Clopidogrel Use and Long-term Clinical Outcomes After Drug-Eluting Stent Implantation

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Clopidogrel Use and Long-term Clinical Outcomes After

Drug-Eluting Stent Implantation

Clopidogrel Use and Long-term Clinical Outcomes After

Drug-Eluting Stent Implantation

Eric Eisenstein, DBA; Kevin Anstrom, PhD; David Kong, MD; Eric Eisenstein, DBA; Kevin Anstrom, PhD; David Kong, MD; Linda Shaw, MS; Robert Tuttle, MSPH; Daniel Mark, MD, MPH; Linda Shaw, MS; Robert Tuttle, MSPH; Daniel Mark, MD, MPH;

Judith Kramer, MD, MS; Robert Harrington, MD; David Matchar, Judith Kramer, MD, MS; Robert Harrington, MD; David Matchar, MD; David Kandzari, MD; Eric Peterson, MD, MPH; Kevin MD; David Kandzari, MD; Eric Peterson, MD, MPH; Kevin

Schulman, MD; Robert Califf, MD Schulman, MD; Robert Califf, MD

Published in JAMAPublished in JAMA

January 10, 2007January 10, 2007

Clopidogrel Use and Long-term Clinical Outcomes After Drug-Eluting Stent Implantation

Clopidogrel Use and Long-term Clinical Outcomes After Drug-Eluting Stent Implantation


Clopidogrel Use and Long-term Clinical Outcomes After Drug-Eluting Stent Implantation: Background

Clopidogrel Use and Long-term Clinical Outcomes After Drug-Eluting Stent Implantation: Background

• Instructions for the use of drug-eluting stents (DES) Instructions for the use of drug-eluting stents (DES) commercially available in the U.S. specify treatment with commercially available in the U.S. specify treatment with clopidogrel for at least 3 months (for sirolimus-coated clopidogrel for at least 3 months (for sirolimus-coated stents) or 6 months (for paclitaxel-coated stents) after stents) or 6 months (for paclitaxel-coated stents) after implantationimplantation

• However, studies of late thrombosis events among patients However, studies of late thrombosis events among patients with DES have cast doubt on whether the recommended with DES have cast doubt on whether the recommended regimens are sufficientregimens are sufficient

• This study assessed the association between clopidogrel This study assessed the association between clopidogrel use and long-term rates of death and death or MI following use and long-term rates of death and death or MI following initial percutaneous coronary intervention (PCI) with DES or initial percutaneous coronary intervention (PCI) with DES or bare-metal stents (BMS)bare-metal stents (BMS)

• Instructions for the use of drug-eluting stents (DES) Instructions for the use of drug-eluting stents (DES) commercially available in the U.S. specify treatment with commercially available in the U.S. specify treatment with clopidogrel for at least 3 months (for sirolimus-coated clopidogrel for at least 3 months (for sirolimus-coated stents) or 6 months (for paclitaxel-coated stents) after stents) or 6 months (for paclitaxel-coated stents) after implantationimplantation

• However, studies of late thrombosis events among patients However, studies of late thrombosis events among patients with DES have cast doubt on whether the recommended with DES have cast doubt on whether the recommended regimens are sufficientregimens are sufficient

• This study assessed the association between clopidogrel This study assessed the association between clopidogrel use and long-term rates of death and death or MI following use and long-term rates of death and death or MI following initial percutaneous coronary intervention (PCI) with DES or initial percutaneous coronary intervention (PCI) with DES or bare-metal stents (BMS)bare-metal stents (BMS)

Eisenstein et al. JAMA. 2007 Jan 10; 297 (2): 159 – 68.Eisenstein et al. JAMA. 2007 Jan 10; 297 (2): 159 – 68.


Clopidogrel Use and Long-term Clinical Outcomes After Drug-Eluting Stent Implantation: Study Design


• Landmark analysis used, and two landmarks were used in Landmark analysis used, and two landmarks were used in this study: this study:

– Starting at 6-months following PCI onward Starting at 6-months following PCI onward


• At the 6-month and 12-month landmark times, the patients At the 6-month and 12-month landmark times, the patients were divided into four groups for analysis: DES with were divided into four groups for analysis: DES with clopidogrel, DES without clopidogrel, BMS with clopidogrel, DES without clopidogrel, BMS with clopidogrel, and BMS without clopidogrel. clopidogrel, and BMS without clopidogrel.

• Outcomes for these groups were evaluated up to 24 Outcomes for these groups were evaluated up to 24 months after initial PCI procedure.months after initial PCI procedure.

• Landmark analysis used, and two landmarks were used in Landmark analysis used, and two landmarks were used in this study: this study:



• At the 6-month and 12-month landmark times, the patients At the 6-month and 12-month landmark times, the patients were divided into four groups for analysis: DES with were divided into four groups for analysis: DES with clopidogrel, DES without clopidogrel, BMS with clopidogrel, DES without clopidogrel, BMS with clopidogrel, and BMS without clopidogrel. clopidogrel, and BMS without clopidogrel.

• Outcomes for these groups were evaluated up to 24 Outcomes for these groups were evaluated up to 24 months after initial PCI procedure.months after initial PCI procedure.





Outcomes analyzed for Death, Nonfatal MI, and Death or MIOutcomes analyzed for Death, Nonfatal MI, and Death or MI Outcomes analyzed for Death, Nonfatal MI, and Death or MIOutcomes analyzed for Death, Nonfatal MI, and Death or MI

DESDESn=1,501n=1,501


BMSBMSn=3,165n=3,165


4,666 patients undergoing PCI with BMS or DES4,666 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.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 Exclusion Criteria: prior CABG surgery or PCI procedure, significant (>75% stenosis) left main coronary artery disease, interventions other than stent placement during PCIartery disease, interventions other than stent placement during PCI




24 mos. follow-up 24 mos. follow-up

Stent type at Baseline Stent type at Baseline

6 mos. Landmark Analysis 6 mos. Landmark Analysis





ClopidogrelClopidogreln=637n=637


No ClopidogrelNo Clopidogreln=579n=579


No ClopidogrelNo Clopidogreln=1,976n=1,976







Outcomes analyzed for Death, Nonfatal MI, and Death or MIOutcomes analyzed for Death, Nonfatal MI, and Death or MI Outcomes analyzed for Death, Nonfatal MI, and Death or MIOutcomes analyzed for Death, Nonfatal MI, and Death or MI










24 mos. follow-up 24 mos. follow-up

Stent type at Baseline Stent type at Baseline

12 mos. Landmark Analysis 12 mos. Landmark Analysis

DESDESn=528n=528DESDES

n=528n=528BMSBMS

n=1,990n=1,990BMSBMS

n=1,990n=1,990










CharacteristicCharacteristicDES w/DES w/ Clop.Clop.

(n=637 )(n=637 )

DES w/oDES w/oClopClop

(n=579)(n=579)

BMS w/BMS w/Clop.Clop.

(n=417)(n=417)

BMS w/oBMS w/oClop.Clop.

(n= 1,976)(n= 1,976)

P for P for TrendTrend

Age, Median (IQR)Age, Median (IQR) 61 (53-71)61 (53-71) 60 (53-70)60 (53-70) 61 (53-70)61 (53-70) 61 (52-71)61 (52-71) 0.730.73

Black race (%)Black race (%) 121 (19.0)121 (19.0) 137 (23.7)137 (23.7) 82 (19.7)82 (19.7) 395 (20.0)395 (20.0) 0.180.18

Male Sex (%)Male Sex (%) 398 (62.5)398 (62.5) 368 (63.6)368 (63.6) 266 (63.8)266 (63.8) 1,233 (62.4)1,233 (62.4) 0.930.93

History of Diabetes History of Diabetes (%)(%) 171 (26.8)171 (26.8) 171 (29.5)171 (29.5) 121 (29.0)121 (29.0) 449 (22.7)449 (22.7) 0.0010.001

History of CHF (%)History of CHF (%) 60 (9.6)60 (9.6) 82 (14.5)82 (14.5) 38 (9.3)38 (9.3) 208 (11.0)208 (11.0) 0.030.03

History of MI (%)History of MI (%) 247 (38.8)247 (38.8) 221 (38.2)221 (38.2) 213 (51.1)213 (51.1) 913 (46.2)913 (46.2) <0.001<0.001

No of Diseased No of Diseased VesselsVessels 11 22 33

370 (58.1)370 (58.1)186 (29.2)186 (29.2)81 (12.7)81 (12.7)

356 (61.5)356 (61.5)178 (30.7)178 (30.7)

45 (7.8)45 (7.8)

275 (65.9)275 (65.9)109 (26.1)109 (26.1)

33 (7.9)33 (7.9)

1,331 (67.4)1,331 (67.4)531 (26.9)531 (26.9)114 (5.8)114 (5.8)

<0.001<0.001

Clopidogrel Use and Long-term Clinical Outcomes After Drug-Eluting Stent Implantation: Baseline Characteristics for 6 mos. patients




CharacteristicCharacteristicDES w/ DES w/ Clop.Clop.

(n=637 )(n=637 )


(n=579)(n=579)


(n=417)(n=417)


(n=1,976 )(n=1,976 )


Income, median Income, median $ In thousands$ In thousands 36.536.5 35.435.4 35.135.1 33.133.1 <0.001<0.001

Avg House Val, $ Avg House Val, $ In thousandsIn thousands 82.982.9 82.682.6 80.480.4 75.775.7 0.0060.006

Aspirin use atAspirin use at 6 mos.6 mos. 12 mos.12 mos. 24 mos.24 mos.

600 (94.2)600 (94.2)478 (91.2)478 (91.2)179 (93.2)179 (93.2)

430 (74.3)430 (74.3)371 (86.3)371 (86.3)148 (85.6)148 (85.6)

360 (86.3)360 (86.3)335 (84.0)335 (84.0)304 (82.2)304 (82.2)

1583 (80.1)1583 (80.1)1569 (85.0)1569 (85.0)1541 (87.1)1541 (87.1)

<0.001<0.0010.0030.0030.0030.003

Clop. use atClop. use at 6 mos.6 mos. 12 mos.12 mos. 24 mos.24 mos.

637 (100)637 (100)382 (72.9)382 (72.9)106 (55.2)106 (55.2)

0 (0)0 (0)64 (14.9)64 (14.9)25 (14.5)25 (14.5)

417 (100)417 (100)309 (77.4)309 (77.4)230 (62.2)230 (62.2)

0 (0)0 (0)93 (5.0)93 (5.0)

143 (8.1)143 (8.1)

<0.001<0.001<0.001<0.001<0.001<0.001





CharacteristicCharacteristicDES w/ DES w/

Clop.Clop.(n=252 )(n=252 )


(n=276)(n=276)


(n=346)(n=346)


(n=1,644 )(n=1,644 )


Age, Median (IQR)Age, Median (IQR) 61 (53-70)61 (53-70) 61 (53-70)61 (53-70) 62 (53-72)62 (53-72) 62 (53-72)62 (53-72) 0.760.76

Black race (%)Black race (%) 36 (14.3)36 (14.3) 62 (22.5)62 (22.5) 69 (19.9)69 (19.9) 310 (18.9)310 (18.9) 0.120.12

Male Sex (%)Male Sex (%) 164 (65.1)164 (65.1) 170 (61.6)170 (61.6) 204 (59.0)204 (59.0) 1,031 (62.7)1,031 (62.7) 0.450.45

History of Diabetes History of Diabetes (%)(%) 69 (27.4)69 (27.4) 79 (28.6)79 (28.6) 109 (31.5)109 (31.5) 364 (22.1)364 (22.1) <0.001<0.001

History of CHF (%)History of CHF (%) 25 (10.0)25 (10.0) 27 (10.0)27 (10.0) 29 (8.5)29 (8.5) 163 (10.0)163 (10.0) 0.870.87

History of MI (%)History of MI (%) 95 (37.7)95 (37.7) 94 (34.1)94 (34.1) 170 (49.1)170 (49.1) 745 (45.3)745 (45.3) <0.001<0.001

No of Diseased No of Diseased VesselsVessels 11 22 33

144 (57.1)144 (57.1)78 (31.0)78 (31.0)30 (11.9)30 (11.9)

173 (62.7)173 (62.7)83 (30.1)83 (30.1)20 (7.3)20 (7.3)

223 (64.5)223 (64.5)98 (28.3)98 (28.3)25 (7.2)25 (7.2)

1,130 (68.7)1,130 (68.7)427 (26.0)427 (26.0)

87 (5.3)87 (5.3)<0.001<0.001

Clopidogrel Use and Long-term Clinical Outcomes After Drug-Eluting Stent Implantation: Baseline Characteristics for 12-mos. Patients




CharacteristicCharacteristicDES w/ DES w/ Clop.Clop.

(n=252 )(n=252 )


(n=276)(n=276)


(n=346)(n=346)


(n=1,644 )(n=1,644 )


Income, median Income, median $ In thousands$ In thousands 35.435.4 36.036.0 33.133.1 33.133.1 0.130.13

Avg House Val, $ Avg House Val, $ In thousandsIn thousands 80.980.9 82.982.9 78.178.1 75.775.7 0.300.30

Aspirin use atAspirin use at 6 mos.6 mos. 12 mos.12 mos. 24 mos.24 mos.

223 (88.5)223 (88.5)234 (92.9)234 (92.9)140 (94.0)140 (94.0)

235 (85.1)235 (85.1)236 (85.5)236 (85.5)151 (86.8)151 (86.8)

277 (80.1)277 (80.1)295 (85.3)295 (85.3)257 (81.1)257 (81.1)

1373 (83.5)1373 (83.5)1398 (85.0)1398 (85.0)1360 (88.1)1360 (88.1)

0.0450.0450.010.01

<0.001<0.001

Clop. use atClop. use at 6 mos.6 mos. 12 mos.12 mos. 24 mos.24 mos.

218 (86.5)218 (86.5)252 (100)252 (100)104 (69.8)104 (69.8)

68 (24.6)68 (24.6)0 (0)0 (0)

14 (8.1)14 (8.1)

271 (78.3)271 (78.3)346 (100)346 (100)221 (69.7)221 (69.7)

74 (4.5)74 (4.5)0 (0)0 (0)

85 (5.5)85 (5.5)

<0.001<0.001<0.001<0.001<0.001<0.001





Clopidogrel Use and Long-term Clinical Outcomes After Drug-Eluting Stent Implantation: Main Outcome MeasuresClopidogrel Use and Long-term Clinical Outcomes After

Drug-Eluting Stent Implantation: Main Outcome Measures

2.0%

5.3%

3.7%4.5%

0%

2%

4%

6%

8%

10%

DES + Clop DES - Clop BMS + Clop BMS - Clop

2.0%

5.3%

3.7%4.5%

0%

2%

4%

6%

8%

10%


En

dp

oin

t (

%)

En

dp

oin

t (

%)

• Adjusted outcomes Adjusted outcomes were analyzed at 24 were analyzed at 24 monthsmonths

• Patients in the DES Patients in the DES with clop. group with clop. group had significantly had significantly lower rates of death lower rates of death than did patients in than did patients in the DES without the DES without clopidogrel groupclopidogrel group

• Among BMS Among BMS patients, there were patients, there were no differences in no differences in deathdeath

• No difference was No difference was observed in observed in nonfatal MInonfatal MI

Difference=-3.3Difference=-3.3±3 ±3

p=0.03p=0.03Difference=-0.7Difference=-0.7±2.1±2.1

p =0.50p =0.50

Adjusted rates of Death for Analysis Starting at 6-monthsAdjusted rates of Death for Analysis Starting at 6-months





3.1%

7.2%

5.5%6.0%

0%

2%

4%

6%

8%

10%


3.1%

7.2%

5.5%6.0%

0%

2%

4%

6%

8%

10%


En

dp

oin

t (

%)

En

dp

oin

t (

%)

• Adjusted Adjusted outcomes were outcomes were analyzed at 24 analyzed at 24 monthsmonths

• Patients in the Patients in the DES with clop. DES with clop. group had group had significantly significantly lower rates of lower rates of death or MI than death or MI than did patients in did patients in the DES without the DES without clopidogrel clopidogrel groupgroup

• Among BMS Among BMS patients, there patients, there were no were no differences in differences in death or MIdeath or MI

Difference=-4.1Difference=-4.1±3.5±3.5

p 0.02p 0.02

Difference=-0.5Difference=-0.5±2.7±2.7

p=0.70p=0.70

Adjusted rates of Death or MI Starting at 6 mos.Adjusted rates of Death or MI Starting at 6 mos.





0.0%

3.5% 3.3%2.7%

0%

2%

4%

6%

8%

10%


0.0%

3.5% 3.3%2.7%

0%

2%

4%

6%

8%

10%


En

dp

oin

t (

%)

En

dp

oin

t (

%)


• Patients in the Patients in the DES with clop. DES with clop. group had group had significantly significantly lower rates of lower rates of death than did death than did patients in the patients in the DES without DES without clopidogrel groupclopidogrel group

• Among BMS Among BMS patients, there patients, there were no were no differences in differences in deathdeath

Difference=-3.5Difference=-3.5±2.4 ±2.4

p=0.004p=0.004Difference=0.6Difference=0.6±2.1 ±2.1

p=0.57p=0.57

Adjusted rates of Death for Analysis Starting at 12-mos.Adjusted rates of Death for Analysis Starting at 12-mos.





0.0%

4.5% 4.7%

3.6%

0%

2%

4%

6%

8%

10%


0.0%

4.5% 4.7%

3.6%

0%

2%

4%

6%

8%

10%


En

dp

oin

t (

%)

En

dp

oin

t (

%)


• Patients in the Patients in the DES with clop. DES with clop. group had group had significantly significantly lower rates of lower rates of death or MI than death or MI than did patients in did patients in the DES without the DES without clopidogrel groupclopidogrel group

• Among BMS Among BMS patients, there patients, there were no were no differences in differences in death or MIdeath or MI

Difference=-4.5Difference=-4.5±2.6 ±2.6

p<0.001p<0.001

Difference=1.0Difference=1.0±2.6±2.6

p=0.44p=0.44

Adjusted rates of Death or MI Analysis Starting at 12-mos.Adjusted rates of Death or MI Analysis Starting at 12-mos.



Clopidogrel Use and Long-term Clinical Outcomes After Drug-Eluting Stent Implantation: Limitations


• Clopidogrel use was not randomly Clopidogrel use was not randomly assigned; thus, the decision to continue the assigned; thus, the decision to continue the drug beyond the periods recommended by drug beyond the periods recommended by the relevant clinical trials may have been the relevant clinical trials may have been correlated with unmeasured prognostic correlated with unmeasured prognostic factors.factors.

• Clopidogrel use was not randomly Clopidogrel use was not randomly assigned; thus, the decision to continue the assigned; thus, the decision to continue the drug beyond the periods recommended by drug beyond the periods recommended by the relevant clinical trials may have been the relevant clinical trials may have been correlated with unmeasured prognostic correlated with unmeasured prognostic factors.factors.





• Clopidogrel use in this analysis was identified by Clopidogrel use in this analysis was identified by patient report at 2 discrete points (6- and 12-month patient report at 2 discrete points (6- and 12-month follow-up). Therefore, these data are subject to follow-up). Therefore, these data are subject to recall bias.recall bias.

• Furthermore, the indications and rationale for long-Furthermore, the indications and rationale for long-term clopidogrel regimens and for its term clopidogrel regimens and for its discontinuations were not collected.discontinuations were not collected.

• Clopidogrel use in this analysis was identified by Clopidogrel use in this analysis was identified by patient report at 2 discrete points (6- and 12-month patient report at 2 discrete points (6- and 12-month follow-up). Therefore, these data are subject to follow-up). Therefore, these data are subject to recall bias.recall bias.

• Furthermore, the indications and rationale for long-Furthermore, the indications and rationale for long-term clopidogrel regimens and for its term clopidogrel regimens and for its discontinuations were not collected.discontinuations were not collected.





• The 24-month event rates of 0% for death, nonfatal MI, and The 24-month event rates of 0% for death, nonfatal MI, and death or MI for the DES with clopidogrel group in the 12-death or MI for the DES with clopidogrel group in the 12-month landmark analysis may underestimate the true event month landmark analysis may underestimate the true event rates. However, 14 patients receiving DES died or had a rates. However, 14 patients receiving DES died or had a nonfatal MI, and none of these 14 patients was in the DES nonfatal MI, and none of these 14 patients was in the DES with clopidogrel group.with clopidogrel group.

• Extended clopidogrel therapy has its own risks and this Extended clopidogrel therapy has its own risks and this analysis does not evaluate the long-term nonfatal analysis does not evaluate the long-term nonfatal implications of its use. implications of its use.

• The 24-month event rates of 0% for death, nonfatal MI, and The 24-month event rates of 0% for death, nonfatal MI, and death or MI for the DES with clopidogrel group in the 12-death or MI for the DES with clopidogrel group in the 12-month landmark analysis may underestimate the true event month landmark analysis may underestimate the true event rates. However, 14 patients receiving DES died or had a rates. However, 14 patients receiving DES died or had a nonfatal MI, and none of these 14 patients was in the DES nonfatal MI, and none of these 14 patients was in the DES with clopidogrel group.with clopidogrel group.

• Extended clopidogrel therapy has its own risks and this Extended clopidogrel therapy has its own risks and this analysis does not evaluate the long-term nonfatal analysis does not evaluate the long-term nonfatal implications of its use. implications of its use.



Clopidogrel Use and Long-term Clinical Outcomes After Drug-Eluting Stent Implantation: Summary

Clopidogrel Use and Long-term Clinical Outcomes After Drug-Eluting Stent Implantation: Summary

• In a large consecutive cohort of contemporary patients In a large consecutive cohort of contemporary patients receiving PCI, the long-term risk for death and major receiving PCI, the long-term risk for death and major cardiac events was significantly increased among cardiac events was significantly increased among patients in the DES group who had discontinued patients in the DES group who had discontinued clopidogrel therapy at 6 or 12 months.clopidogrel therapy at 6 or 12 months.

• Extended-duration clopidogrel therapy following DES Extended-duration clopidogrel therapy following DES implantation was associated with a lower incidence of implantation was associated with a lower incidence of death or MI, a finding that has immediate implications death or MI, a finding that has immediate implications for clinical practice.for clinical practice.

• In a large consecutive cohort of contemporary patients In a large consecutive cohort of contemporary patients receiving PCI, the long-term risk for death and major receiving PCI, the long-term risk for death and major cardiac events was significantly increased among cardiac events was significantly increased among patients in the DES group who had discontinued patients in the DES group who had discontinued clopidogrel therapy at 6 or 12 months.clopidogrel therapy at 6 or 12 months.

• Extended-duration clopidogrel therapy following DES Extended-duration clopidogrel therapy following DES implantation was associated with a lower incidence of implantation was associated with a lower incidence of death or MI, a finding that has immediate implications death or MI, a finding that has immediate implications for clinical practice.for clinical practice.


Clopidogrel Use and Long-term Clinical Outcomes After Drug-Eluting Stent Implantation

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