comprehensive meta-analysis of des vs. bms randomized trials and registries
DESCRIPTION
Comprehensive Meta-Analysis of DES vs. BMS Randomized Trials and Registries. Ajay J. Kirtane, M.D., S.M. Gregg W. Stone, M.D. Conflict of Interest Disclosure. Ajay J. Kirtane Past honorarium from Boston Scientific Corporation (modest) - PowerPoint PPT PresentationTRANSCRIPT
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)
I-V Overall (I-squared = 0.0%, p = 0.927)
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
4,818 patients, 10 trials4,818 patients, 10 trials
Favors DES Favors BMS
Estimate (95% CI) Weight (%)
1.05 (0.84,1.30)1.05 (0.84,1.30), p=0.69
Random Effects*Fixed Effects (I2=0.0%)
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)
I-V Overall (I-squared = 0.0%, p = 0.798)
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
4,049 patients, 12 trials4,049 patients, 12 trials
Favors DES Favors BMS
Estimate (95% CI) Weight (%)
0.84 (0.62,1.13)0.84 (0.62,1.13), p=0.24
Random Effects*Fixed Effects (I2=0.0%)
Mean f/u 1.5 yrs
Ajay J. Kirtane and Gregg W. Stone, 2008
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
Estimate (95% CI) Weight (%)
0.80 (0.72,0.88), p<0.0010.83 (0.79,0.86)
Favors DES
*Random Effects (I2=70.1%)Fixed Effects
Mean f/u 2.5 yrsAjay J. Kirtane and Gregg W. Stone, 2008
All-Cause Mortality: Unadjusted RegistriesAll-Cause Mortality: Unadjusted Registries
NOTE: Weights are from random effects analysis
D+L Overall (I-squared = 75.3%, p = 0.000)
Study ID
DEScover (unadjusted)
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
ERACI III (from RCT)
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
122,989 patients, 22 registries122,989 patients, 22 registries
Favors BMS
Estimate (95% CI) Weight (%)
0.70 (0.63,0.78), p<0.0010.69 (0.66,0.72)
Favors DES
*Random Effects (I2=75.3%)Fixed Effects
Mean f/u 2.1 yrs
Ajay J. Kirtane and Gregg W. Stone, 2008
All-Cause Mortality: Adjusted RegistriesAll-Cause Mortality: Adjusted Registries
NOTE: Weights are from random effects analysis
D+L Overall (I-squared = 76.6%, p = 0.000)
MIDAS (adjusted)
Washington Hosp Center (matched)
NY State (adjusted, unmatched)
NHLBI (off label, adjusted)
Western Denmark (adjusted)
I-V Overall
Study ID
Ontario (matched)
Asan Korea (adjusted)
Wake Forest (adjusted)
Multicenter SVG (adjusted)
STENT (adjusted)
REAL (adjusted)
Liverpool (matched)
GHOST (adjusted)
McMaster STEMI (adjusted)
NHLBI (on label, 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
134,534 patients, 18 registries134,534 patients, 18 registries
Favors BMS
Estimate (95% CI) Weight (%)
0.80 (0.72,0.90), p<0.0010.82 (0.79,0.86)
Favors DES
*Random Effects (I2=76.6%)Fixed Effects
Mean f/u 2.7 yrs
Ajay J. Kirtane and Gregg W. Stone, 2008
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
Ajay J. Kirtane and Gregg W. Stone, 2008
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
I-V Overall (I-squared = 3.0%, p = 0.420)
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
Estimate (95% CI) Weight (%)
0.94 (0.78,1.13)0.94 (0.79,1.13), p=0.54
Favors DES Favors BMS
Random Effects*Fixed Effects (I2=3.0%)
Ajay J. Kirtane and Gregg W. Stone, 2008
Mean f/u 2.9 yrs
MI: RCTs (On Label)MI: RCTs (On Label)
I-V Overall (I-squared = 0.0%, p = 0.761)
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
4,318 patients, 9 trials4,318 patients, 9 trials
Favors DES Favors BMS
Estimate (95% CI) Weight (%)
1.03 (0.81,1.30)1.03 (0.81,1.30), p=0.82
Random Effects*Fixed Effects (I2=0.0%)
Ajay J. Kirtane and Gregg W. Stone, 2008
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
I-V Overall (I-squared = 25.5%, p = 0.194)
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
Estimate (95% CI) Weight (%)
I-V Overall (I-squared = 25.5%, p = 0.194)
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
Favors DES Favors BMS
0.77 (0.54,1.10)0.83 (0.62,1.10), p=0.19
Random Effects*Fixed Effects (I2=25.5%)
Ajay J. Kirtane and Gregg W. Stone, 2008
Mean f/u 1.5 yrs
MI: All RegistriesMI: All Registries
NOTE: Weights are from random effects analysis
D+L Overall (I-squared = 57.9%, p = 0.000)
ACUITY (from RCT)Melbourne
ARTS II (from RCT)
Asan Korea (adjusted)
Ontario (matched)
Study ID
NHLBI (on label, adjusted)
Washington Hosp Center (matched)
STENT (adjusted)
ERACI III (from RCT)
Wake Forest (adjusted)
Germany Metabolic Syndrome
NHLBI (off label, adjusted)
Western Denmark (adjusted)
GHOST (adjusted)
SCAAR (adjusted)
REAL (adjusted)
RESTEM
DEScover (unadjusted)
Brazil Large Vessels
Cedars Acute MI
Massachusetts (matched)
Italian Diabetic Multivessel (adjusted)
I-V Overall
Mayo FFR Substudy
McMaster STEMI (adjusted)
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
129,955 patients, 24 registries129,955 patients, 24 registries
Favors DES Favors BMS
Estimate (95% CI) Weight (%)
0.89 (0.80,0.98), p=0.023 0.96 (0.91,1.01)
*Random Effects (I2=57.9%)Fixed Effects
*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
NOTE: Weights are from random effects analysis
D+L Overall (I-squared = 77.8%, p = 0.000)
NHLBI (off label, unadjusted)
RESTEM
I-V Overall
McMaster STEMI (unadjusted)
ARTS II (from RCT)
Western Denmark (unadjusted)
NHLBI (on label, unadjusted)
REAL (unadjusted)
DEScover (unadjusted)
Asan Korea (unadjusted)
Cedars Acute MI
Massachusetts (unadjusted)
Melbourne
ACUITY (from RCT)
Mayo FFR Substudy
Study ID
Germany Metabolic Syndrome
Brazil Large Vessels
STENT (unadjusted)
ERACI III (from RCT)
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
88,221 patients, 18 registries88,221 patients, 18 registries
Favors DES Favors BMS
Estimate (95% CI) Weight (%)
0.83 (0.70,0.97), p=0.0230.88 (0.83,0.93)
*Random Effects (I2=77.8%)Fixed Effects
*MI is QWMI in Washington Hospital Center, RESTEM
Ajay J. Kirtane and Gregg W. Stone, 2008
Mean f/u 2.0 yrs
MI: Adjusted RegistriesMI: Adjusted Registries
NOTE: Weights are from random effects analysis
D+L Overall (I-squared = 60.8%, p = 0.002)
Washington Hosp Center (matched)
Wake Forest (adjusted)
GHOST (adjusted)
Massachusetts (matched)
Ontario (matched)
NHLBI (off label, adjusted)
REAL (adjusted)
I-V Overall
Asan Korea (adjusted)
Western Denmark (adjusted)
STENT (adjusted)
Study ID
McMaster STEMI (adjusted)
NHLBI (on label, adjusted)
Italian Diabetic Multivessel (adjusted)
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
107,294 patients, 14 registries107,294 patients, 14 registries
Favors DES Favors BMS
Estimate (95% CI) Weight (%)
0.91 (0.81,1.01), p=0.0830.96 (0.91,1.01)
*Random Effects (I2=60.8%)Fixed Effects
*MI is QWMI in Washington Hospital Center
Ajay J. Kirtane and Gregg W. Stone, 2008
Mean f/u 2.8 yrs
TVR: All RCTsTVR: All RCTs
NOTE: Weights are from random effects analysis
D+L Overall (I-squared = 53.2%, p = 0.006)
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
7,291 patients, 16 trials7,291 patients, 16 trials
Favors DES Favors BMS
Estimate (95% CI) Weight (%)
0.45 (0.37,0.54), p<0.0010.51 (0.45,0.57)
*Random Effects (I2=53.2%)Fixed Effects
Mean f/u 3.2 yrsAjay J. Kirtane and Gregg W. Stone, 2008
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
Ajay J. Kirtane and Gregg W. Stone, 2008
.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
NOTE: Weights are from random effects analysis
D+L Overall (I-squared = 71.2%, p = 0.000)
DEScover (adjusted)
McMaster STEMI (adjusted)
Wake Forest (adjusted)
GHOST (adjusted)
Montevergine
STENT (adjusted)
Washington Hosp Center (matched)
I-V Overall
Asan Korea (adjusted)
NY State (adjusted, unmatched)
RESTEM
Ontario (matched)
Cedars Acute MI
Brazil Large Vessels
REAL (adjusted)
Multicenter SVG (adjusted)
Study ID
Mayo FFR Substudy
ERACI III (from RCT)
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
73,819 patients, 17 registries73,819 patients, 17 registries
Favors DES Favors BMS
Estimate (95% CI) Weight (%)
0.53 (0.47,0.61), p<0.001 0.57 (0.54,0.60)
*Random Effects (I2=71.2%)Fixed Effects
Mean f/u 2.2 yrsAjay J. Kirtane and Gregg W. Stone, 2008
TVR: Unadjusted RegistriesTVR: Unadjusted Registries
NOTE: Weights are from random effects analysis
D+L Overall (I-squared = 88.9%, p = 0.000)
RESTEM
NY State (unadjusted, unmatched)
I-V Overall
Montevergine
Study ID
ERACI III (from RCT)
DEScover (unadjusted)
STENT (unadjusted)
Mayo FFR Substudy
McMaster STEMI (unadjusted)
Brazil Large Vessels
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
55,531 patients, 12 registries55,531 patients, 12 registries
Favors DES Favors BMS
Estimate (95% CI) Weight (%)
0.60 (0.48,0.74), p<0.0010.73 (0.69,0.77)
*Random Effects (I2=88.9%)Fixed Effects
Mean f/u 2.2 yrsAjay J. Kirtane and Gregg W. Stone, 2008
TVR: Adjusted RegistriesTVR: Adjusted Registries63,456 patients, 11 registries63,456 patients, 11 registries
NOTE: Weights are from random effects analysis
D+L Overall (I-squared = 79.4%, p = 0.000)
McMaster STEMI (adjusted)
REAL (adjusted)
Study ID
I-V Overall
Multicenter SVG (adjusted)
Washington Hosp Center (matched)
GHOST (adjusted)
Asan Korea (adjusted)
Wake Forest (adjusted)
Ontario (matched)
STENT (adjusted)
DEScover (adjusted)
NY State (adjusted, unmatched)
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
Estimate (95% CI) Weight (%)
0.54 (0.46,0.63), p<0.0010.58 (0.54,0.61)
*Random Effects (I2=79.4%)Fixed Effects
Mean f/u 2.2 yrs
Ajay J. Kirtane and Gregg W. Stone, 2008
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”