1. Clinical Trial Results. org Clopidogrel Use and Long-term Clinical Outcomes After Drug-Eluting Stent Implantation Eric Eisenstein, DBA; Kevin Anstrom, PhD; David Kong, MD; Linda Shaw, MS; Robert Tuttle, MSPH; Daniel Mark, MD, MPH; Judith Kramer, MD, MS; Robert Harrington, MD; David Matchar, MD; David Kandzari, MD; Eric Peterson, MD, MPH; Kevin Schulman, MD; Robert Califf, MD Published in JAMA January 10, 2007 Clopidogrel Use and Long-term Clinical Outcomes After Drug-Eluting Stent Implantation

2. Clinical Trial Results. org Clopidogrel Use and Long-term Clinical Outcomes After Drug-Eluting Stent Implantation: Background Instructions for the use of drug-eluting stents (DES) commercially available in the U.S. specify treatment with clopidogrel for at least 3 months (for sirolimus-coated stents) or 6 months (for paclitaxel-coated stents) after implantationInstructions for the use of drug-eluting stents (DES) commercially available in the U.S. specify treatment with clopidogrel for at least 3 months (for sirolimus-coated stents) or 6 months (for paclitaxel-coated stents) after implantation However, studies of late thrombosis events among patients with DES have cast doubt on whether the recommended regimens are sufficientHowever, studies of late thrombosis events among patients with DES have cast doubt on whether the recommended regimens are sufficient This study assessed the association between clopidogrel use and long-term rates of death and death or MI following initial percutaneous coronary intervention (PCI) with DES or bare-metal stents (BMS)This study assessed the association between clopidogrel use and long-term rates of death and death or MI following initial percutaneous coronary intervention (PCI) with DES or bare-metal stents (BMS) Instructions for the use of drug-eluting stents (DES) commercially available in the U.S. specify treatment with clopidogrel for at least 3 months (for sirolimus-coated stents) or 6 months (for paclitaxel-coated stents) after implantationInstructions for the use of drug-eluting stents (DES) commercially available in the U.S. specify treatment with clopidogrel for at least 3 months (for sirolimus-coated stents) or 6 months (for paclitaxel-coated stents) after implantation However, studies of late thrombosis events among patients with DES have cast doubt on whether the recommended regimens are sufficientHowever, studies of late thrombosis events among patients with DES have cast doubt on whether the recommended regimens are sufficient This study assessed the association between clopidogrel use and long-term rates of death and death or MI following initial percutaneous coronary intervention (PCI) with DES or bare-metal stents (BMS)This study assessed the association between clopidogrel use and long-term rates of death and death or MI following initial percutaneous coronary intervention (PCI) with DES or bare-metal stents (BMS) Eisenstein et al. JAMA. 2007 Jan 10; 297 (2): 159 – 68.

3. Clinical Trial Results. org Clopidogrel Use and Long-term Clinical Outcomes After Drug-Eluting Stent Implantation: Study Design Landmark analysis used, and two landmarks were used in this study:Landmark analysis used, and two landmarks were used in this study: –Starting at 6-months following PCI onward –Starting at 12-months following PCI onward At the 6-month and 12-month landmark times, the patients were divided into four groups for analysis: DES with clopidogrel, DES without clopidogrel, BMS with clopidogrel, and BMS without clopidogrel.At the 6-month and 12-month landmark times, the patients were divided into four groups for analysis: DES with clopidogrel, DES without clopidogrel, BMS with clopidogrel, and BMS without clopidogrel. Outcomes for these groups were evaluated up to 24 months after initial PCI procedure.Outcomes for these groups were evaluated up to 24 months after initial PCI procedure. Landmark analysis used, and two landmarks were used in this study:Landmark analysis used, and two landmarks were used in this study: –Starting at 6-months following PCI onward –Starting at 12-months following PCI onward At the 6-month and 12-month landmark times, the patients were divided into four groups for analysis: DES with clopidogrel, DES without clopidogrel, BMS with clopidogrel, and BMS without clopidogrel.At the 6-month and 12-month landmark times, the patients were divided into four groups for analysis: DES with clopidogrel, DES without clopidogrel, BMS with clopidogrel, and BMS without clopidogrel. Outcomes for these groups were evaluated up to 24 months after initial PCI procedure.Outcomes for these groups were evaluated up to 24 months after initial PCI procedure. Eisenstein et al. JAMA. 2007 Jan 10; 297 (2): 159 – 68.

4. Clinical Trial Results. org Clopidogrel Use and Long-term Clinical Outcomes After Drug- Eluting Stent Implantation: Study Design  Outcomes analyzed for Death, Nonfatal MI, and Death or MI DESn=1,501DESn=1,501BMSn=3,165BMSn=3,165 4,666 patients undergoing PCI with BMS or DES Prospective. Landmark analysis (starting at 6 or 12 mos after PCI). Follow-up at 12, 18, and up to 24-mos. Exclusion Criteria: prior CABG surgery or PCI procedure, significant (>75% stenosis) left main coronary artery disease, interventions other than stent placement during PCI 4,666 patients undergoing PCI with BMS or DES Prospective. Landmark analysis (starting at 6 or 12 mos after PCI). Follow-up at 12, 18, and up to 24-mos. Exclusion Criteria: prior CABG surgery or PCI procedure, significant (>75% stenosis) left main coronary artery disease, interventions other than stent placement during PCI Eisenstein et al. JAMA. 2007 Jan 10; 297 (2): 159 – 68. 24 mos. follow-up Stent type at Baseline 6 mos. Landmark Analysis DESn=1,216DESn=1,216 BMSn=2,393BMSn=2,393 Clopidogreln=637Clopidogreln=637 No Clopidogrel n=579 n=579 n=1,976 n=1,976 Clopidogreln=416Clopidogreln=416

5. Clinical Trial Results. org Clopidogrel Use and Long-term Clinical Outcomes After Drug- Eluting Stent Implantation: Study Design  Outcomes analyzed for Death, Nonfatal MI, and Death or MI DESn=1,501DESn=1,501BMSn=3,165BMSn=3,165 4,666 patients undergoing PCI with BMS or DES Prospective. Landmark analysis (starting at 6 or 12 mos after PCI). Follow-up at 12, 18, and up to 24-mos. Exclusion Criteria: prior CABG surgery or PCI procedure, significant (>75% stenosis) left main coronary artery disease, interventions other than stent placement during PCI 4,666 patients undergoing PCI with BMS or DES Prospective. Landmark analysis (starting at 6 or 12 mos after PCI). Follow-up at 12, 18, and up to 24-mos. Exclusion Criteria: prior CABG surgery or PCI procedure, significant (>75% stenosis) left main coronary artery disease, interventions other than stent placement during PCI Eisenstein et al. JAMA. 2007 Jan 10; 297 (2): 159 – 68. 24 mos. follow-up Stent type at Baseline 12 mos. Landmark Analysis DESn=528DESn=528 BMSn=1,990BMSn=1,990 Clopidogreln=252Clopidogreln=252 No Clopidogrel n=276 n=276 n=1,644 n=1,644 Clopidogreln=326Clopidogreln=326

6. Clinical Trial Results. org Characteristic DES w/ Clop. (n=637 ) Clop. (n=637 ) DES w/o Clop (n=579) BMS w/ Clop.(n=417) BMS w/o Clop. (n= 1,976) P for Trend Age, Median (IQR) 61 (53-71) 60 (53-70) 61 (53-70) 61 (52-71) 0.73 Black race (%) 121 (19.0) 137 (23.7) 82 (19.7) 395 (20.0) 0.18 Male Sex (%) 398 (62.5) 368 (63.6) 266 (63.8) 1,233 (62.4) 0.93 History of Diabetes (%) 171 (26.8) 171 (29.5) 121 (29.0) 449 (22.7) 0.001 History of CHF (%) 60 (9.6) 82 (14.5) 38 (9.3) 208 (11.0) 0.03 History of MI (%) 247 (38.8) 221 (38.2) 213 (51.1) 913 (46.2) <0.001 No of Diseased Vessels 1 2 3 370 (58.1) 186 (29.2) 81 (12.7) 356 (61.5) 178 (30.7) 45 (7.8) 275 (65.9) 109 (26.1) 33 (7.9) 1,331 (67.4) 531 (26.9) 114 (5.8) <0.001 Clopidogrel Use and Long-term Clinical Outcomes After Drug-Eluting Stent Implantation: Baseline Characteristics for 6 mos. patients Eisenstein et al. JAMA. 2007 Jan 10; 297 (2): 159 – 68.

7. Clinical Trial Results. org Characteristic DES w/ Clop. (n=637 ) DES w/o Clop (n=579) BMS w/ Clop.(n=417) BMS w/o Clop. (n=1,976 ) P for Trend Income, median $ In thousands 36.535.435.133.1<0.001 Avg House Val, $ In thousands 82.982.680.475.70.006 Aspirin use at 6 mos. 6 mos. 12 mos. 12 mos. 24 mos. 24 mos. 600 (94.2) 478 (91.2) 179 (93.2) 430 (74.3) 371 (86.3) 148 (85.6) 360 (86.3) 335 (84.0) 304 (82.2) 1583 (80.1) 1569 (85.0) 1541 (87.1) <0.0010.0030.003 Clop. use at 6 mos. 6 mos. 12 mos. 12 mos. 24 mos. 24 mos. 637 (100) 382 (72.9) 106 (55.2) 0 (0) 64 (14.9) 25 (14.5) 417 (100) 309 (77.4) 230 (62.2) 0 (0) 93 (5.0) 143 (8.1) <0.001<0.001<0.001 Clopidogrel Use and Long-term Clinical Outcomes After Drug-Eluting Stent Implantation: Baseline Characteristics for 6 mos. patients Eisenstein et al. JAMA. 2007 Jan 10; 297 (2): 159 – 68.

8. Clinical Trial Results. org Characteristic DES w/ Clop. (n=252 ) DES w/o Clop (n=276) BMS w/ Clop.(n=346) BMS w/o Clop. (n=1,644 ) P for Trend Age, Median (IQR) 61 (53-70) 62 (53-72) 0.76 Black race (%) 36 (14.3) 62 (22.5) 69 (19.9) 310 (18.9) 0.12 Male Sex (%) 164 (65.1) 170 (61.6) 204 (59.0) 1,031 (62.7) 0.45 History of Diabetes (%) 69 (27.4) 79 (28.6) 109 (31.5) 364 (22.1) <0.001 History of CHF (%) 25 (10.0) 27 (10.0) 29 (8.5) 163 (10.0) 0.87 History of MI (%) 95 (37.7) 94 (34.1) 170 (49.1) 745 (45.3) <0.001 No of Diseased Vessels 1 2 3 144 (57.1) 78 (31.0) 30 (11.9) 173 (62.7) 83 (30.1) 20 (7.3) 223 (64.5) 98 (28.3) 25 (7.2) 1,130 (68.7) 427 (26.0) 87 (5.3) <0.001 Clopidogrel Use and Long-term Clinical Outcomes After Drug-Eluting Stent Implantation: Baseline Characteristics for 12-mos. Patients Eisenstein et al. JAMA. 2007 Jan 10; 297 (2): 159 – 68.

9. Clinical Trial Results. org Characteristic DES w/ Clop. (n=252 ) DES w/o Clop (n=276) BMS w/ Clop.(n=346) BMS w/o Clop. (n=1,644 ) P for Trend Income, median $ In thousands 35.436.033.133.10.13 Avg House Val, $ In thousands 80.982.978.175.70.30 Aspirin use at 6 mos. 6 mos. 12 mos. 12 mos. 24 mos. 24 mos. 223 (88.5) 234 (92.9) 140 (94.0) 235 (85.1) 236 (85.5) 151 (86.8) 277 (80.1) 295 (85.3) 257 (81.1) 1373 (83.5) 1398 (85.0) 1360 (88.1) 0.0450.01<0.001 Clop. use at 6 mos. 6 mos. 12 mos. 12 mos. 24 mos. 24 mos. 218 (86.5) 252 (100) 104 (69.8) 68 (24.6) 0 (0) 14 (8.1) 271 (78.3) 346 (100) 221 (69.7) 74 (4.5) 0 (0) 85 (5.5) <0.001<0.001<0.001 Clopidogrel Use and Long-term Clinical Outcomes After Drug-Eluting Stent Implantation: Baseline Characteristics for 12-mos. Patients Eisenstein et al. JAMA. 2007 Jan 10; 297 (2): 159 – 68.

10. Clinical Trial Results. org Clopidogrel Use and Long-term Clinical Outcomes After Drug-Eluting Stent Implantation: Main Outcome Measures Endpoint (%) Endpoint (%) Adjusted outcomes were analyzed at 24 monthsAdjusted outcomes were analyzed at 24 months Patients in the DES with clop. group had significantly lower rates of death than did patients in the DES without clopidogrel groupPatients in the DES with clop. group had significantly lower rates of death than did patients in the DES without clopidogrel group Among BMS patients, there were no differences in deathAmong BMS patients, there were no differences in death No difference was observed in nonfatal MINo difference was observed in nonfatal MI Difference=-3.3±3 p=0.03 Difference=-0.7±2.1 p =0.50 Adjusted rates of Death for Analysis Starting at 6-months Eisenstein et al. JAMA. 2007 Jan 10; 297 (2): 159 – 68.

11. Clinical Trial Results. org Clopidogrel Use and Long-term Clinical Outcomes After Drug-Eluting Stent Implantation: Main Outcome Measures Endpoint (%) Endpoint (%) Adjusted outcomes were analyzed at 24 monthsAdjusted outcomes were analyzed at 24 months Patients in the DES with clop. group had significantly lower rates of death or MI than did patients in the DES without clopidogrel groupPatients in the DES with clop. group had significantly lower rates of death or MI than did patients in the DES without clopidogrel group Among BMS patients, there were no differences in death or MIAmong BMS patients, there were no differences in death or MI Difference=-4.1±3.5 p 0.02 Difference=-0.5±2.7 p=0.70 Adjusted rates of Death or MI Starting at 6 mos. Eisenstein et al. JAMA. 2007 Jan 10; 297 (2): 159 – 68.

12. Clinical Trial Results. org Clopidogrel Use and Long-term Clinical Outcomes After Drug-Eluting Stent Implantation: Main Outcome Measures Endpoint (%) Endpoint (%) Adjusted outcomes were analyzed at 24 monthsAdjusted outcomes were analyzed at 24 months Patients in the DES with clop. group had significantly lower rates of death than did patients in the DES without clopidogrel groupPatients in the DES with clop. group had significantly lower rates of death than did patients in the DES without clopidogrel group Among BMS patients, there were no differences in deathAmong BMS patients, there were no differences in death Difference=-3.5±2.4 p=0.004 Difference=0.6±2.1 p=0.57 Adjusted rates of Death for Analysis Starting at 12-mos. Eisenstein et al. JAMA. 2007 Jan 10; 297 (2): 159 – 68.

13. Clinical Trial Results. org Clopidogrel Use and Long-term Clinical Outcomes After Drug-Eluting Stent Implantation: Main Outcome Measures Endpoint (%) Endpoint (%) Adjusted outcomes were analyzed at 24 monthsAdjusted outcomes were analyzed at 24 months Patients in the DES with clop. group had significantly lower rates of death or MI than did patients in the DES without clopidogrel groupPatients in the DES with clop. group had significantly lower rates of death or MI than did patients in the DES without clopidogrel group Among BMS patients, there were no differences in death or MIAmong BMS patients, there were no differences in death or MI Difference=-4.5±2.6 p<0.001 Difference=1.0±2.6 p=0.44 Adjusted rates of Death or MI Analysis Starting at 12-mos. Eisenstein et al. JAMA. 2007 Jan 10; 297 (2): 159 – 68.

14. Clinical Trial Results. org Clopidogrel Use and Long-term Clinical Outcomes After Drug-Eluting Stent Implantation: Limitations Clopidogrel use was not randomly assigned; thus, the decision to continue the drug beyond the periods recommended by the relevant clinical trials may have been correlated with unmeasured prognostic factors.Clopidogrel use was not randomly assigned; thus, the decision to continue the drug beyond the periods recommended by the relevant clinical trials may have been correlated with unmeasured prognostic factors. Eisenstein et al. JAMA. 2007 Jan 10; 297 (2): 159 – 68.

15. Clinical Trial Results. org Clopidogrel Use and Long-term Clinical Outcomes After Drug-Eluting Stent Implantation: Limitations Clopidogrel use in this analysis was identified by patient report at 2 discrete points (6- and 12-month follow-up). Therefore, these data are subject to recall bias.Clopidogrel use in this analysis was identified by patient report at 2 discrete points (6- and 12-month follow-up). Therefore, these data are subject to recall bias. Furthermore, the indications and rationale for long- term clopidogrel regimens and for its discontinuations were not collected.Furthermore, the indications and rationale for long- term clopidogrel regimens and for its discontinuations were not collected. Clopidogrel use in this analysis was identified by patient report at 2 discrete points (6- and 12-month follow-up). Therefore, these data are subject to recall bias.Clopidogrel use in this analysis was identified by patient report at 2 discrete points (6- and 12-month follow-up). Therefore, these data are subject to recall bias. Furthermore, the indications and rationale for long- term clopidogrel regimens and for its discontinuations were not collected.Furthermore, the indications and rationale for long- term clopidogrel regimens and for its discontinuations were not collected. Eisenstein et al. JAMA. 2007 Jan 10; 297 (2): 159 – 68.

16. Clinical Trial Results. org Clopidogrel Use and Long-term Clinical Outcomes After Drug-Eluting Stent Implantation: Limitations The 24-month event rates of 0% for death, nonfatal MI, and death or MI for the DES with clopidogrel group in the 12- month landmark analysis may underestimate the true event rates. However, 14 patients receiving DES died or had a nonfatal MI, and none of these 14 patients was in the DES with clopidogrel group.The 24-month event rates of 0% for death, nonfatal MI, and death or MI for the DES with clopidogrel group in the 12- month landmark analysis may underestimate the true event rates. However, 14 patients receiving DES died or had a nonfatal MI, and none of these 14 patients was in the DES with clopidogrel group. Extended clopidogrel therapy has its own risks and this analysis does not evaluate the long-term nonfatal implications of its use.Extended clopidogrel therapy has its own risks and this analysis does not evaluate the long-term nonfatal implications of its use. The 24-month event rates of 0% for death, nonfatal MI, and death or MI for the DES with clopidogrel group in the 12- month landmark analysis may underestimate the true event rates. However, 14 patients receiving DES died or had a nonfatal MI, and none of these 14 patients was in the DES with clopidogrel group.The 24-month event rates of 0% for death, nonfatal MI, and death or MI for the DES with clopidogrel group in the 12- month landmark analysis may underestimate the true event rates. However, 14 patients receiving DES died or had a nonfatal MI, and none of these 14 patients was in the DES with clopidogrel group. Extended clopidogrel therapy has its own risks and this analysis does not evaluate the long-term nonfatal implications of its use.Extended clopidogrel therapy has its own risks and this analysis does not evaluate the long-term nonfatal implications of its use. Eisenstein et al. JAMA. 2007 Jan 10; 297 (2): 159 – 68.

17. Clinical Trial Results. org Clopidogrel Use and Long-term Clinical Outcomes After Drug-Eluting Stent Implantation: Summary In a large consecutive cohort of contemporary patients receiving PCI, the long-term risk for death and major cardiac events was significantly increased among patients in the DES group who had discontinued clopidogrel therapy at 6 or 12 months.In a large consecutive cohort of contemporary patients receiving PCI, the long-term risk for death and major cardiac events was significantly increased among patients in the DES group who had discontinued clopidogrel therapy at 6 or 12 months. Extended-duration clopidogrel therapy following DES implantation was associated with a lower incidence of death or MI, a finding that has immediate implications for clinical practice.Extended-duration clopidogrel therapy following DES implantation was associated with a lower incidence of death or MI, a finding that has immediate implications for clinical practice. In a large consecutive cohort of contemporary patients receiving PCI, the long-term risk for death and major cardiac events was significantly increased among patients in the DES group who had discontinued clopidogrel therapy at 6 or 12 months.In a large consecutive cohort of contemporary patients receiving PCI, the long-term risk for death and major cardiac events was significantly increased among patients in the DES group who had discontinued clopidogrel therapy at 6 or 12 months. Extended-duration clopidogrel therapy following DES implantation was associated with a lower incidence of death or MI, a finding that has immediate implications for clinical practice.Extended-duration clopidogrel therapy following DES implantation was associated with a lower incidence of death or MI, a finding that has immediate implications for clinical practice. Eisenstein et al. JAMA. 2007 Jan 10; 297 (2): 159 – 68.