMU-STENT

BASKET (All)

Typhoon

TAXUS II

PRISON II

D+L Overall0.94 (0.79, 1.13)

1.00 (0.20, 4.88)

0.83 (0.26, 2.69)

0.59 (0.14, 2.47)

1.24 (0.49, 3.14)

0.99 (0.66, 1.48)1.27 (0.79, 2.04)

0.82 (0.23, 2.95)

0.96 (0.59, 1.55)

0.60 (0.20, 1.50)

0.62 (0.28, 1.39)

1.94 (0.93, 4.02)

0.33 (0.09, 1.18)

ES (95% CI)

1.50 (0.26, 8.61)

0.16 (0.04, 0.67)0.82 (0.31, 2.40)

0.25 (0.03, 2.19)

1.15 (0.64, 2.08)

0.80 (0.22, 2.97)

0.63 (0.23, 1.72)

0.83 (0.26, 2.64)

0.94 (0.78, 1.13)100.00

1.29

2.40

1.59

3.80

20.13

Weight

14.59

2.02

14.07

3.23

5.11

6.13

%

1.98

(I-V)

1.07

1.653.13

0.71

9.45

1.94

3.24

2.44

1.1 1 10


0.94 (0.78,1.13)0.94 (0.79,1.13), p=0.54




Mean f/u 2.9 yrs

MI: RCTs (On Label)MI: RCTs (On Label)


RAVEL

Study ID

D+L Overall

SIRIUS

E-SIRIUS

TAXUS II

TAXUS IV

C-SIRIUS

TAXUS V - Simple

SCORPIUS

Ortolani et al

1.03 (0.81, 1.30)

1.24 (0.49, 3.14)

ES (95% CI)

1.03 (0.81, 1.30)

0.96 (0.59, 1.55)

1.94 (0.93, 4.02)

0.63 (0.23, 1.72)

0.99 (0.66, 1.48)

0.59 (0.14, 2.47)

0.98 (0.52, 1.81)

0.82 (0.23, 2.95)

1.50 (0.26, 8.61)

100.00

6.29

(I-V)

23.26

%

10.13

5.36

33.28

2.63

13.95

Weight

3.33

1.77

1.1 1 10




1.03 (0.81,1.30)1.03 (0.81,1.30), p=0.82



Mean f/u 4.4 yrs

MI: RCT’s (Off Label)MI: RCT’s (Off Label)4,532 patients, 12 trials4,532 patients, 12 trials

1.1 1 10


SCANDSTENT

HAAMU-STENT

Typhoon

D+L Overall

SES-SMART

PRISON II

TAXUS V - complex

Passion

Study ID

STRATEGY

MISSION!

SESAMI

BASKET (All)

DIABETES

0.83 (0.62, 1.10)

0.33 (0.09, 1.18)

0.25 (0.03, 2.19)

0.80 (0.22, 2.97)

0.77 (0.54, 1.10)

0.16 (0.04, 0.67)

0.83 (0.26, 2.64)

1.84 (0.86, 3.94)

0.83 (0.26, 2.69)

ES (95% CI)

0.82 (0.31, 2.40)

0.62 (0.28, 1.39)

1.00 (0.20, 4.88)

1.15 (0.64, 2.08)

0.60 (0.20, 1.50)

100.00

5.08

1.83

4.97

4.24

Weight

6.26

%

14.52

6.16

(I-V)

8.03

13.11

3.30

24.22

8.29

1.1 1 10



SCANDSTENT

HAAMU-STENT

Typhoon

D+L Overall

SES-SMART

PRISON II

TAXUS V - complex

Passion

Study ID

STRATEGY

MISSION!

SESAMI

BASKET (All)

DIABETES

0.83 (0.62, 1.10)

0.33 (0.09, 1.18)

0.25 (0.03, 2.19)

0.80 (0.22, 2.97)

0.77 (0.54, 1.10)

0.16 (0.04, 0.67)

0.83 (0.26, 2.64)

1.84 (0.86, 3.94)

0.83 (0.26, 2.69)

ES (95% CI)

0.82 (0.31, 2.40)

0.62 (0.28, 1.39)

1.00 (0.20, 4.88)

1.15 (0.64, 2.08)

0.60 (0.20, 1.50)

100.00

5.08

1.83

4.97

4.24

Weight

6.26

%

14.52

6.16

(I-V)

8.03

13.11

3.30

24.22

8.29

1.1 1 10


0.77 (0.54,1.10)0.83 (0.62,1.10), p=0.19



Mean f/u 1.5 yrs

MI: All RegistriesMI: All Registries



ACUITY (from RCT)Melbourne

ARTS II (from RCT)


Ontario (matched)

Study ID



STENT (adjusted)






GHOST (adjusted)

SCAAR (adjusted)

REAL (adjusted)

RESTEM


Brazil Large Vessels

Cedars Acute MI



I-V Overall

Mayo FFR Substudy


0.89 (0.80, 0.98)

1.07 (0.91, 1.25)1.00 (0.39, 2.58)

0.53 (0.32, 0.88)

0.66 (0.42, 1.05)

1.10 (0.91, 1.32)

ES (95% CI)

0.71 (0.47, 1.05)

0.51 (0.29, 0.88)

0.69 (0.52, 0.92)

2.30 (0.91, 5.96)

0.84 (0.60, 1.18)

0.23 (0.07, 0.78)

0.71 (0.50, 1.00)

1.29 (1.06, 1.57)

1.12 (0.74, 1.70)

1.01 (0.91, 1.11)

0.92 (0.76, 1.11)

0.80 (0.52, 1.23)

0.69 (0.40, 1.18)

1.50 (0.25, 8.90)

0.25 (0.06, 1.16)

0.92 (0.83, 1.02)

1.02 (0.46, 2.25)

0.96 (0.91, 1.01)

0.67 (0.12, 3.84)

0.28 (0.04, 1.71)

100.00

8.901.10

3.09

3.55

8.26

(D+L)

4.21

2.69

6.10

1.11

5.15

0.70

5.01

Weight%

8.02

4.03

10.17

8.18

3.86

2.80

0.33

0.48

10.10

1.50

0.35

0.30

0.89 (0.80, 0.98)

1.07 (0.91, 1.25)1.00 (0.39, 2.58)

0.53 (0.32, 0.88)

0.66 (0.42, 1.05)

1.10 (0.91, 1.32)

ES (95% CI)

0.71 (0.47, 1.05)

0.51 (0.29, 0.88)

0.69 (0.52, 0.92)

2.30 (0.91, 5.96)

0.84 (0.60, 1.18)

0.23 (0.07, 0.78)

0.71 (0.50, 1.00)

1.29 (1.06, 1.57)

1.12 (0.74, 1.70)

1.01 (0.91, 1.11)

0.92 (0.76, 1.11)

0.80 (0.52, 1.23)

0.69 (0.40, 1.18)

1.50 (0.25, 8.90)

0.25 (0.06, 1.16)

0.92 (0.83, 1.02)

1.02 (0.46, 2.25)

0.96 (0.91, 1.01)

0.67 (0.12, 3.84)

0.28 (0.04, 1.71)

100.00

8.901.10

3.09

3.55

8.26

(D+L)

4.21

2.69

6.10

1.11

5.15

0.70

5.01

Weight%

8.02

4.03

10.17

8.18

3.86

2.80

0.33

0.48

10.10

1.50

0.35

0.30

1.1 1 10




0.89 (0.80,0.98), p=0.023 0.96 (0.91,1.01)


*MI is QWMI in Washington Hospital Center, RESTEM

Ajay J. Kirtane and Gregg W. Stone, 2008Mean f/u 2.5 yrs

MI: Unadjusted RegistriesMI: Unadjusted Registries



NHLBI (off label, unadjusted)

RESTEM

I-V Overall


ARTS II (from RCT)

Western Denmark (unadjusted)

NHLBI (on label, unadjusted)

REAL (unadjusted)


Asan Korea (unadjusted)

Cedars Acute MI

Massachusetts (unadjusted)

Melbourne

ACUITY (from RCT)

Mayo FFR Substudy

Study ID



STENT (unadjusted)


0.83 (0.70, 0.97)

0.75 (0.55, 1.01)

0.80 (0.52, 1.23)

0.88 (0.83, 0.93)

0.29 (0.04, 1.86)

0.53 (0.32, 0.88)

1.19 (0.99, 1.43)

0.80 (0.56, 1.16)

1.15 (1.02, 1.30)

0.69 (0.40, 1.18)

0.78 (0.55, 1.11)

0.25 (0.06, 1.16)

0.75 (0.69, 0.82)

1.00 (0.39, 2.58)

1.07 (0.91, 1.25)

0.67 (0.12, 3.84)

ES (95% CI)

0.23 (0.07, 0.78)

1.50 (0.25, 8.90)

0.62 (0.49, 0.78)

2.30 (0.91, 5.96)

100.00

8.11

6.31

0.67

5.40

9.89

7.22

10.65

%

5.02

7.41

1.09

10.97

2.34

10.22

0.82

(D+L)

Weight

1.56

0.77

9.19

2.36

0.83 (0.70, 0.97)

0.75 (0.55, 1.01)

0.80 (0.52, 1.23)

0.88 (0.83, 0.93)

0.29 (0.04, 1.86)

0.53 (0.32, 0.88)

1.19 (0.99, 1.43)

0.80 (0.56, 1.16)

1.15 (1.02, 1.30)

0.69 (0.40, 1.18)

0.78 (0.55, 1.11)

0.25 (0.06, 1.16)

0.75 (0.69, 0.82)

1.00 (0.39, 2.58)

1.07 (0.91, 1.25)

0.67 (0.12, 3.84)

ES (95% CI)

0.23 (0.07, 0.78)

1.50 (0.25, 8.90)

0.62 (0.49, 0.78)

2.30 (0.91, 5.96)

100.00

8.11

6.31

0.67

5.40

9.89

7.22

10.65

%

5.02

7.41

1.09

10.97

2.34

10.22

0.82

(D+L)

Weight

1.56

0.77

9.19

2.36

1.1 1 10




0.83 (0.70,0.97), p=0.0230.88 (0.83,0.93)


*MI is QWMI in Washington Hospital Center, RESTEM


Mean f/u 2.0 yrs

MI: Adjusted RegistriesMI: Adjusted Registries





GHOST (adjusted)


Ontario (matched)


REAL (adjusted)

I-V Overall



STENT (adjusted)

Study ID




SCAAR (adjusted)

0.91 (0.81, 1.01)

0.51 (0.29, 0.88)

0.84 (0.60, 1.18)

1.12 (0.74, 1.70)

0.92 (0.83, 1.02)

1.10 (0.91, 1.32)

0.71 (0.50, 1.00)

0.92 (0.76, 1.11)

0.96 (0.91, 1.01)

0.66 (0.42, 1.05)

1.29 (1.06, 1.57)

0.69 (0.52, 0.92)

ES (95% CI)

0.28 (0.04, 1.71)

0.71 (0.47, 1.05)

1.02 (0.46, 2.25)

1.01 (0.91, 1.11)

100.00

3.16

6.37

4.87

13.94

10.94

6.18

10.81

4.25

10.56

7.70

(D+L)

0.34

Weight

%

5.11

1.72

14.06

1.1 1 10




0.91 (0.81,1.01), p=0.0830.96 (0.91,1.01)


*MI is QWMI in Washington Hospital Center


Mean f/u 2.8 yrs

TVR: All RCTsTVR: All RCTs



Pache et al

Study ID

HAAMU-STENT

C-SIRIUS

Typhoon

STRATEGY

SIRIUS

SCANDSTENT

TAXUS II

PRISON II

TAXUS IV

E-SIRIUS

MISSION!

Ortolani et al

SESAMI

I-V Overall

TAXUS V

RAVEL

0.45 (0.37, 0.54)

0.38 (0.23, 0.64)

ES (95% CI)

0.33 (0.09, 1.19)

0.30 (0.10, 0.93)

0.42 (0.25, 0.69)

0.34 (0.16, 0.77)

0.48 (0.37, 0.62)

0.17 (0.09, 0.33)

0.61 (0.35, 1.08)

0.37 (0.19, 0.69)

0.57 (0.45, 0.72)

0.35 (0.21, 0.56)

0.38 (0.17, 0.85)

0.58 (0.25, 1.36)

0.36 (0.17, 0.79)

0.51 (0.45, 0.57)

0.77 (0.60, 0.98)

0.51 (0.25, 1.04)

100.00

7.14

(D+L)

1.91

2.45

7.20

4.22

11.51

5.44

%

6.44

5.49

11.94

Weight

7.45

4.08

3.78

4.36

11.75

4.83

1.1 1 10




0.45 (0.37,0.54), p<0.0010.51 (0.45,0.57)



TVR: RCTsTVR: RCTsMeta-Regression on Percent Angiographic F/UMeta-Regression on Percent Angiographic F/U

*log(HR) regressed on percentage of pts with angiographic f/u; figure displayed on exponentiated scale


.2.4

.6.8

20 40 60 80 100perangfu

tvr_hr Fitted values

p=0.73

*Haz

ard

Rat

io

Percentage of Patients with Angiographic F/U

TVR: All RegistriesTVR: All Registries



DEScover (adjusted)



GHOST (adjusted)

Montevergine

STENT (adjusted)


I-V Overall



RESTEM

Ontario (matched)

Cedars Acute MI


REAL (adjusted)


Study ID

Mayo FFR Substudy


0.53 (0.47, 0.61)

0.58 (0.40, 0.83)

0.32 (0.05, 1.92)

0.63 (0.48, 0.83)

0.28 (0.20, 0.39)

0.51 (0.39, 0.68)

0.58 (0.47, 0.71)

0.65 (0.49, 0.85)

0.57 (0.54, 0.60)

0.32 (0.24, 0.43)

0.54 (0.50, 0.60)

0.62 (0.47, 0.80)

0.69 (0.60, 0.80)

0.22 (0.08, 0.62)

0.43 (0.17, 1.10)

0.67 (0.59, 0.76)

0.58 (0.28, 1.18)

ES (95% CI)

0.18 (0.04, 0.78)

0.58 (0.39, 0.86)

100.00

5.81

0.46

7.38

6.31

7.30

8.70

7.35

Weight

7.05

10.70

7.53

9.88

1.34

1.57

10.17

2.41

(D+L)

0.68

5.35

%

1.1 1 10




0.53 (0.47,0.61), p<0.001 0.57 (0.54,0.60)



TVR: Unadjusted RegistriesTVR: Unadjusted Registries



RESTEM

NY State (unadjusted, unmatched)

I-V Overall

Montevergine

Study ID



STENT (unadjusted)

Mayo FFR Substudy



Wake Forest (unadjusted)

REAL (unadjusted)

Cedars Acute MI

0.60 (0.48, 0.74)

0.62 (0.47, 0.80)

0.56 (0.51, 0.62)

0.73 (0.69, 0.77)

0.51 (0.39, 0.68)

ES (95% CI)

0.58 (0.39, 0.86)

0.63 (0.46, 0.87)

0.74 (0.63, 0.87)

0.18 (0.04, 0.78)

0.29 (0.04, 1.86)

0.43 (0.17, 1.10)

0.62 (0.48, 0.80)

0.99 (0.91, 1.08)

0.22 (0.08, 0.62)

100.00

Weight

10.93

12.76

10.77

(D+L)

%

9.11

10.20

12.21

1.82

1.16

3.80

11.08

12.84

3.32

1.1 1 10




0.60 (0.48,0.74), p<0.0010.73 (0.69,0.77)



TVR: Adjusted RegistriesTVR: Adjusted Registries63,456 patients, 11 registries63,456 patients, 11 registries




REAL (adjusted)

Study ID

I-V Overall



GHOST (adjusted)



Ontario (matched)

STENT (adjusted)

DEScover (adjusted)


0.54 (0.46, 0.63)

0.32 (0.05, 1.92)

0.67 (0.59, 0.76)

ES (95% CI)

0.58 (0.54, 0.61)

0.58 (0.28, 1.18)

0.65 (0.49, 0.85)

0.28 (0.20, 0.39)

0.32 (0.24, 0.43)

0.63 (0.48, 0.83)

0.69 (0.60, 0.80)

0.58 (0.47, 0.71)

0.58 (0.40, 0.83)

0.54 (0.50, 0.60)

100.00

0.66

13.05

(D+L)

3.39

9.74

8.46

9.38

9.78

12.72

11.34

7.83

Weight

13.65

%

1.1 1 10Favors DES Favors BMS


0.54 (0.46,0.63), p<0.0010.58 (0.54,0.61)


Mean f/u 2.2 yrs


Summary: DES vs. BMSSummary: DES vs. BMS Treatment Effect EstimatesTreatment Effect Estimates

MortalityMortality MIMI TVRTVR

RCTsRCTs 8,867 pts, 8,867 pts, 21 trials 21 trials

8,850 pts, 8,850 pts, 20 trials 20 trials

7,291 pts, 7,291 pts, 16 trials 16 trials

- Fixed effectsFixed effects- Random effectsRandom effects

0.970.970.970.97

0.940.940.940.94

0.510.510.45*0.45*

RegistriesRegistries 161,232 pts, 161,232 pts, 28 studies 28 studies

129,955 pts, 129,955 pts, 24 studies 24 studies

73,819 pts, 73,819 pts, 17 studies 17 studies

- Fixed effectsFixed effects- Random effectsRandom effects

0.830.830.80*0.80*

0.960.960.89*0.89*

0.570.570.53*0.53*

<1.0 <1.0 DES better DES better

Study LimitationsStudy Limitations• Randomized trial analyses are still underpowered

to assess these clinical endpoints• Registry analyses are based upon observational,

non-randomized analyses• Potential for residual confounding• Significant heterogeneity, despite attempts to

address this through random effects models, meta-regression and sensitivity analyses

• Analysis was primarily of summary-level data and included unpublished studies

• Use of hazard ratio / relative risk assumes constant hazards throughout the FU period

Conclusions (1)Conclusions (1)In 22 RCTs in which 9,470 pts were randomized to DES or BMS and followed for ≥1 yr, DES resulted in:

• Non significant 3% and 6% reductions in mortality and MI respectively• A highly significant 55% reduction in TVR

In 30 registries in which 174,302 pts were treated with either DES or BMS (non-randomized) and followed for ≥1 yr, DES was associated with:

• A highly significant 20% reduction in mortality• A significant 11% reduction in MI• A highly significant 47% reduction in TVR

Conclusions (2)Conclusions (2)The favorable results of DES from the RCT and registry analysis populations were robust and consistent for both on-label and off-label use, and for clinical f/u extending to 3-4 years

These findings, derived from more than 180,000 pts treated in 52 studies, strongly suggest that DES are safe for both on-label and off-label use, and have comparable efficacy in both RCTs and in the “real-world”

comprehensive meta-analysis of des vs. bms randomized trials and registries

Documents

label rcts

des outcomes

analysis of des

benefits of des

individual rcts

pivotal rcts

realworld des userct

registry comparisons