JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 64, NO. 9, 2014
ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER INC.
Letters
Short Versus Long Duration of DAPT After DES Implantation: A Meta-Analysis
OPTIMIZE
(Optimized
Duration
of
Clopidogrel
Therapy Following Treatment With the Endeavor Zotarolimus-Eluting Stent in Real World Clinical Practice) (5). Results are presented in Figure 1. Short-term DAPT was associated with a reduced risk of any bleeding as compared with guidelinerecommended DAPT (RR: 0.64; 95% confidence interval: 0.46 to 0.89). Risks of cardiac death or MI
The optimal duration of dual antiplatelet therapy
(RR: 1.08; 95% confidence interval: 0.89 to 1.32)
(DAPT) after percutaneous coronary intervention
and stent thrombosis (RR: 1.24; 95% confidence
(PCI) with drug-eluting stents (DES) has not been
interval: 0.76 to 2.02) did not differ between short-
determined. Current American College of Cardiology
term
Foundation/American Heart Association (ACCF/AHA)
There was no significant heterogeneity across trials
guidelines recommend 12-month DAPT on the basis of
for the analyzed outcomes.
DAPT
and
guideline-recommended
DAPT.
observational evidence suggesting an increased risk
Little evidence is available on the optimal duration
of stent thrombosis after premature cessation of DAPT
of DAPT after DES implantation. Pivotal DES trials
(1). We performed a meta-analysis of randomized
applied short-term DAPT (2 to 6 months). However,
trials comparing short-term DAPT (#6 months)
in 2006, observational findings from more complex
with ACCF/AHA guideline–recommended duration
patient populations revealed an increased risk of
of DAPT (at least 12 months) among patients
stent thrombosis after premature discontinuation
undergoing PCI with DES.
of DAPT. The U.S. Food and Drug Administration
In March 2014, we searched PubMed, EMBASE,
convened an expert advisory board meeting to
and Cochrane Clinical Trials for published random-
address the safety issues surrounding use of DES,
ized trials directly comparing short-term DAPT
which led to the implementation of at least a
(#6 months) with ACCF/AHA guideline–recommended
12-month duration of DAPT after DES implanta-
DAPT (at least 12 months) after PCI with DES. Risk
tion in the ACCF/AHA guidelines (1). Since that time,
ratios (RRs) were applied as the metric of choice for
several randomized trials have investigated different
treatment effects using random- and fixed-effects
durations of DAPT. In our meta-analysis, we included
models. I-square index was used to assess heteroge-
trials directly comparing short-term with ACCF/
neity across trials. The primary safety and efficacy
AHA guideline–recommended DAPT, all of which
outcomes were any bleeding and the composite
were powered for composite clinical endpoints.
of cardiac death and myocardial infarction (MI),
We provide evidence of a significant bleeding risk
respectively. The secondary efficacy outcome was
reduction with short-term DAPT compared with
definite or probable stent thrombosis. Meta-analyses
ACCF/AHA guideline–recommended DAPT after DES
were performed using Stata software (StataCorp,
implantation. The reduced risk of bleeding was
College Station, Texas).
paralleled by similar risks of cardiac death or MI as
Four eligible trials were identified that included
well as stent thrombosis with the 2 DAPT regimens,
8,649 patients with at least 12 months of follow-
suggesting that short-term DAPT is associated with
up: EXCELLENT (Efficacy of Xience/Promus Versus
a safety benefit while preserving antithrombotic
Cypher to Reduce Late Loss After Stenting) (2),
efficacy.
PRODIGY (PROlonging Dual Antiplatelet Treatment
Stenting and Antithrombotic Regimen: Safety And
In Patients With Coronary Artery Disease After
EFficacy of Six Months Dual Antiplatelet Therapy
Graded Stent-induced Intimal Hyperplasia study)
After Drug-Eluting Stenting) trial plans inclusion of
(3), RESET (REal Safety and Efficacy of 3-month
6,000 patients to test noninferiority of 6-month
dual
DAPT
antiplatelet
Therapy
following
Endeavor
zotarolimus-eluting stent implantation) (4), and
The
ongoing
compared
with
ISAR-SAFE
12-month
(Intracoronary
DAPT
for
the
composite endpoint of death, MI, stent thrombosis,
JACC VOL. 64, NO. 9, 2014
Letters
954
SEPTEMBER 2, 2014:953–8
of bleeding but preserved antithrombotic efficacy Short DAPT
Standard DAPT
RR (95% CI)
EXCELLENT
4/722
10/721
0.40 (0.13, 1.27)
PRODIGY
15/983
27/987
0.56 (0.30, 1.04)
RESET
5/1,059
10/1,058
0.50 (0.17, 1.46)
OPTIMIZE
35/1,563
45/1,556
0.77 (0.50, 1.20)
compared with guideline-recommended 12-month DAPT after DES implantation. These hypothesis-
Bleeding
REM (I−squared = 0.0%, p = 0.623)
0.65 (0.47, 0.89)
FEM
0.64 (0.46, 0.89)
Cardiac Death or MI EXCELLENT
17/722
14/721
1.21 (0.60, 2.44)
PRODIGY
94/983
88/987
1.07 (0.81, 1.41)
RESET
4/1,059
7/1,058
0.57 (0.17, 1.94)
OPTIMIZE
70/1,563 62/1,556
1.12 (0.80, 1.57)
REM (I−squared = 0.0%, p = 0.753)
1.08 (0.89, 1.33)
FEM
1.08 (0.89, 1.32)
Stent Thrombosis EXCELLENT
6/722
1/721
5.99 (0.72, 49.64)
PRODIGY
15/983
13/987
1.16 (0.55, 2.42)
RESET
2/1,059
3/1,058
0.67 (0.11, 3.98)
OPTIMIZE
13/1,563
12/1,556
1.08 (0.49, 2.36)
REM (I−squared = 0.0%, p = 0.431)
1.18 (0.72, 1.95)
FEM
1.24 (0.76, 2.02)
generating
findings
need
to
be
confirmed
by
adequately powered randomized trials.
Giulio G. Stefanini, MDy George C.M. Siontis, MDy Davide Cao, MDy Dik Heg, PhDz Peter Jüni, MDz *Stephan Windecker, MDy *Department of Cardiology Bern University Hospital 3010 Bern, Switzerland E-mail: [email protected] http://dx.doi.org/10.1016/j.jacc.2014.06.1158
0.1
0.2
0.5
Short DAPT Better
1 Risk Ratio
2
5
10
Standard DAPT Better
F I G U R E 1 Clinical Outcomes With Short (#6 Months) Versus Standard
(At Least 12 Months) DAPT
The extracted number of events was based on intention-to-treat analysis in each study. The composite of all-cause death or MI was extracted for the EXCELLENT and PRODIGY trials, because the composite of cardiac death or MI was not reported. CI ¼ confidence interval; DAPT ¼ dual antiplatelet therapy; EXCELLENT ¼ Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting; FEM ¼ fixed-effects models; MI ¼ myocardial infarction; PRODIGY ¼ PROlonging Dual Antiplatelet Treatment In Patients With Coronary Artery Disease After Graded Stent-induced Intimal Hyperplasia study; REM ¼ random-effects models; RR ¼ risk ratio.
stroke, or bleeding, assuming an event rate of 10% and specifying a noninferiority margin of 1.2, with 80% power and an alpha level of 0.05 (NCT00661206). This meta-analysis needs to be interpreted in light of the following limitations. First, findings need to be considered average effects because we did not have access to patient-level data; as such, they may not apply across specific subgroups. Sec-
From the yDepartment of Cardiology, Bern University Hospital, Bern, Switzerland; and zCTU Bern, Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland. Please note: CTU Bern, which is part of the University of Bern, has a staff policy of not accepting honoraria or consultancy fees. However, CTU Bern is involved in the design, conduct, or analysis of clinical studies funded by Abbott Vascular, Ablynx, Amgen, AstraZeneca, Biosensors, Biotronik, Boehringer Ingelheim, Eisai, Eli Lilly, Exelixis, Geron, Gilead Sciences, Nestlé, Novartis, Novo Nordisk, Padma, Roche, Schering-Plough, St. Jude Medical, and Swiss Cardio Technologies. Dr. Stefanini has received speaker fees from Abbott Vascular, Biosensors, and Biotronik. Dr. Jüni is an unpaid steering committee or statistical executive committee member of trials funded by Abbott Vascular, Biosensors, Medtronic, and Johnson & Johnson. Dr. Windecker’s institution has received research grants from Biotronik and St. Jude Medical. All other authors have reported they have no relationships relevant to the contents of this paper to disclose.
REFERENCES 1. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol 2011;58:e44–122. 2. Gwon HC, Hahn JY, Park KW, et al. Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized, multicenter study. Circulation 2012; 125:505–13.
ond, short-term DAPT regimens varied between the included trials. The optimal duration of shortterm DAPT will need to be investigated in future studies. Third, different DES were used in the included trials and results may vary according to DES type. Finally, our findings are limited to clopidogrel and may differ with the use of newer P2Y 12 inhibitors. In conclusion, this meta-analysis indicates that short-term DAPT is associated with a reduced risk
3. Valgimigli M, Campo G, Monti M, et al. Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation 2012;125:2015–26. 4. Kim BK, Hong MK, Shin DH, et al. A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation). J Am Coll Cardiol 2012;60: 1340–8. 5. Feres F, Costa RA, Abizaid A, et al. Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial. JAMA 2013;310:2510–22.
VOL. 64, NO. 9, 2014
ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER INC.
Letters
Short Versus Long Duration of DAPT After DES Implantation: A Meta-Analysis
OPTIMIZE
(Optimized
Duration
of
Clopidogrel
Therapy Following Treatment With the Endeavor Zotarolimus-Eluting Stent in Real World Clinical Practice) (5). Results are presented in Figure 1. Short-term DAPT was associated with a reduced risk of any bleeding as compared with guidelinerecommended DAPT (RR: 0.64; 95% confidence interval: 0.46 to 0.89). Risks of cardiac death or MI
The optimal duration of dual antiplatelet therapy
(RR: 1.08; 95% confidence interval: 0.89 to 1.32)
(DAPT) after percutaneous coronary intervention
and stent thrombosis (RR: 1.24; 95% confidence
(PCI) with drug-eluting stents (DES) has not been
interval: 0.76 to 2.02) did not differ between short-
determined. Current American College of Cardiology
term
Foundation/American Heart Association (ACCF/AHA)
There was no significant heterogeneity across trials
guidelines recommend 12-month DAPT on the basis of
for the analyzed outcomes.
DAPT
and
guideline-recommended
DAPT.
observational evidence suggesting an increased risk
Little evidence is available on the optimal duration
of stent thrombosis after premature cessation of DAPT
of DAPT after DES implantation. Pivotal DES trials
(1). We performed a meta-analysis of randomized
applied short-term DAPT (2 to 6 months). However,
trials comparing short-term DAPT (#6 months)
in 2006, observational findings from more complex
with ACCF/AHA guideline–recommended duration
patient populations revealed an increased risk of
of DAPT (at least 12 months) among patients
stent thrombosis after premature discontinuation
undergoing PCI with DES.
of DAPT. The U.S. Food and Drug Administration
In March 2014, we searched PubMed, EMBASE,
convened an expert advisory board meeting to
and Cochrane Clinical Trials for published random-
address the safety issues surrounding use of DES,
ized trials directly comparing short-term DAPT
which led to the implementation of at least a
(#6 months) with ACCF/AHA guideline–recommended
12-month duration of DAPT after DES implanta-
DAPT (at least 12 months) after PCI with DES. Risk
tion in the ACCF/AHA guidelines (1). Since that time,
ratios (RRs) were applied as the metric of choice for
several randomized trials have investigated different
treatment effects using random- and fixed-effects
durations of DAPT. In our meta-analysis, we included
models. I-square index was used to assess heteroge-
trials directly comparing short-term with ACCF/
neity across trials. The primary safety and efficacy
AHA guideline–recommended DAPT, all of which
outcomes were any bleeding and the composite
were powered for composite clinical endpoints.
of cardiac death and myocardial infarction (MI),
We provide evidence of a significant bleeding risk
respectively. The secondary efficacy outcome was
reduction with short-term DAPT compared with
definite or probable stent thrombosis. Meta-analyses
ACCF/AHA guideline–recommended DAPT after DES
were performed using Stata software (StataCorp,
implantation. The reduced risk of bleeding was
College Station, Texas).
paralleled by similar risks of cardiac death or MI as
Four eligible trials were identified that included
well as stent thrombosis with the 2 DAPT regimens,
8,649 patients with at least 12 months of follow-
suggesting that short-term DAPT is associated with
up: EXCELLENT (Efficacy of Xience/Promus Versus
a safety benefit while preserving antithrombotic
Cypher to Reduce Late Loss After Stenting) (2),
efficacy.
PRODIGY (PROlonging Dual Antiplatelet Treatment
Stenting and Antithrombotic Regimen: Safety And
In Patients With Coronary Artery Disease After
EFficacy of Six Months Dual Antiplatelet Therapy
Graded Stent-induced Intimal Hyperplasia study)
After Drug-Eluting Stenting) trial plans inclusion of
(3), RESET (REal Safety and Efficacy of 3-month
6,000 patients to test noninferiority of 6-month
dual
DAPT
antiplatelet
Therapy
following
Endeavor
zotarolimus-eluting stent implantation) (4), and
The
ongoing
compared
with
ISAR-SAFE
12-month
(Intracoronary
DAPT
for
the
composite endpoint of death, MI, stent thrombosis,
JACC VOL. 64, NO. 9, 2014
Letters
954
SEPTEMBER 2, 2014:953–8
of bleeding but preserved antithrombotic efficacy Short DAPT
Standard DAPT
RR (95% CI)
EXCELLENT
4/722
10/721
0.40 (0.13, 1.27)
PRODIGY
15/983
27/987
0.56 (0.30, 1.04)
RESET
5/1,059
10/1,058
0.50 (0.17, 1.46)
OPTIMIZE
35/1,563
45/1,556
0.77 (0.50, 1.20)
compared with guideline-recommended 12-month DAPT after DES implantation. These hypothesis-
Bleeding
REM (I−squared = 0.0%, p = 0.623)
0.65 (0.47, 0.89)
FEM
0.64 (0.46, 0.89)
Cardiac Death or MI EXCELLENT
17/722
14/721
1.21 (0.60, 2.44)
PRODIGY
94/983
88/987
1.07 (0.81, 1.41)
RESET
4/1,059
7/1,058
0.57 (0.17, 1.94)
OPTIMIZE
70/1,563 62/1,556
1.12 (0.80, 1.57)
REM (I−squared = 0.0%, p = 0.753)
1.08 (0.89, 1.33)
FEM
1.08 (0.89, 1.32)
Stent Thrombosis EXCELLENT
6/722
1/721
5.99 (0.72, 49.64)
PRODIGY
15/983
13/987
1.16 (0.55, 2.42)
RESET
2/1,059
3/1,058
0.67 (0.11, 3.98)
OPTIMIZE
13/1,563
12/1,556
1.08 (0.49, 2.36)
REM (I−squared = 0.0%, p = 0.431)
1.18 (0.72, 1.95)
FEM
1.24 (0.76, 2.02)
generating
findings
need
to
be
confirmed
by
adequately powered randomized trials.
Giulio G. Stefanini, MDy George C.M. Siontis, MDy Davide Cao, MDy Dik Heg, PhDz Peter Jüni, MDz *Stephan Windecker, MDy *Department of Cardiology Bern University Hospital 3010 Bern, Switzerland E-mail: [email protected] http://dx.doi.org/10.1016/j.jacc.2014.06.1158
0.1
0.2
0.5
Short DAPT Better
1 Risk Ratio
2
5
10
Standard DAPT Better
F I G U R E 1 Clinical Outcomes With Short (#6 Months) Versus Standard
(At Least 12 Months) DAPT
The extracted number of events was based on intention-to-treat analysis in each study. The composite of all-cause death or MI was extracted for the EXCELLENT and PRODIGY trials, because the composite of cardiac death or MI was not reported. CI ¼ confidence interval; DAPT ¼ dual antiplatelet therapy; EXCELLENT ¼ Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting; FEM ¼ fixed-effects models; MI ¼ myocardial infarction; PRODIGY ¼ PROlonging Dual Antiplatelet Treatment In Patients With Coronary Artery Disease After Graded Stent-induced Intimal Hyperplasia study; REM ¼ random-effects models; RR ¼ risk ratio.
stroke, or bleeding, assuming an event rate of 10% and specifying a noninferiority margin of 1.2, with 80% power and an alpha level of 0.05 (NCT00661206). This meta-analysis needs to be interpreted in light of the following limitations. First, findings need to be considered average effects because we did not have access to patient-level data; as such, they may not apply across specific subgroups. Sec-
From the yDepartment of Cardiology, Bern University Hospital, Bern, Switzerland; and zCTU Bern, Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland. Please note: CTU Bern, which is part of the University of Bern, has a staff policy of not accepting honoraria or consultancy fees. However, CTU Bern is involved in the design, conduct, or analysis of clinical studies funded by Abbott Vascular, Ablynx, Amgen, AstraZeneca, Biosensors, Biotronik, Boehringer Ingelheim, Eisai, Eli Lilly, Exelixis, Geron, Gilead Sciences, Nestlé, Novartis, Novo Nordisk, Padma, Roche, Schering-Plough, St. Jude Medical, and Swiss Cardio Technologies. Dr. Stefanini has received speaker fees from Abbott Vascular, Biosensors, and Biotronik. Dr. Jüni is an unpaid steering committee or statistical executive committee member of trials funded by Abbott Vascular, Biosensors, Medtronic, and Johnson & Johnson. Dr. Windecker’s institution has received research grants from Biotronik and St. Jude Medical. All other authors have reported they have no relationships relevant to the contents of this paper to disclose.
REFERENCES 1. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol 2011;58:e44–122. 2. Gwon HC, Hahn JY, Park KW, et al. Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized, multicenter study. Circulation 2012; 125:505–13.
ond, short-term DAPT regimens varied between the included trials. The optimal duration of shortterm DAPT will need to be investigated in future studies. Third, different DES were used in the included trials and results may vary according to DES type. Finally, our findings are limited to clopidogrel and may differ with the use of newer P2Y 12 inhibitors. In conclusion, this meta-analysis indicates that short-term DAPT is associated with a reduced risk
3. Valgimigli M, Campo G, Monti M, et al. Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation 2012;125:2015–26. 4. Kim BK, Hong MK, Shin DH, et al. A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation). J Am Coll Cardiol 2012;60: 1340–8. 5. Feres F, Costa RA, Abizaid A, et al. Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial. JAMA 2013;310:2510–22.
