Stettler Windecker Meta Analysis 18k 10 20 07 V04
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Stettler Windecker Meta Analysis 18k 10 20 07 V04 Stettler Windecker Meta Analysis 18k 10 20 07 V04 Presentation Transcript

  • A Pooled Analysis of 38 Trials Comparing Drug-Eluting Stents and Bare-Metal Stents Funding and Validation of Statistical Models The Swiss National Science Foundation Stettler C., et al., Lancet 2007;370:937-48. Outcomes Associated with Drug-Eluting and Bare-Metal Stents: A Collaborative Network Meta-Analysis
  • Introduction
    • The long-term safety of drug-eluting stents (DES) has been questioned by recent studies reporting  rates of death, myocardial infarction (MI), or late stent thrombosis (ST) compared with bare-metal stents (BMS)
      • Daemen J, et al., Lancet 2007; 369(9562):667-78.
      • Pfisterer M, et al., J Am Coll Cardiol 2006; 48(12):2584-91.
      • Nordmann AJ, et al.,. Eur Heart J 2006; 27(23):2784-814.
      • Camenzind E, et al., Circulation 2007; 115(11):1440-55.
      • Katritsis DG, Am J Cardiol 2005;95(5):640-3.
    • However, these studies were hampered by low numbers of patients limited duration of follow-up, or observational studies
    • A subsequent series of pooled analyses of randomized trials comparing DES with BMS in a single issue of NEJM in February 2007 found no evidence for  death or MI rates with DES and inconsistent evidence for  risk of LST with DES
    Stettler C., et al., Lancet 2007;370:937-48.
  • Rationale for Network Analysis
    • Novel analytical techniques called network meta-analysis 1,2 or mixed treatment comparison 3,4,5 allow a unified, coherent analysis of the entire set of all randomized controlled trials comparing either of the two DES with BMS, or performed a head-to-head comparison of SES and PES, while fully respecting randomization
    • 1 Lumley T. Stat Med 2002; 21 (16) : 2313-24. 2 Psaty BM, et al., JAMA 2003; 289 (19) : 2534-44. 3 Lu G, Ades AE. Stat Med 2004; 23 (20) : 3105-24. 4 Caldwell DM, et al., BMJ 2005; 331 (7521) : 897-900. 5 and Cooper NJ, et al., Arch Intern Med 2006; 166 (12) : 1269-75.
    • The authors established a collaborative group of investigators, who provided trial data based on standardized definitions of outcomes, and conducted a network meta-analysis
    Stettler C., et al., Lancet 2007;370:937-48.
  • Objectives
    • Analysis of all 38 randomized controlled trials, including 18,023 patients, was conducted by the Swiss National Science Foundation in an effort to increase the precision of estimates for effectiveness and safety of DES compared to BMS
    • A subgroup analysis of mortality in 3,870 diabetic patients was conducted to address recent concerns about SES in this population
    Stettler C., et al., Lancet 2007;370:937-48.
  • Methods
    • Literature searches were performed in MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials for relevant studies in any language from inception to March 2007
    • Websites dedicated to dissemination of results from cardiovascular trials ( www.acc.org , www.tctmd.com , www.theheart.org , www.clinicaltrialresults.org ) were also searched
    • Other sources included conference abstracts, relevant book chapters, proceedings of relevant FDA advisory panels
    • 2 investigators independently assessed reports for eligibility
    Stettler C., et al., Lancet 2007;370:937-48.
  • Study Eligibility Criteria
    • Randomized controlled trials (RCT)
    • Patients with signs of myocardial ischemia due to coronary artery disease
    • Comparison of SES and PES
    • Comparison of either DES with BMS
    • Clinical follow-up duration of at least 6 months
    Stettler C., et al., Lancet 2007;370:937-48.
  • Identification of Eligible Randomized Trials 870 potentially eligible reports identified and screened for retrieval 786 reports excluded: 424 with different interventions 254 reviews or pooled analyses 98 observational studies 10 case reports 84 reports retrieved for detailed evaluation (41 trials) 6 reports excluded (3 trials): 2 (1 trial) with different interventions 4 (2 trials) subgroup analyses 78 reports included (38 trials with 40 comparisons): 7 PES vs. BMS 16 SES vs. BMS 14 PES vs. SES 1 PES vs. SES vs. BMS Stettler C., et al., Lancet 2007;370:937-48.
  • 16 SES vs. BMS Trials Included * Cardiac death ** Vessel-related death SES vs. BMS Study N Primary Endpoint Lesion Length (mm) RVD (mm) # of Sites Stettler C., et al., Lancet 2007;370:937-48. 1 NA  28 Late Lumen Loss 104 Ortolani et al. 1 NA NA Late Lumen Loss 308 MISSION 1 2.5-4.0  66 Late Lumen Loss 75 RRISC 16 2.5-3.5  42 Late Lumen Loss 200 SCORPIUS NA NA NA Late Lumen Loss 83 DECODE 1 NR NR Binary Restenosis 320 SESAMI 48 2.25-3.5  30 VRD**, AMI, TVR 715 TYPHOON 4 2.25-4.5  15* Min Lumen Diam 322 SCANDSTENT 2 NR NR Binary Restonsis 200 PRISON II 2 NR NR Binary Restenosis 500 Pache et al 4 < 4.0 NR Late Lumen Loss 160 DIABETES 20 < 2.75  33 Binary Restenosis 257 SES-SMART 8 2.5-3.0 15-32 Min Lumen Diam 100 C-SIRIUS 35 2.5-3.0 15-32 Min Lumen Diam 352 E-SIRIUS 53 2.5-3.5 15-30 CD*, AMI, TVR 1,058 SIRIUS 19 2.5-3.5  18 Late Lumen Loss 238 RAVEL
  • 7 PES vs. BMS Trials Included PES vs. BMS Study N Primary Endpoint Lesion Length (mm) RVD (mm) # of Sites Stettler C., et al., Lancet 2007;370:937-48. 1 NA NA NA 164 HAAMU-STENT 2 > 2.5 NR Cardiac Death, AMI, TLR 619 PASSION 44 2.5-3.75 18-40 TVR 446 TAXUS VI 66 2.25-4.0 10-46 TVR 1172 TAXUS V 73 2.5-3.75 10-28 TVR 1314 TAXUS IV 38 3.0-3.5  12 Neointimal Proliferation 536 TAXUS II 3 3.0-3.5  12 Death, AMI, TVR, ST 61 TAXUS I
  • 15 SES vs. PES Trials Included SES vs. PES Study N Primary Endpoint Lesion Length (mm) RVD (mm) # of Sites SES vs. PES vs. BMS Study N Primary Endpoint Lesion Length (mm) RVD (mm) # of Sites Stettler C., et al., Lancet 2007;370:937-48. NA NA NA NA 416 Han et al. 1 2.5-3.7  16 NIH 100 Petronio et al. 1 < 2.5 > 20 NIH 70 Cervinka et al. 5 NA NA Cardiac Death, AMI, TLR, TVR, TVF 2098 SORT OUT II NA NA NA Late Lumen Loss 231 PROSIT 5  2.5  25 Binary Restenosis 500 LONG DES II 1 2.5-3.5 NA Death, AMI, TVR 449 Zhang et al 2 < 2.8 NR Late Lumen Loss 360 ISAR-SMART-3 90 2.25-3.0 > 15 Binary Restenosis 1353 REALITY 2 < 2.5 < 20 Binary Restenosis 652 CORPAL 2 2.25-4.0 NR MACE 1012 SIRTAX 2 NR NR Late lumen Loss 250 ISAR-DIABETES 2 NR NR Binary Restenosis 200 ISAR-DESIRE 1 NR NR Death, AMI, TLR, ST 202 TAXi 1  4 NR Cardiac Death, MI, TVR 826 BASKET
  • Key Baseline Predictors of Restenosis in Complex DES vs. BMS Trials* Study Les. Length (mm) RVD (mm) DM (%) * Excludes RCTs enrolling simple/moderate patients/lesions: RAVEL, SIRIUS trials, Pache, and Ortolani, TAXUS II, and TAXUS IV ** Occlusion length † SCANDSTENT enrolled patients with occluded, bifurcational, ostial, or angulated lesions; TAXUS V focused enrollment to include patients with longer lesions and patients requiring either 2.25 or 4.0 mm stents. TAXUS VI focused on enrolling patients with longer lesions. Type Stent Length (mm) n Pt / Vessel Type Citations: 1. JAMA 2004;292:2727-34 2. Circulation 2006;114:921-28 3. JACC 2006;48:2423-31 4. Am J Cardiol 2005;96(7A):31H 5. Annual Transcatheter Cardiovascular Therapeutics meeting Oct 22-27, 2006 Abstract 288 6. Circulation 2005;112:2175-83 7. JACC 2006;47:449-55 8. JAMA 2005;294:1215-23 9. Circulation 2005;112:3306-13 10. NEJM 2006;355:1093-104 11. JACC 2007;49:1924-30 12. Annual AHA meeting Nov 12-15, 2006 13. NEJM 2006;355: 1105-13 14. Annual Transcatheter Cardiovascular Therapeutics meeting Oct 22-27, 2006 Abstract 178 HAAMU-STENT 14 PASSION 13 MISSION 12 SESAMI 11 TYPHOON 10 TAXUS VI 9 TAXUS V 8 SCANDSTENT 7 DIABETES 6 SCORPIUS 5 DECODE 4 RRISC 3 PRISON II 2 SES-SMART 1 AMI High-Risk † DM SVG CTO RVD  2.75 2.86 ± 0.53 26 18.8 ± 13.0 18 322 SES 2.33 ± 0.6 NA 14.6 ± 8 100 160 SES 2.78 ± 0.50 22.1 ± 8.6 NA 16 715 SES 2.81 ± 0.48 33.7 ± 10.79 20.94 ± 7.21 20 446 PES 19.0 ± 5.6 26.5 ± 12.8 16.9 ± 4.1 28.7 ± 13.2 19.6 ± 9.0 20.9 ± 8.45 23.4 ± 7.0 31.9 ± 15.3 16.99 ± 5.71 Not reported 15 164 PES 3.13 ± 0.43 NA 11 619 PES 2.75 ± 0.54 NA NA 308 SES 21 32 100 100 15 13 25 NA NA 320 SES 2.68 ± 0.58 17.3 ± 9.0 1172 PES 2.54 ± 0.45 11.2 ± 4.6 200 SES 2.51 ± 0.35 15.06 ± 6.34 83 SES 2.38 ± 0.57 NA 75 SES 2.53 ± 0.67 16.0 ± 9.3** 200 SES 2.22 ± 0.29 13.01 ± 6.53 257 SES
  • Pre-Specified Endpoints
    • Overall mortality
    • Cardiac death, defined as any death due to cardiac cause, procedure-related deaths and those related to concomitant treatment and death of unknown cause
    • MI, including fatal and non-fatal non-Q-wave or Q-wave MI
    • Composite of death or MI
    • Definite stent thrombosis (confirmed by angiography or post-mortem examination) in accordance with the Academic Research Consortium (ARC)
      • Early (0 to 30 days) and Late Events (> 30 days) were also evaluated separately
    • Target Lesion Revascularization
      • TVR was used as a proxy for 3 studies (BASKET, HAAMU-STENT, and Zhang, et al.,)
    Stettler C., et al., Lancet 2007;370:937-48.
  • Additional Analyses Related to Stent Thrombosis (ST)
    • Post hoc analyses:
      • ST occurring > 30 days to 1 year
      • ST occurring > 1 year to 4 years
      • Analyses using per protocol definitions of RCTs
    • Sensitivity analyses:
      • Restricted the network to trials with adequate concealment of allocation, blind adjudication of clinical outcomes, and intention-to-treat analysis and high quality trials satisfying all 3 criteria
      • Since strut thickness or stent platform may influence clinical outcomes, the authors performed sensitivity analyses adjusted for strut thickness and adjusted for type of stent platform
    • Pooled estimates were derived from standard random-effects meta-analyses of direct within-trial comparisons
    Stettler C., et al., Lancet 2007;370:937-48.
  • Outcomes Testing for Interaction with Presence of Diabetes
    • In addition to the primary network meta-analyses in all patients, the authors stratified analyses of mortality and the composite of death or MI according to the presence or absence of diabetes and performed a test for interaction between estimated hazard ratios and diabetes
    Stettler C., et al., Lancet 2007;370:937-48.
  • Statistical Analysis Used by Swiss National Science Foundation
    • The study employed an extension of multivariable Bayesian hierarchical random effects models for mixed treatment comparisons using Markov chain Monte Carlo simulation methods with vague priors
    • If performed appropriately, such an analysis will avoid confounding bias and increase the precision of the estimates of effectiveness and safety
    Stettler C., et al., Lancet 2007;370:937-48.
  • Cumulative Incidence of TLR
      • TVR was used as a proxy for 3 studies
    Stettler C., et al., Lancet 2007;370:937-48.
  • Cumulative Incidence of All Death Stettler C., et al., Lancet 2007;370:937-48.
  • Cumulative Incidence of Cardiac Death Stettler C., et al., Lancet 2007;370:937-48.
  • Cumulative Incidence of Myocardial Infarction Stettler C., et al., Lancet 2007;370:937-48.
  • Cumulative Incidence of Death or Myocardial Infarction Stettler C., et al., Lancet 2007;370:937-48.
  • Cumulative Incidence of ARC Definite Stent Thrombosis Stettler C., et al., Lancet 2007;370:937-48.
  • Definite ARC Stent Thrombosis PES vs. BMS HR 95% CI p SES vs. BMS HR 95% CI p SES vs. PES HR 95% CI p Stettler C., et al., Lancet 2007;370:937-48. 1.43 1.14 1.14 1.02 1.00 0.10 0.43 0.04 0.90 0.21 (0.09-1.32) (0.26-1.64) (0.26-0.98) (0.46-3.17) (0.48-1.13) 0.39 0.68 0.54 1.05 0.71 0.64 0.78 0.71 0.96 1.00 (0.27-6.24) (0.45-2.88) (0.62-2.26) (0.46-2.67) (0.68-1.63) 0.07 0.23 0.02 0.90 0.14 (0.86-16.85) (0.65-4.04) (1.19-4.23) (0.38-2.53) (0.96-2.24) 3.57 1.61 2.11 0.95 1.38 >1 - 4 Years BMS PES SES n = 8 n = 26 n = 14 >30 Days – 1 Year BMS PES SES n = 14 n = 16 n = 16 >30 Days – 4 Years BMS PES SES n = 22 n = 42 n = 30 0 – 30 Days BMS PES SES n = 28 n = 30 n = 36 0 Days- 4 Years BMS PES SES n = 50 n = 72 n = 66
  • Protocol Stent Thrombosis PES vs. BMS HR 95% CI p SES vs. BMS HR 95% CI p SES vs. PES HR 95% CI p Stettler C., et al., Lancet 2007;370:937-48. 5.82 0.92 1.13 0.86 1.03 0.046 0.32 0.01 0.63 0.08 (0.05-0.98) (0.32-1.35) (0.25-0.79) (0.42-1.89) (0.41-1.06) 0.30 0.74 0.45 0.84 0.65 0.07 0.80 0.57 0.59 0.92 (0.88-76.89) (0.37-1.69) (0.66-2.81) (0.47-1.70) (0.59-1.67) 0.001 0.62 0.01 0.98 0.13 (3.92-221.7) (0.66-3.07) (1.23-7.00) (0.48-2.07) (0.84-2.58) 20.0 1.32 2.36 1.01 1.56 >1 - 4 Years BMS PES SES n = 2 n = 27 n = 12 >30 Days – 1 Year BMS PES SES n = 20 n = 20 n = 23 >30 Days – 4 Years BMS PES SES n = 22 n = 47 n = 35 0 – 30 Days BMS PES SES n = 35 n = 35 n = 38 0 Days- 4 Years BMS PES SES n = 57 n = 96 n = 85
  • Cumulative Incidence of Death Overall: DM vs. Non-DM Diabetics Non-Diabetics Stettler C., et al., Lancet 2007;370:937-48.
  • Cumulative Incidence of Overall Death or MI: DM vs. Non-DM Diabetics Non-Diabetics Stettler C., et al., Lancet 2007;370:937-48.
  • BMS Strut-Thickness * ISAR-STEREO: RCT enrolling 628 patients with CAD in > 2.8 mm native vessels comparing thin (50  m ACS RX Multi-Link) vs. thick (140  m; Bx Velocity) strut stents: - Angiographic Restenosis at 6 months: 15.0% vs. 25.8%; P=0.003 - Clinical restenosis at 1 year: 8.6% vs. 13.8%; P=0.03 Kastrati A., et al., Circulation 2001;103;2816-2821 This concept is still a debated issue since several analyses of BMS studies have found that strut thickness is not a predictor of TLR: www.TCTMD.com Cutlip D., Strut Thickness: Strut Thickness Has a Minor Impact on Restenosis-Most Bare Metal Stents Are More Alike Than Different!; Monday, December 08, 2003).
  • Analyses Adjusted for Type of Stent Platform
    • “Thirty-seven trials (17,859 patients) contributed to the analyses adjusted for type of stent platform and adjusted for strut thickness.”
    • “Results were generally robust to the different analytical approaches used in the sensitivity analyses.”
    • “When adjusting for the type of stent platform, however, differences in ST between PES and the other two stent types tended to become more pronounced.”
    Stettler C., et al., Lancet 2007;370:937-48.
  • Influence of Strut Thickness: Death or MI Stettler C., et al., Lancet 2007;370:937-48. SES vs. PES (Adjusted for strut thickness): 0.85 (0.78-0.99)
  • Influence of Strut Thickness: TLR
      • TVR was used as a proxy for 3 studies
    Stettler C., et al., Lancet 2007;370:937-48. SES vs. PES (Adjusted for strut thickness): 0.64 (0.52-0.78)
  • Summary of Key Network Analysis Findings Stettler C., et al., Lancet 2007;370:937-48. 0.70 (0.56-0.84) p = 0.0021 0.30 (0.24-0.37) p < 0.0001 0.42 (0.33-0.53) p<0.0001 TLR Protocol-Defined ST ARC-Definite ST 0.65 (0.41-1.06) p = 0.08 1.03 (0.59-1.67) p = 0.92 1.56 (0.84-2.58) p = 0.13 Overall (0 days-4yrs) 0.71 (0.48-1.13) p = 0.21 1.00 (0.68-1.63) p = 1.00 1.38 (0.96-2.24) p = 0.14 Overall (0 days-4yrs) 0.30 (0.05-0.98) p = 0.046 5.82 (0.88-76.89) p = 0.07 20.02 (3.92-221.7) p = 0.001 Very Late (>1yr-4yrs) 0.74 (0.32-1.35) p = 0.32 0.92 (0.37-1.69) p = 0.80 1.32 (0.66-3.07) p = 0.62 Late (>30 days-1yr) 0.68 (0.26-1.64) p = 0.43 1.14 (0.45-2.88) p = 0.78 1.61 (0.65-4.04) p = 0.23 Late (>30 days-1yr) 0.39 (0.09-1.32) p = 0.10 1.43 (0.27-6.24) p = 0.64 3.57 (0.86-16.85) p = 0.071 Very Late (>1yr-4yrs) 0.83 (0.71-1.00) p = 0.045 0.81 (0.66-0.97) p = 0.030 1.00 (0.81-1.23) p = 0.99 MI 0.96 (0.83-1.24) p = 0.80 1.00 (0.82-1.25) p = 0.89 1.03 (0.84-1.22) p = 0.75 Death SES vs. PES HR (95% CI) SES vs. BMS HR (95% CI) PES vs. BMS HR (95% CI)
  • Statistical Heterogeneity
    • Estimates of statistical heterogeneity between trials were low and criteria for an adequate fit of the model were all satisfied for all outcomes, except TLR
    • In conventional meta-analyses, all estimates of statistical heterogeneity between trials were low, except for comparisons of SES versus BMS and PES versus BMS on TLR
    Stettler C., et al., Lancet 2007;370:937-48.
  • Consistency of the Network
    • Criteria for consistency were satisfied for all outcomes, except ST and TLR:
      • Stent Thrombosis:
        • The goodness of fit of the model was excellent and estimates of between-trial heterogeneity were low.
        • A p-value for inconsistency of 0.69 suggested that the observed inconsistency may have been due to chance alone.
      • Target Lesion Revascularization:
        • Goodness of fit of the model was not optimal and there was some evidence for heterogeneity between trials and inconsistency of the network.
        • The magnitude of effects, the fully concordant results of conventional random-effects meta-analyses of direct within-trial comparisons and the lack of heterogeneity between trials for the comparison of SES versus PES in network and conventional meta-analysis on this outcome indicate, however, that observed differences in TLR between stent types are real.
        • Results were also robust in sensitivity analyses restricted to trials of high methodological quality and after adjusting for the strut thickness or the type of stent platform used
    • The authors stated that the estimates are reliable also for ST and TLR.
    Stettler C., et al., Lancet 2007;370:937-48.
  • Consistency of Efficacy Findings Stettler C., et al., Lancet 2007;370:937-48.
      • Patient-level Direct Comparison HR 0.72
      • Network Analysis HR 0.70
    Kastrati A., et al., J Am Coll Cardiol 2007; 50: e-publication (August 21, 2007). SES PES SES PES
  • Consistency of Safety Findings: Death or MI Stettler C., et al., Lancet 2007;370:937-48. Death or MI Through Latest Follow-up 0.86 (95 CI: 0.72-1.01) P = 0.07
      • Direct Comparison HR 0.86
      • Network Analysis HR 0.92
    Kastrati A., et al., J Am Coll Cardiol 2007; 50: e-publication (August 21, 2007). 0.5 1.0 1.5 Favors SES Favors PES
  • Conclusions from Publication (Efficacy)
    • “A secondary analysis showed a marked reduction in TLR with both DES, which was more pronounced for SES than for PES.”
    • “About six patients will have to receive a SES rather than a BMS to prevent one TLR over 4 years; 35 would need to receive a SES rather than a PES to prevent one such event.”
    Stettler C., et al., Lancet 2007;370:937-48.
  • Summary from Publication
    • “This collaborative network meta-analysis of randomized controlled trials indicates that overall and cardiac mortality associated with DES and BMS are similar. Relevant harms associated with SES compared with BMS are unlikely, while rates of TLR and MI are lower with SES than with PES and BMS. We conclude, therefore, that SES seem to be clinically better than BMS and PES.”
    Stettler C., et al., Lancet 2007;370:937-48.
  • Conclusions from Publication (Safety)
    • “ Our collaborative network meta-analysis indicates that drug-eluting stents and bare-metal stents are associated with similar rates of overall and cardiac mortality, and that the use of sirolimus-eluting stents is associated with a reduction in the risk of myocardial infarction compared with the use of bare-metal and paclitaxel-eluting stents.”
    • “ About 100 patients will have to receive SES, rather than BMS or PES, to prevent one MI over 4 years .”
    • “ Although there was little evidence of an overall increase in definite stent thrombosis associated with DES, we found PES to be associated with an increased incidence of late stent thrombosis (>30 days-4 years) compared with BMS and SES.”
      • “ Wide credibility intervals precluded definite conclusions about a potential increase of late stent thrombosis with SES compared with BMS.”
    • “ Lastly, we found little evidence of an increased risk of mortality associated with either DES in diabetic patients, but wide credibility intervals precluded definite conclusions.”
    Stettler C., et al., Lancet 2007;370:937-48.