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Safety of Drug Eluting Stents Do 2 nd generation DES have a lower risk of stent thrombosis?

Safety of Drug Eluting Stents Do 2 nd generation DES have a lower risk of stent thrombosis?. Keith G Oldroyd West of Scotland Regional Heart & Lung Centre Golden Jubilee National Hospital. Conflicts of Interest Advisory boards for Biosensors; Cordis; BSCI. Safety of Drug Eluting Stents.

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Safety of Drug Eluting Stents Do 2 nd generation DES have a lower risk of stent thrombosis?

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  1. Safety of Drug Eluting StentsDo 2nd generation DES have a lower risk of stent thrombosis? Keith G Oldroyd West of Scotland Regional Heart & Lung Centre Golden Jubilee National Hospital

  2. Conflicts of InterestAdvisory boards for Biosensors; Cordis; BSCI

  3. Safety of Drug Eluting Stents • Cypher/Taxus vs BMS • Cypher/Taxus vs Endeavor • Cypher/Taxus vs Xience/Promus • Cypher vs Biomatrix • Cypher vs Yukon

  4. Safety and Efficacy of Sirolimus Eluting Stents(NEJM 2007; 356: 998-1008)

  5. Safety and Efficacy of Paclitaxel Eluting Stents(NEJM 2007; 356: 998-1008)

  6. Scottish Coronary Revascularisation RegisterAll-cause mortality for “off-label” use of DES

  7. HORIZONS - Stent Thrombosis (ARC Definite or Probable) 4 TAXUS DES (n=2238) 3.4% EXPRESS BMS (n=744) 3.1% 3 Stent Thrombosis (%) HR [95%CI] 0.92 [0.58,1.45] p=0.72 2 1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Time in Months Number at risk TAXUS DES 2238 2122 2098 2078 1884 EXPRESS BMS 744 701 694 683 629

  8. MASS Registry: PS matched risks and risk differences at 3 years in diabetic patients Garg P et al. Circulation 2008

  9. Meta-analysis DES vs BMS In 22 RCTs involving 9,470 patients randomized to DES or BMS and followed for ≥1 year, DES resulted in: A non-significant 3% reduction in mortality - HR 0.97 (0.81,1.15) A non-significant 6% reduction in MI - HR 0.94 (0.79,1.13) A significant 55% reduction in TVR –HR 0.45 (0.37,0.54) In 30 Registries with 174,302 patients treated with either DES or BMS and followed for ≥1 year, DES resulted in: A significant 20% reduction in mortality- HR 0.80 (0.72,0.88) A significant 11% reduction in MI –HR 0.89 (0.80-0.98) A significant 47% reduction in TVR –HR 0.53 (0.47-0.61)

  10. This is not a class effect for “drug-eluting stents”. The sirolimus-eluting CYPHER stent has a wide therapeutic window and does not have a problem with either early or late thromboses Jeff Moses. TCT 04

  11. Pooled Odds Ratio

  12. Endeavor IIStent thrombosis Driver Endeavor 1.2% (7) 1.2% (7) Days 1 2 3 4 5 6 7 8 9 10 11 12 13 14 30 50 100 125 150 200 225 270 0.5%(3) 0.5%(3)

  13. “Does even distribution of neointima explain the unsurpassed stent thrombosis rates with Endeavor?” Professor Martin Rothman 2005

  14. ENDEAVOR IV – 2 year outcomes TCT 08

  15. SORTOUT-III Definite Stent Thrombosis Hazard Ratio (95% CI) 4.62 (1.33 – 16.1) p=0.02

  16. SORTOUT-III Myocardial Infarction Hazard Ratio (95% CI) 3.47 (1.14 – 10.5) p=0.03

  17. SORTOUT-III Clinically Significant Restenosis Hazard Ratio (95% CI) 6.59 (2.57 – 16.9) p<0.0001

  18. Western Denmark Heart RegistryEndeavor vs Cypher Thuesen L. TCT 2008

  19. SPIRIT III - 2 Year ResultsARC Definite / Probable Stent Thrombosis P=0.77 P=NR P=NR P=0.34 SPIRIT III Presentation, Gregg W. Stone, MD, PCR 2008. Refer to glossary

  20. SPIRIT III - 2 Year ResultsProtocol* Stent Thrombosis *ACS with thrombus or unexplained death or AMI in the target lesion distribution within 30 days.

  21. Xience/Promus vs Cypher?

  22. LEADERSCardiac Death & Myocardial Infarction Biolimus Stent Sirolimus Stent 6.7% 6.6%

  23. LEADERSDefinite Stent Thrombosis Biolimus Stent Sirolimus Stent 2.0% 2.0%

  24. ISAR-TEST 3 Yukon

  25. Conclusion • There is as yet no convincing evidence of any important safety differences between any of the currently available DES. • It may never be possible to convincingly demonstrate such differences even if they exist. • Any differences that do exist in the risk of stent thrombosis between DES are very small and less important than several other potential causative factors including • the patient • the lesion • the operator • response to and premature discontinuation of DAPT

  26. ISAR-TEST 3 Yukon

  27. Future Studies on DES Safety - DAPT • Designed to enroll more than 15 000 patients being treated with one of the four DES currently approved in the US and more than 5000 patients treated with a BMS. • All patients will receive DAPT - clopidogrel or prasugrel for 12 months. • At 12 months, after the exclusion of any patients with MACCE or major bleeding patients will be randomised to either placebo or ongoing DAPT out to 30 months. • Follow-up will end at 33 months, to include a possible "rebound period.“ • The co-primary end points will be stent thrombosis and MACCE, and the major safety end point will be major bleeding.

  28. DES and BMS for Acute Myocardial Infarction N=4,016 patients with DES for MI N=3,200 patients with BMS for MI Propensity score matched pairs 2629 MI 2629 MI 2,453 (61.1%) DES for NSTEMI 1,382 (43.2%) BMS for NSTEMI matched pairs 1,221 NSTEMI 1,221 NSTEMI 1,563 (38.9%) DES for STEMI 1,818 (56.8%) BMS for STEMI matched pairs 1,302 STEMI 1,302 STEMI Mauri L et al. N Engl J Med 2008; 359:1330-1342.

  29. DES and BMS for Acute Myocardial Infarction Risk Differences in Matched MI Patient Groups at 2 years MI n=2629 pairs NSTEMI n=1221 pairs STEMI n=1302 pairs Favors DES Favors DES Favors BMS Favors BMS Risk Difference (95% CI), DES v. BMS Recurrent MI Death -2.7% [-4.5%, 0%] P=0.002 -1.5% [-3.1%, 0.2%] P=0.08 -2.4% [-5.0%, 0.3%] P=0.07 -1.9% [-4.6%, 0.9%] P=0.18 -3.1% [-5.4%, -0.8%] P=0.009 -1.6% [-3.7%, 0.5%] P=0.127 Mauri L et al. N Engl J Med 2008; 359:1330-1342.

  30. SPIRIT III – 2 year outcomes Among patients who stopped DAPT @ 6 months there were fewer stent thrombosis "episodes" in Xience V-treated patients compared to Taxus-treated patients but ………………. E-PCR 2008

  31. SORTOUT-III Cardiac Mortality Hazard Ratio (95% CI) 2.17 (0.75 – 6.24) p=0.14

  32. Meta-analysis DES vs. BMSMortality RCT and Registry Analysis Mortality: All Registries 161,232 patients, 28 registries** Mortality: All RCTs 8,867 patients, 21 trials** Estimate (95% CI) Weight (%) Estimate (95% CI) Weight (%) Random Effects *Fixed Effects (I2=0.0%) 0.97 (0.81,1.15) 0.97 (0.81,1.15), p=0.72 0.80 (0.72,0.88), p<0.001 0.83 (0.79,0.86) *Random Effects (I2=70.1%) Fixed Effects Favors DES Favors BMS Favors DES Favors BMS <1.0  Favors DES; * = significant **All-cause mortality data was available in 21 of 22 RCTs and 28 of 30 Registries. • Presented by Gregg W. Stone MD and Ajay Kirtane MD, ACC 2008.Point estimates are represented by red circles; Confidence intervals by red lines and Weight by yellow boxes (based on primary model); No significant effect of number of patients (total or DES patients) or diabetic patients by meta-regression; Random effects used except if I2<25.

  33. Meta-analysis DES vs. BMSMI RCT and Registry Analysis MI: All RCTs 8,850 patients, 20 trials** MI: All Registries 129,955 patients, 24 registries** Estimate (95% CI) Weight (%) 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 0.89 (0.80,0.98), p=0.023 0.96 (0.91,1.01) *Random Effects (I2=57.9%) Fixed Effects Favors DES Favors BMS Favors DES Favors BMS <1.0  Favors DES; * = significant ***MI data was available in 20 of 22 RCTs and 24 of 30 Registries • Presented by Gregg W. Stone MD and Ajay Kirtane MD, ACC 2008. Point estimates are represented by red circles; Confidence intervals by red lines and Weight by yellow boxes (based on primary model); No significant effect of number of patients (total or DES patients) or diabetic patients by meta-regression; Random effects used except if I2<25%. Refer to glossary

  34. Drug-Eluting and Bare Metal Stenting for Acute Myocardial InfarctionPatient Characteristics after Match *%SD = Percent Standardized Difference Values <10% reflect well-matched characteristics

  35. Drug-Eluting and Bare Metal Stenting for Acute Myocardial InfarctionPatient Characteristics after Match *%SD = Percent Standardized Difference Values <10% reflect well-matched characteristics

  36. Drug-Eluting and Bare Metal Stenting for Acute Myocardial InfarctionProcedure Indications after Match

  37. Drug-Eluting and Bare Metal Stenting for Acute Myocardial InfarctionProcedural Characteristics after Match *%SD = Percent Standardized Difference Values <10% reflect well-matched characteristics

  38. Drug-Eluting & Bare Metal Stenting in Massachusetts Risk Differences in Matched MI Patient Groups at 2 years MI n=2629 pairs -3.6% [-5.2%, -2.0%] P<0.001 -5.3% [-7.4%, -3.2%] P<0.001 NSTEMI n=1221 pairs -2.9% [-5.4%, -0.5%] P=0.02 -5.3% [-8.4%, -2.3%] P<0.001 STEMI n=1302 pairs -3.5% [-5.8%, -1.3%] P=0.002 -6.0% [-9.0%, -3.0%] P<0.001 Favors DES Favors DES Favors BMS Favors BMS Risk Difference (95% CI), DES v. BMS Revascularization TVR

  39. Angiographic results, accounting for 32% of treated lesions, in CREATE Han Y. American College of Cardiology 2008 Scientific Sessions/ i2 Summit-SCAI Annual Meeting; March 31, 2008; Chicago, IL.

  40. Clinical outcomes in CREATE *Primary end point MACE=major adverse cardiac events TLR=target-lesion revascularization Han Y. American College of Cardiology 2008 Scientific Sessions/ i2 Summit-SCAI Annual Meeting; March 31, 2008; Chicago, IL.

  41. Angiographic outcomes at six months and two years in SPIRIT-2*: Xience-V vs Taxus Serruys PW, et al. March 31, 2008; Chicago, IL.

  42. Intravascular ultrasound measurements at six months and two years in SPIRIT-2*: Xience-V vs Taxus Serruys PW, et al. March 31, 2008; Chicago, IL.

  43. Clinical outcomes at six months and two years in SPIRIT-2: Xience-V vs Taxus Serruys PW, et al. March 31, 2008; Chicago, IL.

  44. S.T.E.N.T. Registry SESPES (n=2282) (n=1476) n % n % p Death 61 2.7 31 2.1 0.26 MI 50 2.2 27 1.8 0.44 TVR 95 4.2 50 3.4 0.23 CABG Target Vessel 12 0.5 11 0.7 0.40 Re-PCI Target Vessel 84 3.7 41 2.8 0.13 MACE 180 7.9 100 6.8 0.20 Stent Thrombosis 15 0.7 7 0.5 0.52 < 24 hours 1 2 24 hours to 30 days 11 1 > 30 days 3 4

  45. Future Studies on DES SafetyDAPT No stent-stent or drug-drug comparisons • Only the FDA and the DSMB will have access to all the device- and drug-level data • This is “fully appropriate” given the lack of any statistical power in a study this size to make comparisons between devices or drugs. Dr William Maisel (Beth Israel Deaconess Medical Center) commented… "I find it ironic that after months and years of hearing about how stents are different and that one company's stent, for biologic or platform or endothelialisation reasons, has different rates of stent thrombosis, we're suddenly lumping them all together."

  46. Massachusetts Registry -2 year risk-adjusted outcomes Mauri L et al. N Engl J Med 2008; 359:1330-1342.

  47. SPIRIT III Clinical Trial 2-Year ResultsARC Definite / Probable Stent Thrombosis P= NR P= 0.77 Incidence Rate (%) XIENCE™ V (PROMUS™) Stent n=669 TAXUSTM Express2TM Stent n=333 P Value from Log Rank test Adapted from SPIRIT III Presentation, Gregg W. Stone, MD, PCR 2008. Refer to glossary

  48. SPIRIT III Clinical Trial 2-Year ResultsProtocol* Stent Thrombosis P= NR P= 0.35 Incidence Rate (%) XIENCE™ V (PROMUS™) Stent n=669 TAXUSTM Express2TM Stent n=333 *ACS with thrombus or unexplained death or AMI in the target lesion distribution within 30 days. P Value from Log Rank test Adapted from SPIRIT III Presentation, Gregg W. Stone, MD, PCR 2008. Refer to glossary

  49. ENDEAVOR II, III, and IV Studies9-month Safety Results p=0.342 p=1.00 p=0.772 p=0.287 p=NA p=1.00 QWMI (%) Death (%) 95% CI [0.1%, 1.6%] p=0.224 p=NA p=0.124 p=NR p=NR ARC (Def + Prob) ST (%) Protocol ST (%) 92.3% of EndeavorTM Stent patients were on DAPT through 6 months ENDEAVOR II ENDEAVOR III ENDEAVOR IV EndeavorTM Stent n = 592 EndeavorTMStent n = 323 EndeavorTMStent n = 740 DriverTM Stent n = 591 CypherTM Stent n = 113 TAXUSTM Stent n = 734 ENDEAVOR II Fajadet et al, Circulation, August 22, 2006. ENDEAVOR III Kandzari et al., JACC, December 19, 2006. ENDEAVOR IV www.fda.gov. All ARC (def+prob) stent thrombosis rates www.fda.gov. Refer to glossary

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