Mauri et al. Causes of Late Mortality with Dual Antiplatelet Therapy After Coronary Stents
Causes of Late Mortality with Dual Antiplatelet Therapy after Coronary Stents
Laura Mauri, M.D., Sammy Elmariah, M.D., Robert W. Yeh, M.D., Donald E. Cutlip, M.D., P.
Gabriel Steg, M.D., Stephan Windecker, M.D., Stephen D. Wiviott, M.D., David J. Cohen,
M.D., Joseph M. Massaro, P.h.D., Ralph B. D’Agostino, Sr., Ph.D., Eugene Braunwald, M.D.,
Dean J. Kereiakes, M.D., for the DAPT Study Investigators
Supplemental Appendix
Table of Contents
Clinical Events Committee Members ............................................................................................................ 2
Clinical Events Committee Procedures ......................................................................................................... 4
Definitions ..................................................................................................................................................... 6
Additional Statistical Information ................................................................................................................. 7
Tables and Figures ........................................................................................................................................ 8
References .................................................................................................................................................. 13
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Mauri et al. Causes of Late Mortality with Dual Antiplatelet Therapy After Coronary Stents
Clinical Events Committee Members
The Clinical Events Committee (CEC) members who adjudicated all end point events throughout
the course of the trial are listed as follows:
Clinical Events Committee
Adjudicators – Interventional Cardiology
Clifford Berger (Boston Medical Center, Brigham and Women’s Hospital, Boston, MA, US, St.
Elizabeth Medical Center, Brighton, MA, US, Good Samaritan Medical Center, Brockton, MA,
US)
David Litvak (South Shore Hospital, South Weymouth, MA, US, Boston University Medical
Center, Boston, MA, US)
Amjad AlMahameed (Beth Israel Deaconess Medical Center, Boston, MA, US)
Carey Kimmelstiel (Tufts Medical Center, Boston, MA, US)
Adjudicators – Cardiology
Laurence Epstein (Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, US)
Thomas Hauser (Beth Israel Deaconess Medical Center)
Seth McClennen (Brigham and Women’s Hospital, South Shore Hospital)
Eli Gelfand (Beth Israel Deaconess Medical Center, Boston, MA, US)
John Markis (Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, US)
David Gossman (St. Elizabeth Medical Center, Brighton, MA, US)
Peter Oettgen (Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA,
US)
Joseph Kannam (Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA,
US)
Robb Kociol (Beth Israel Deaconess Medical Center, Boston, MA, US)
Adjudicators – Neurology
Megan Leary (Holy Name Medical Center, Teaneck, NJ, US)
David Thaler (Tufts Medical Center, Boston, MA, US)
John Dashe (St. Elizabeth Medical Center, Brighton, MA, US, Tufts Medical Center, Boston,
MA, US)
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Mauri et al. Causes of Late Mortality with Dual Antiplatelet Therapy After Coronary Stents
The additional CEC, convened after the completion of the DAPT Study, further investigated
previously adjudicated deaths of patients in the DAPT Study as to the relatedness to cancer,
bleeding and trauma, and the mechanism of death. The members of this committee are listed as
follows:
Adjudicators:
Clifford Berger (Boston Medical Center, Brigham and Women’s Hospital, Boston, MA, US, St.
Elizabeth Medical Center, Brighton, MA, US, Good Samaritan Medical Center, Brockton, MA,
US)
Gretchen Gignac (Boston Medical Center, Boston, MA)
Thomas Hauser (Beth Israel Deaconess Medical Center, Boston, MA, US)
Andrew Lane (Dana Farber Cancer Institute, Boston, MA)
Ann LaCasce (Dana Farber Cancer Institute, Boston, MA)
Andrew Wagner (Dana Farber Cancer Institute, Boston, MA)
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Mauri et al. Causes of Late Mortality with Dual Antiplatelet Therapy After Coronary Stents
Clinical Events Committee Procedures
All possible primary endpoint events, including death, underwent independent, blinded
adjudication by a Clinical Events Committee (CEC) during the course of the study. Deaths were
classified as cardiac, vascular, or non-cardiovascular, according to ARC definition.1 Specifically,
deaths were considered cardiac if due to an immediate cardiac cause (e.g. MI, low-output failure,
fatal arrhythmia) or if death was unwitnessed and of unknown cause. Vascular death included
death due to cerebrovascular disease, pulmonary embolism, ruptured aortic aneurysm, or other
vascular cause, and non-cardiovascular death included death due to causes not included in the
aforementioned definitions, including infection, malignancy, pulmonary causes, accident,
suicide, or trauma.
Upon recognition of a mortality signal within the primary analysis (DES-treated cohort),2 a
second blinded CEC composed of two cardiologists and four clinical oncologists with experience
in event adjudication was established to review and categorize causes of death as to the
relatedness to bleeding and/or cancer in a blinded fashion. All available source documents from
adverse events, and previously adjudicated events, including death, were provided to this
committee.
All deaths were reviewed regardless of the initial adjudicated cause of death. Clinical reviewers
(Three licensed registered nurses) at the Harvard Clinical Research Institute (HCRI, Boston,
MA) queried all source documents for terms suggestive of cancer or bleeding, and noted the
location of these terms was noted to expedite review by the CEC. All source documents were
then provided to the CEC for event adjudication. Bleeding-related death was categorized as any
death that was possibly, probably or definitely related to any prior clinically evident bleeding
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Mauri et al. Causes of Late Mortality with Dual Antiplatelet Therapy After Coronary Stents
event. Cancer-related deaths were similarly categorized as any death that was possibly, probably,
or definitely related to a given malignancy or complications from treatments specifically
administered for the malignancy. Death with a history of cancer included any death in a patient
with a history of cancer, including those that may have been in remission or cured prior to
enrollment in the study. In addition, the second CEC adjudicated characteristics of the
malignancy, including date of diagnosis, type, stage, classification, location, and treatment type.
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Mauri et al. Causes of Late Mortality with Dual Antiplatelet Therapy After Coronary Stents
Definitions
Deaths may have been classified in more than one category of the following:
Cancer-related death vs. not: Death that was directly related to the progression of a given
malignancy or due to complications from treatments that were administered specifically for the
malignancy (e.g. chemotherapy, radiation, immunotherapy, surgical resection). Cancer-related
deaths were only to be determined when there was sufficient source documentation that
described the subject’s clinical condition and treatment before and at the time of death and/or
when an autopsy report was not available. All other deaths, including those with insufficient
source documentation, un-witnessed deaths at home, or sudden deaths without a clear
relationship to malignancy progression will be considered to be not malignancy-related.
Bleeding-related death: Death that was preceded by clinically evident bleeding, but not
necessarily meeting the threshold for transfusion or intervention, but, in the opinion of the
reviewer, may have contributed to the patient’s death.
Trauma-related death: Death that was directly related to a traumatic injury and its subsequent
manifestations, including complications during a trauma-related hospitalization.
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Mauri et al. Causes of Late Mortality with Dual Antiplatelet Therapy After Coronary Stents
Additional Statistical Information
Baseline Covariates Used for Adjustment of Treatment Interaction
In the Supplemental Table 1, P values for interaction were adjusted for baseline covariates as
follows:
For “Thienopyridine at randomization”, variables used in adjustment were imputed, including:
Age, Gender, Race (White vs. Non-White), Body mass index, Diabetes mellitus, Hypertension,
Current cigarette smoker or within past year, History of transient ischemic attack, History of
major bleeds, Congestive heart failure, Peripheral arterial disease, Prior percutaneous coronary
revascularization, Prior coronary artery bypass graft, Atrial fibrillation, History of cancer, Prior
myocardial Infarction, ST-Elevation myocardial infarction, Non- ST-elevation myocardial
infarction, Renal insufficiency or failure, Left ventricular ejection fraction < 30%, Bifurcation
lesion with side branch ≥ 2.5 mm, Lesion classification (B2/C vs A/B1), TIMI Flow, Pre
procedure (grade 0, 1 vs 2, 3), Reference vessel diameter (mm) pre-procedure, % Stenosis preprocedure, Lesion length (mm) pre-procedure, % Stenosis post-procedure, Number of stents
implanted, Minimum stent diameter (mm), Total stent length (mm), Number of treated lesions,
Number of treated vessels, Vessel location (left anterior descending/left main vs. others), Region
(North America vs. other), DES stent type.
For “Stent type”, the P value for interaction and stratified HR are both stratified by presence of
risk factors for stent thrombosis, drug at randomization, and region.
For “Region”, the P value for interaction is adjusted by presence of risk factors for stent
thrombosis, and drug at randomization.
For “ACS”, the P value for interaction is adjusted by drug at randomization and region.
For other variables, P values for interaction are adjusted by presence of risk factors for stent
thrombosis, drug at randomization, and region.
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Mauri et al. Causes of Late Mortality with Dual Antiplatelet Therapy After Coronary Stents
Tables and Figures
Supplemental Figure 1. Enrollment, Randomization, and Follow-up. Patients were enrolled after stent
placement and were followed for 12 months while they received open-label treatment with thienopyridine
plus aspirin. They were then randomized to continued thienopyridine therapy or placebo (each in addition
to aspirin) for an additional 18 months. At 30 months, study drug was discontinued and patients remained
on aspirin for another 3 months.
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Mauri et al. Causes of Late Mortality with Dual Antiplatelet Therapy After Coronary Stents
Supplemental Table 1. All-cause mortality by subgroup. Within each subgroup, Kaplan Meier
estimated rates for continued thienopyridine and placebo randomized treatment groups and hazard ratios
and 95% confidence intervals are shown for the outcome of death at 12-33 months follow-up among all
randomized subjects. The P value for interaction represents the test for homogeneity of treatment effect
between complementary subgroups.
Age
< 75
≥ 75
Race
White
Non-White
Sex
Male
Female
Body Mass Index
< Median
≥ Median
Medical History
Diabetes
No diabetes
Current Tobacco Use
No Current Tobacco Use
Prior MI
No Prior MI
Prior PCI
No Prior PCI
Prior CABG
No Prior CABG
History of Cancer
No History of Cancer
Region
North America
European Union
Australia/New Zealand
Indication for PCI
MI
No MI
Aspirin dose at Randomization
≤ 100 mg
> 100 mg
Thienopyridine at Randomization
Clopidogrel
Prasugrel
Stent type
Drug eluting stent
Bare metal stent
N
Continued
Thienopyridine
%
Placebo
%
HR (95% CI)
N=10463
N=1185
2.0
4.4
1.6
3.3
1.26 (0.94,1.69)
1.33 (0.73,2.44)
N=10450
N=980
2.1
3.4
1.7
2.2
1.28 (0.96,1.70)
1.52 (0.69,3.35)
N=8723
N=2925
2.4
1.7
1.9
1.4
1.28 (0.95,1.72)
1.23 (0.67,2.25)
N=5781
N=5770
2.1
2.3
1.5
2.0
1.43 (0.96,2.13)
1.19 (0.83,1.70)
N=3391
N=8257
N=3142
N=8506
N=2456
N=9192
N=3368
N=8280
N=1249
N=10399
N=1070
N=10578
3.4
1.7
2.7
2.0
3.6
1.9
3.4
1.8
4.5
1.9
2.9
2.2
2.5
1.4
2.1
1.6
3.1
1.4
2.8
1.3
2.7
1.6
2.8
1.7
1.36 (0.90,2.03)
1.20 (0.84,1.70)
1.26 (0.79,2.00)
1.28 (0.93,1.77)
1.14 (0.73,1.77)
1.34 (0.96,1.87)
1.21 (0.82,1.80)
1.34 (0.94,1.91)
1.73 (0.93,3.21)
1.19 (0.89,1.60)
1.03 (0.50,2.14)
1.31 (0.99,1.75)
N=9946
N=1411
N=291
2.4
1.3
2.1
1.8
1.3
2.1
1.31 (0.99,1.74)
1.00 (0.40,2.51)
1.00 (0.20,4.97)
N=3576
N=8072
1.8
2.4
1.9
1.7
0.94 (0.58,1.55)
1.44 (1.05,1.97)
N=5879
N=4551
2.0
2.5
1.7
1.7
1.18 (0.80,1.72)
1.53 (1.00,2.32)
N=7962
N=3686
2.4
1.8
1.7
1.8
1.43 (1.01,2.03)
0.96 (0.57,1.62)
N=9961
N=1687
2.3
1.5
1.8
1.7
1.36 (1.02,1.82)
1.00 (0.45,2.23)
P Value for
Interaction†
0.67
0.92
0.87
0.46
0.73
0.86
0.45
0.61
0.37
0.28
0.66
0.16
0.42
0.15
0.48
Abbreviations: CABG, coronary artery bypass graft; PAD, peripheral arterial disease; MI, myocardial infarction, PCI,
percutaneous coronary intervention.
† P values for interaction are adjusted for baseline covariates as described in detail in the the Additional Statistical
Information section above.
Event rates are expressed as Kaplan-Meier estimates.
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Mauri et al. Causes of Late Mortality with Dual Antiplatelet Therapy After Coronary Stents
Supplemental Table 2. Mortality Rates by Treatment Arm During Randomised Treatment and
Extended Follow-Up Using Competing Risk Models.
Outcome
Continued
Thienopyridine
(N=5862)
N (%)
Placebo
(N=5786)
N (%)
HR (95% CI)
P-Value
0.71
12-30 months (randomised period)
Cardiovascular
54 (1.0)
57 (1.0)
1.01 (0.69, 1.47)
Non-Cardiovascular
52 (0.9)
27 (0.5)
1.94 (1.20, 3.15)
0.01
Cancer Related
30 (0.5)
11 (0.2)
2.53 (1.26, 5.08)
<0.01
12-33 months (combined randomised and aspirin alone periods)
Cardiovascular
67 (1.2)
62 (1.1)
1.12 (0.79,1.60)
0.51
Non-Cardiovascular
58 (1.0)
35 (0.6)
1.65 (1.07,2.54)
0.02
Cancer Related
34 (0.6)
17 (0.3)
1.81 (1.00,3.27)
0.02
Event rates are competing risk estimates.
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Mauri et al. Causes of Late Mortality with Dual Antiplatelet Therapy After Coronary Stents
Supplemental Table 3. Bleeding events from 12-33 months by randomized treatment arm.
Continued
Two-Sided P
Placebo
Thienopyridine
Risk
Value for
Bleeding Complications
(N=5291)
(N=5235)
Difference (95% CI)
Difference
GUSTO Severe/Moderate
2.7%
1.8%
0.89% [0.33%,1.45%]
0.002
GUSTO Severe
0.9%
0.7%
0.22% [-0.11%,0.55%]
0.19
GUSTO Moderate
1.8%
1.2%
0.61% [0.15%,1.07%]
0.01
BARC Types 2, 3, or 5
5.9%
3.2%
2.71% [1.91%,3.50%]
<.001
BARC Type 2
3.4%
1.6%
1.76% [1.17%,2.35%]
<.001
BARC Type 3
2.7%
1.6%
1.06% [0.50%,1.62%]
<.001
0.4%
0.4%
-0.00% [-0.23%,0.23%]
0.97
0.2%
0.1%
0.02% [-0.13%,0.16%]
0.81
BARC Type 3c
BARC Type 5
The primary safety end point was moderate or severe bleeding as assessed according to the Global Utilization of
Streptokinase and Tissue Plasminogen Activator for Occluded Arteries (GUSTO) criteria. The secondary analysis of
bleeding was assessed according to the criteria of the Bleeding Academic Research Consortium (BARC). Only
patients who could be evaluated were included in this analysis (i.e., patients whose last contact date was ≥600 days
after randomization or who had any adjudicated bleeding event at or before 630 days). Patients could have had more
than one bleeding episode.
Event rates expressed as absolute percentages.
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Mauri et al. Causes of Late Mortality with Dual Antiplatelet Therapy After Coronary Stents
Supplemental Table 4. Cancer characteristics in patients with cancer-related deaths.
Continued
Placebo
Thienopyridine
N=17
N=34
Timing of diagnosis of the fatal malignancy
Prior to enrollment
8 (23.5%)
1 (5.9%)
Between enrollment and randomization
1 (2.9%)
2 (11.8%)
After randomization
21 (61.8%)
13 (76.5%)
Undetermined
4 (11.8%)
1 (5.9%)
Timing of death (median [interquartle range]
days)
Cancer diagnosis to death
116 (62, 1240)
175 (62, 305)
Randomization to death
348 (212, 495)
404 (188, 573)
Discontinuation of study drug to death
60 (30, 115)
118 (64, 181)
Stage of cancer at diagnosis
1
1 (2.9%)
0 (0.0%))
2
0 (0.0%)
0 (0.0%))
3
3 (8.8%)
2 (11.8%)
4
12 (35.3%)
9 (52.9%)
5
1 (2.9%)
0 (0.0%)
Not applicable
2 (5.9%)
2 (11.8%)
Unknown
15 (44.1%)
4 (23.5%)
General classification
Local
4 (12.1%)
0 (0.0%)
Regional
1 (3.0%)
1 (6.7%)
Metastatic
11 (33.3%)
7 (46.7%)
Not applicable
5 (15.2%)
3 (20.0%)
Unknown
12 (36.4%)
4 (26.7%)
Cancer treatment
Radiation therapy
3 (8.8%)
2 (11.8%)
Chemotherapy
8 (23.5%)
8 (47.1%)
Hormonal therapy
2 (5.9%)
0 (0.0%)
Surgery
9 (26.5%)
3 (17.6%)
No treatment
8 (23.5%)
2 (11.8%)
Event rates are expressed as absolute percentages.
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Mauri et al. Causes of Late Mortality with Dual Antiplatelet Therapy After Coronary Stents
References
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Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a
case for standardized definitions. Circulation 2007;115:2344-51.
2.
Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy
after drug-eluting stents. N Engl J Med 2014;371:2155-66.
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