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Comprehensive Meta-Analysis of DES vs. BMS Randomized Trials and Registries

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)

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Comprehensive Meta-Analysis of DES vs. BMS Randomized Trials and Registries

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  1. Comprehensive Meta-Analysis of DES vs. BMS Randomized Trials and Registries Ajay J. Kirtane, M.D., S.M. Gregg W. Stone, M.D.

  2. Conflict of Interest Disclosure • Ajay J. Kirtane • Past honorarium from Boston Scientific Corporation (modest) • Consultant/Speaker: Medtronic Vascular, Abbott Vascular (modest) • Gregg W. Stone • Research grants from Boston Scientific and Abbott Vascular

  3. 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

  4. 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

  5. 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 al N Engl J Med 2007; 356(10).

  6. 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

  7. 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 Analyses • To 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

  8. Methods: Inclusion Criteria • English language RCTs or registries which reported a direct comparison of DES (commercialized formulations of SES and PES only) vs. BMS. • Criteria for each study: • ≥100 patients total • Mortality reported (± MI and/or TVR) • ≥1 year of cumulative follow-up reported, with the outcome assessed at the same time point in both comparator arms

  9. Methods: Exclusion Criteria • “DES era” vs. pure “BMS era” studies in which the DES era group did not exclude BMS pts • Excepting intent-to-treat RCTs • Study used a control group from another study already in the meta-analysis • Study was itself a meta-analysis (although data abstracted from individual studies in a published meta-analysis could be used)

  10. Methods: Search Strategy (1) • 2 PUBMED searches • Focused: (eluting stent OR DES OR drug-eluting stent) AND (bare OR uncoated OR standard OR BMS) AND (("2002"[PDat] : "2008"[PDat]) AND (Humans[Mesh]) AND (English[lang])) AND (coronary) NOT (cost-effectiveness) NOT review[pt] NOT case reports[pt] NOT editorial[pt] NOT comment[pt] • Broad: stent AND bare AND (eluting OR sirolimus OR paclitaxel) • Cochrane database • Eurointervention journal

  11. Methods: Search Strategy (2) • Abstracts/presentations from 2007 meetings: • ACC SCAI/I2 Summit • ESC • TCT • AHA • Data requested from study PI’s for large registries • For most updated data • Where not publicly available or to clarify methodology

  12. Methods: Analysis • Pre-specified separate analysis of RCTs and Registries performed given clinical heterogeneity • RCTs: Direct randomization to DES vs. BMS • Registries: Non-rand comparison of DES vs. BMS (including non-rand comparisons within a RCT) • All analyses cumulative • No landmarks • Single time point estimate for each study assuming constant hazard of DES vs. BMS through study period (hence use of HR or RR as the estimate) • Higher quality estimate picked for primary analyses (adjusted > unadjusted)

  13. Methods: Statistical Analysis • All analyses were performed at The Cardiovascular Research Foundation/Columbia University • Models (both reported): • Fixed effects (Inverse-Variance weighted) • Random effects (DerSimonian and Laird)* • Fixed effects model was considered the primary model if significant heterogeneity was not present; otherwise random effects was considered primary • Formal heterogeneity testing was performed using the I2 statistic; heterogeneity was defined as I2 ≥ 25% *Weights displayed in figures are based upon the primary model used

  14. GRACE Non-landmark data not available (PI contacted as well) Unequal follow-up in comparator arms (data not presented at fixed timepoint) RRISC Less than 100 patients Medicare Data Comparison of pre-DES era with post-DES rather than DES vs. BMS Selected Excluded Studies

  15. All-Cause Mortality: All RCTs 8,867 patients, 21 trials Weight (%) Estimate (95% CI) Random Effects *Fixed Effects (I2=0.0%) 0.97 (0.81,1.15) 0.97 (0.81,1.15), p=0.72 Favors DES Favors BMS Mean f/u 2.9 yrs Ajay J. Kirtane and Gregg W. Stone, 2008

  16. All-Cause Mortality: RCTs (On-Label) 4,818 patients, 10 trials Weight (%) Estimate (95% CI) Random Effects *Fixed Effects (I2=0.0%) 1.05 (0.84,1.30) 1.05 (0.84,1.30), p=0.69 Favors DES Favors BMS Mean f/u 4.0 yrs Ajay J. Kirtane and Gregg W. Stone, 2008

  17. All-Cause Mortality: RCT’s (Off-Label) 4,049 patients, 12 trials Weight (%) Estimate (95% CI) Random Effects *Fixed Effects (I2=0.0%) 0.84 (0.62,1.13) 0.84 (0.62,1.13), p=0.24 Favors DES Favors BMS Mean f/u 1.5 yrs Ajay J. Kirtane and Gregg W. Stone, 2008

  18. All-Cause Mortality: All Registries 161,232 patients, 28 registries Weight (%) Estimate (95% CI) *Random Effects (I2=70.1%) Fixed Effects 0.80 (0.72,0.88), p<0.001 0.83 (0.79,0.86) Favors DES Favors BMS Mean f/u 2.5 yrs Ajay J. Kirtane and Gregg W. Stone, 2008

  19. All-Cause Mortality: Unadjusted Registries 122,989 patients, 22 registries Weight (%) Estimate (95% CI) *Random Effects (I2=75.3%) Fixed Effects 0.70 (0.63,0.78), p<0.001 0.69 (0.66,0.72) Favors DES Favors BMS Mean f/u 2.1 yrs Ajay J. Kirtane and Gregg W. Stone, 2008

  20. All-Cause Mortality: Adjusted Registries 134,534 patients, 18 registries Estimate (95% CI) Weight (%) *Random Effects (I2=76.6%) Fixed Effects 0.80 (0.72,0.90), p<0.001 0.82 (0.79,0.86) Favors DES Favors BMS Mean f/u 2.7 yrs Ajay J. Kirtane and Gregg W. Stone, 2008

  21. All-Cause Mortality: Registries Begg’s Funnel Plot p=0.92 log(Hazard Ratio) Standard Error of log(Hazard Ratio) Ajay J. Kirtane and Gregg W. Stone, 2008

  22. MI: All RCTs 8,850 patients, 20 trials Estimate (95% CI) Weight (%) Random Effects *Fixed Effects (I2=3.0%) 0.94 (0.78,1.13) 0.94 (0.79,1.13), p=0.54 Favors DES Favors BMS Mean f/u 2.9 yrs Ajay J. Kirtane and Gregg W. Stone, 2008

  23. MI: RCTs (On Label) 4,318 patients, 9 trials Estimate (95% CI) Weight (%) Random Effects *Fixed Effects (I2=0.0%) 1.03 (0.81,1.30) 1.03 (0.81,1.30), p=0.82 Favors DES Favors BMS Mean f/u 4.4 yrs Ajay J. Kirtane and Gregg W. Stone, 2008

  24. MI: RCT’s (Off Label) 4,532 patients, 12 trials Estimate (95% CI) Weight (%) 0.77 (0.54,1.10) 0.83 (0.62,1.10), p=0.19 Random Effects *Fixed Effects (I2=25.5%) Favors DES Favors BMS Mean f/u 1.5 yrs Ajay J. Kirtane and Gregg W. Stone, 2008

  25. MI: All Registries 129,955 patients, 24 registries 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 Favors DES Favors BMS Mean f/u 2.5 yrs Ajay J. Kirtane and Gregg W. Stone, 2008

  26. MI: Unadjusted Registries 88,221 patients, 18 registries Estimate (95% CI) Weight (%) *Random Effects (I2=77.8%) Fixed Effects 0.83 (0.70,0.97), p=0.023 0.88 (0.83,0.93) *MI is QWMI in Washington Hospital Center, RESTEM Favors DES Favors BMS Mean f/u 2.0 yrs Ajay J. Kirtane and Gregg W. Stone, 2008

  27. MI: Adjusted Registries 107,294 patients, 14 registries Estimate (95% CI) Weight (%) *Random Effects (I2=60.8%) Fixed Effects 0.91 (0.81,1.01), p=0.083 0.96 (0.91,1.01) *MI is QWMI in Washington Hospital Center Favors DES Favors BMS Mean f/u 2.8 yrs Ajay J. Kirtane and Gregg W. Stone, 2008

  28. TVR: All RCTs 7,291 patients, 16 trials Estimate (95% CI) Weight (%) *Random Effects (I2=53.2%) Fixed Effects 0.45 (0.37,0.54), p<0.001 0.51 (0.45,0.57) Favors DES Favors BMS Mean f/u 3.2 yrs Ajay J. Kirtane and Gregg W. Stone, 2008

  29. TVR: RCTs Meta-Regression on Percent Angiographic F/U *Hazard Ratio p=0.73 Percentage of Patients with 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

  30. TVR: All Registries 73,819 patients, 17 registries Estimate (95% CI) Weight (%) *Random Effects (I2=71.2%) Fixed Effects 0.53 (0.47,0.61), p<0.001 0.57 (0.54,0.60) Favors DES Favors BMS Mean f/u 2.2 yrs Ajay J. Kirtane and Gregg W. Stone, 2008

  31. TVR: Unadjusted Registries 55,531 patients, 12 registries Estimate (95% CI) Weight (%) *Random Effects (I2=88.9%) Fixed Effects 0.60 (0.48,0.74), p<0.001 0.73 (0.69,0.77) Favors DES Favors BMS Mean f/u 2.2 yrs Ajay J. Kirtane and Gregg W. Stone, 2008

  32. TVR: Adjusted Registries 63,456 patients, 11 registries Estimate (95% CI) Weight (%) *Random Effects (I2=79.4%) Fixed Effects 0.54 (0.46,0.63), p<0.001 0.58 (0.54,0.61) Favors DES Favors BMS Mean f/u 2.2 yrs Ajay J. Kirtane and Gregg W. Stone, 2008

  33. Summary: DES vs. BMSTreatment Effect Estimates <1.0  DES better

  34. Study 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

  35. 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

  36. 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”

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