1. Recurrent Myocardial Infarction After Primary Percutaneous
Coronary Intervention for ST-Segment Elevation
Myocardial Infarction
Wouter J. Kikkert, MD, Loes P. Hoebers, MD, Peter Damman, MD, PhD, Krystien V.V. Lieve,
Bimmer E.P.M. Claessen, MD, PhD, Marije M. Vis, MD, PhD, Jan Baan, Jr., MD, PhD,
Karel T. Koch, MD, PhD, Robbert J. de Winter, MD, PhD, Jan J. Piek, MD, PhD, Jan G.P. Tijssen, PhD,
and Jose P.S. Henriques, MD, PhD*
The determinants and prognostic value of recurrent myocardial infarction (MI) in
a contemporary cohort of ST-segment elevation MI patients treated with primary percu-
taneous coronary intervention (PPCI) and stenting are currently unknown. We investigated
the predictors and prognostic impact of recurrent MI on subsequent clinical outcome in
1,700 ST-segment elevation MI patients treated with PPCI and stenting between January 1,
2003, and July 31, 2008. Two hundred forty patients had a recurrent MI during a median
follow-up of 4 years and 7 months (Kaplan Meier estimate 21.2%). By multivariable
analysis, recurrent MI was associated with a higher risk of subsequent cardiac mortality
(hazard ratio [HR] 6.86, 95% confidence interval [CI] 4.24 to 8.72), noncardiac mortality
(HR 2.02, 95% CI 1.10 to 3.69), stroke (HR 3.68, 95% CI 2.02 to 6.72), and Global Use of
Strategies to Open Occluded Coronary Arteries criteria severe or moderate bleeding
(HR 3.17, 95% CI 1.79 to 5.60). Early recurrent MI (within 1 day of the initial PPCI) was
associated with higher unadjusted cardiac mortality rates (64.4%) compared with recurrent
MIs occurring ‡1 day after PPCI. However, after multivariable adjustment, late recurrent
MI (occurring >1 year after PPCI) was associated with the highest risk of subsequent
cardiac mortality (HR 7.98, 95% CI 5.05 to 12.6). The risk of cardiac death was irrespective
of the presence of persistent ST-segment elevation during the recurrent MI. In conclusion,
recurrent MI after PPCI remains a relatively common complication in contemporary
practice and confers a significantly increased risk of death, stroke, and bleeding. Ó 2014
Elsevier Inc. All rights reserved. (Am J Cardiol 2014;113:229e235)
Recurrent myocardial infarction (MI) after ST-segment
elevation MI (STEMI) is associated with increased
morbidity and mortality.1e3
Fortunately, however, mortality
rates after recurrent MI have recently been shown to be
declining over the past 2 decades.4
The introduction of new
high-sensitive biomarker assays has enabled the detection of
recurrent MIs with smaller amounts of myocardial necrosis,
which may explain in part the reduced mortality after
recurrent MI. Moreover, current treatment strategies,
including advances in revascularization therapy have
decreased mortality after recurrent MI.5
Routine stenting of
the culprit lesion is recommended over balloon angioplasty
during primary percutaneous coronary intervention (PPCI)
to prevent coronary restenosis.6
Although treatment with
bare-metal or drug-eluting stents has not resulted in reduced
rates of recurrent MI after PPCI, it is possible that clinical
and angiographic correlates of recurrent MI have changed
with the introduction of coronary stents.7
These correlates
have not been well-described in a contemporary cohort of
STEMI patients treated with coronary stenting and double or
triple antithrombotic therapy, however. Therefore, the aim
of this study was to investigate the predictors and clinical
outcome after recurrent MI within 5 years’ follow-up after
PPCI in STEMI patients treated with double antiplatelet
therapy.
Methods
The data analyzed in this study were obtained from
STEMI patients who were accepted for PPCI at the
Academic Medical Center, University of Amsterdam,
between January 1, 2003, and July 31, 2008. The study
complied with the Declaration of Helsinki, and the local
ethics committee approved the study protocol. In general,
patients qualified for PPCI if they had typical ischemic chest
pain and at least 1-mm ST-segment elevation in !2
contiguous leads, a new left bundle branch block, or a true
posterior MI. The PPCI and adjunctive pharmacologic
treatment were performed according to American College of
Cardiology, American Heart Association, and European
Society of Cardiology guidelines. Patients received a stan-
dard 300- to 600-mg loading dose of clopidogrel. If
a coronary stent was implanted, clopidogrel was prescribed
Department of Cardiology, Academic Medical Center, University of
Amsterdam, Amsterdam, The Netherlands. Manuscript received July 10,
2013; revised manuscript received and accepted August 28, 2013.
This work was supported by the Nuts OHRA foundation, the Netherlands
(grant SNO-T-0702-61).
See page 235 for disclosure information.
*Corresponding author: Tel: (þ31) 20-5669111; fax: (þ31) 20-6962609.
E-mail address: j.p.henriques@amc.uva.nl (J.P.S. Henriques).
0002-9149/13/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. www.ajconline.org
http://dx.doi.org/10.1016/j.amjcard.2013.08.039

2. for !1 month to patients with a bare metal stent and for 6 to
12 months to patients with a dug-eluting stent. Patients were
routinely pretreated with 300 mg aspirin and 5,000 IU
unfractionated heparin. An additional heparin bolus was
administered at the catheterization laboratory if necessary to
achieve a targeted activated clotting time of 300 seconds
followed by an infusion of 12 U/kg/h with titration to achieve
a target activated partial thromboplastin time (aPTT) of 1.5 to
2.0 times the control. Glycoprotein IIb/IIIa inhibitors were
used at in a bailout setting at the discretion of the operator.
Procedural and angiographic data were prospectively
collected by interventional cardiologists and specialized
nurses in a dedicated database. Chart review for consecutive
STEMI patients with available aPTT measurements was
performed in the context of a study designed to investigate the
relationship between aPTT and clinical outcome in STEMI
patients treated with PPCI. A detailed description of the study
protocol has been previously published.8
We obtained clinical
history, detailed information on peri-procedural treatment and
follow-up of clinical outcome, including recurrent MI, stroke,
stent thrombosis, and bleeding by reviewing inpatient and
outpatient charts in the tertiary percutaneous coronary inter-
vention (PCI) center and referring hospitals between 2011
and 2012. For every patient, we systematically checked
inpatient charts of every hospital admission for the occurrence
of the aforementioned clinical events. Follow-up of clinical
events was censored at the actual date of chart review.
Patients whose whereabouts could not be traced were
considered lost to follow-up from the date of last known
medical contact. Follow-up information regarding vital status
was obtained from computerized, long-term mortality records
from the National Death Index between January 1, 2012, and
April 30, 2012. If a patient could not be identified in these
records (e.g., foreign patients), censoring was at the date of
last contact.
Table 1
Baseline characteristics for patients with and without recurrent myocardial infarction
Variable Recurrent MI p Value
Yes (n ¼ 240) No (n ¼ 1,460)
Men 166 (69.2%) 1,037 (71.0%) 0.56
Age (yrs), median (IQR) 63 (53e76) 62 (52e71) 0.075
BMI, median (IQR) 26.3 (24.0e29.1) 26.1 (24.2e28.7) 0.26
History of
Diabetes mellitus 55 (22.9%) 171 (11.7%) <0.001
IDDM 17 (7.1%) 43 (2.9%)
NIDDM 38 (15.8%) 128 (8.8%)
Hypertension 108 (45.0%) 527 (36.1%) 0.008
Dyslipidemia 66 (27.5%) 309 (21.2%) 0.028
Previous stroke or TIA 16 (6.7%) 91 (6.2%) 0.80
Peripheral artery disease 23 (9.6%) 75 (5.1%) 0.006
Preexistent malignant disease 18 (7.5%) 110 (7.5%) 0.99
Recent surgery (<10 days) 1 (0.4%) 19 (1.3%) 0.24
Bleeding 14 (5.8%) 48 (3.3%) 0.051
Current smoking 105 (43.8%) 670 (45.9%) 0.54
Previous MI 43 (17.9%) 139 (9.5%) <0.001
Previous PCI 27 (11.3%) 101 (6.9%) 0.018
Previous CABG 9 (3.8%) 21 (1.4%) 0.012
Family history CAD 95 (39.7%) 552 (37.8%) 0.60
Laboratory values
Hemoglobin (mmol/L), median (IQR) 8.8 (8.0e9.4) 8.9 (8.2e9.5) 0.25
Leucocyte count (Â109
/L) 11.2 (9.1e14.3) 11.3 (8.9e14.4) 0.77
Creatinine clearance (ml/min/1.73 m2
), median (IQR) 84.2 (62.8e119.5) 93.0 (70.0e118) 0.064
Thrombocyte count (Â109
/L) 0.55
<150 7/239 (2.9%) 58/1,444 (4.0%) —
150e400 226/239 (94.6%) 1,337/1,444 (92.5%) —
>400 6/239 (2.5%) 49/1,444 (3.4%) —
BMI ¼ body mass index; CAD ¼ coronary artery disease; IDDM ¼ insulin dependent diabetes mellitus; IQR ¼ interquartile range; NIIDM ¼ noeinsulin
dependent diabetes mellitus; TIA ¼ transient ischemic attack.
Figure 1. Cumulative incidence of recurrent MI.
230 The American Journal of Cardiology (www.ajconline.org)

3. The study cohort consisted of all STEMI patients
included in our study database, who were alive at the end of
the procedure. We excluded patients in whom no coronary
stent was implanted during the initial PPCI. A recurrent MI
was defined according to the Academic Research Consor-
tium criteria for MI (a detailed description can be found in
the online Supplemental Material).9
Procedure (PCI or coronary artery bypass graft [CABG])-
related MIs during follow-up were not considered recurrent
MIs in the current study. Only the first recurrent MI was
taken into consideration and categorized as STEMI or non-
STEMI (NSTEMI). STEMI was defined as an MI charac-
terized by new ST-segment elevation of !1 mm in 2
contiguous leads, a new left bundle branch block, or a true
posterior infarction. NSTEMI was defined as a recurrent MI
not meeting the criteria for STEMI.
We investigated the impact of recurrent MI on subse-
quent clinical outcome including, all-cause, cardiac and
noncardiac mortality, ischemic and hemorrhagic stroke, and
bleeding. Cardiac death was defined according to the
Academic Research Consortium criteria.9
Bleeding
complications were defined according to the Global Utili-
zation of Streptokinase and Tissue Plasminogen Activator
for Occluded Arteries (GUSTO) criteria.10
Stroke was
defined as an irreversible neurologic deficit, as classified by
the treating neurologist, on the basis of supporting infor-
mation, including brain images and neurologic evaluation.
Normally distributed continuous variables were reported
as the mean with SD and compared with Student’s t test,
skewed distributed variables were presented as the median
with interquartile range and compared with the Wilcoxon
rank-sum test. Categorical variables were presented as
Table 2
Procedural and angiographic characteristics of patients with and without recurrent myocardial infarction
Variable Recurrent MI p Value
Yes (n ¼ 240) No (n ¼ 1,460)
Total ischemic time (min), Median (IQR) 190 (128e270) 177 (128e268) 0.48
Peak CK-MB release (mmol/L), Median (IQR) 239 (99.2e469) 230 (103e433) 0.35
Shock 18/239 (7.4%) 108/1,453 (7.5%) 0.96
Loading dose clopidogrel 230/235 (97.9%) 1,408/1,422 (99.0%) 0.016
300 mg 170/235 (72.3%) 913/1,422 (64.2%)
600 mg 60/235 (25.5%) 487/1,422 (34.2%)
Other 0/235 (0.0%) 8/1,422 (0.6%)
Glycoprotein IIb/IIIa inhibitor 86 (35.8%) 395 (27.1%) 0.005
IRA 0.46
RCA or LCx 12 (53.8%) 822 (56.3%)
LAD or LM 111 (46.3%) 638 (43.7%)
Preprocedural TIMI flow in IRA 0.71
0e1 163/225 (72.4%) 983/1,380 (71.2%)
2e3 62/225 (27.6%) 397/1,380 (28.8%)
Postprocedural TIMI flow in IRA 0.054
0e1 4/236 (1.7%) 8/1,444 (0.6%)
2e3 232/236 (98.3%) 1436/1,444 (99.4%)
Multivessel disease 114/236 (48.3%) 499/1,422 (34.8%) <0.001
Chronic total occlusion 46/236 (19.5%) 179/1,432 (12.5%) 0.004
Intracoronary thrombus 149 (62.1%) 860 (58.9%) 0.35
Ostial lesion 41 (17.1%) 171 (11.7%) 0.020
Calcification 72 (30.0%) 281 (19.2%) <0.001
Preexisting dissection 49 (20.4%) 285 (19.5%) 0.75
Amount of lesions treated 0.089
1 231 (96.3%) 1,432 (98.1%)
2 9 (3.8%) 25 (1.7%)
3 0 (0.0%) 3 (0.2%)
Stent 0.044
Bare-metal stent* 229 (95.4%) 1,426 (97.7%)
Drug-eluting stent 11 (4.6%) 34 (2.3%)
Amount of stents 0.36
1 192 (80.0%) 1,224 (83.8%)
2 41 (17.1%) 201 (13.8%)
3 7 (2.9%) 31 (2.1%)
4 0 (0.0%) 4 (0.3%)
Vessel diameter (mm), median (IQR) 3.5 (3.0e3.5) 3.5 (3.0e3.5) 0.001
Stent length (mm), median (IQR) 20 (15e26) 18 (15e24) 0.19
CK-MB ¼ creatine kinase myocardial band; IRA ¼ Infarct-related artery; IQR ¼ interquartile range; LAD ¼ left anterior descending artery; LCx ¼ left
circumflex artery; LM ¼ left main artery; RCA ¼ right coronary artery; TIMI: thrombolysis in myocardial infarction.
* Includes 10 patients who were treated with an endothelial progenitor cellecapturing stent.
Coronary Artery Disease/Recurrent MI After PPCI for STEMI 231

4. proportions and compared with the chi-square test. Event
rates of recurrent MI and cardiac death were estimated using
Kaplan-Meier analyses. We used stepwise backward selec-
tion Cox proportional hazards models to determine inde-
pendent predictors of recurrent MI. Entry and exit criteria
were set at the p <0.05 and p <0.1 level, respectively.
We investigated predictors of recurrent MI occurring (1)
in the first 30 days, (2) between 30 days and 1 year, and (3)
beyond 1 year. Patients who survived for 30 days without
recurrent MI were included in the landmark analyses for
recurrent MIs after 30 days, and patients who survived for
1 year without recurrent MI were included in the landmark
analyses recurrent MIs occurring after 1 year.
The relation between the occurrence of recurrent MI and
subsequent clinical outcomes (including cardiac, noncar-
diac, and all-cause mortality, stroke, and GUSTO severe and
moderate bleeding) was investigated by inserting the
occurrence of a recurrent MI as a time-dependent variable in
2 sets of Cox proportional hazards models for each
outcome: unadjusted models and models adjusted for rele-
vant predictors of the clinical outcomes. Relevant predictors
were determined by performing backward selection step-
wise Cox models. To investigate if the magnitude of risk of
subsequent cardiac mortality was dependent on the presence
of ST-segment elevation during recurrent MI, we performed
additional univariate and multivariate time-dependent Cox
models simultaneously including recurrent STEMI and
NSTEMI as time-dependent covariates.
To investigate if the timing of the recurrent MI in relation
to the index MI had significant impact on the prognostic
value for subsequent cardiac mortality, we developed
additional time dependent Cox models in which the time
elapsed after the index MI was stratified in the time intervals
of 0 to 1 days, 2 to 7 days, 8 to 30 days, 31 to 365 days, and
beyond 365 days. For each time interval, the subsequent
cardiac mortality was estimated using Kaplan-Meier anal-
yses, and hazard ratios were calculated using Cox models.
Data were complete for all outcomes and for 26 of 40
covariates. Table 1 in the online Supplemental Material
presents the percentage of missingness for all covariates.
Missing patient-level covariates were assumed to be missing
at random and were imputed with the use of multiple impu-
tations. The imputation procedure and subsequent Cox
proportional hazards regression estimation were performed
according to Rubin’s protocol.11
Pooled estimates of the
imputed data were considered primary analyses. As a sensi-
tivity analysis, we repeated all analyses in the original dataset
(complete case analysis). All analyses were performed with
Statistical Package for Social Sciences software (SPSS
version 19.0, Chicago, Illinois).
Results
Of the 2,009 STEMI patients recorded in our database,
2,002 were alive at the end of the procedure. Eighty patients
did not undergo PCI, and 222 were treated with balloon
angioplasty only; 1,700 were treated with a stent during the
index PPCI and comprise the study cohort for the present
analysis. Figure 1 displays the Kaplan-Meier curve for the
occurrence of recurrent MI after STEMI. In total, there were
240 recurrent MIs during a median follow-up of 5 years and
5 months (interquartile range 4.2 to 6.8 years), of which 46
(19.2%) were caused by a definite stent thrombosis of !1 of
the stents implanted during the index PCI. Fifty-seven (3.5%)
patients suffered a recurrent MI within 30 days. Of these, 30
presented with persistent ST-segment elevation, and 27 pre-
sented without persistent ST-segment elevation. Twenty-two
of the 57 (38.6%) recurrent MIs within 30 days were caused
by stent thrombosis. Of the 240 patients who suffered
a recurrent MI, 88 suffered a recurrent MI with persistent ST-
segment elevation (36.7%), and 152 suffered a recurrent MI
without persistent ST-segment elevation (63.3%).
Tables 1 and 2 display baseline clinical, procedural, and
angiographic characteristics of patients with and without
recurrent MI during follow-up. Table 3 displays the inde-
pendent predictors of a recurrent MI occurring in the first
30 days, between day 31 and 1 year, and beyond 1 year.
Supplementary Tables 2 through 4 of the Online Supple-
ment display predictors of recurrent MI with and without
Table 3
Multivariable predictors of recurrent myocardial infarction
HR 95% CI p Value
30 day recurrent MI
Multivessel disease without CTO 2.98 1.62e5.49 <0.001
Multivessel disease with CTO 2.91 1.43e5.90 0.003
Calcification of the culprit vessel 1.74 1.19e3.55 0.052
History of stroke or TIA 2.17 1.02e4.63 0.045
Family history of CAD 1.64 0.97e2.78 0.066
Intracoronary thrombus 1.69 0.95e3.00 0.076
Vessel diameter (per 1-mm decrease) 1.96 1.08e3.57 0.028
Total ischemic time (per 30 min) 1.03 1.01e1.04 0.003
Recurrent MI between 31 days and 1 yr
Diabetes mellitus
NIDDM 2.47 1.32e4.61 0.005
IDDM 3.63 1.64e8.00 0.001
Peripheral artery disease 3.83 1.94e7.58 <0.001
Ostial lesion 2.68 1.53e4.71 0.001
Previous MI 2.20 1.20e4.03 0.011
Vessel diameter (per 1-mm decrease) 1.60 0.95e2.68 0.075
Recurrent MI after 1 yr
Diabetes mellitus
NIDDM 1.92 1.49e2.47 0.009
IDDM 1.49 0.94e2.37 0.50
Previous MI 1.70 1.33e2.18 0.030
Calcification of the culprit vessel 1.53 1.25e1.89 0.039
Stent length (per 1-mm increase) 1.02 1.02e1.03 0.001
All recurrent MIs
Diabetes mellitus
NIDDM 1.69 1.18e2.41 0.004
IDDM 2.29 1.38e3.81 0.001
History of bleeding 1.89 1.09e3.27 0.024
Peripheral vascular disease 1.89 1.22e2.92 0.004
GP IIbeIIIa inhibitors 1.53 1.17e2.00 0.002
Total ischemic time (per 30 min) 1.02 1.00e1.03 0.026
Multivessel disease without CTO 1.52 1.12e2.06 0.007
Multivessel disease with CTO 1.61 1.13e2.31 0.009
Previous MI 1.47 1.03e2.10 0.032
Calcification of the culprit vessel 1.55 1.16e2.06 0.003
Vessel diameter (per 1-mm decrease) 1.47 1.12e1.94 0.006
Total ischemic time (per 30 min) 1.01 1.00e1.03 0.042
CTO ¼ chronic total occlusions; IDDM ¼ insulin dependent diabetes
mellitus; NIIDM ¼ noneinsulin dependent diabetes mellitus.
232 The American Journal of Cardiology (www.ajconline.org)

5. persistent ST-segment elevation and predictors of recurrent
MI caused by stent thrombosis. None of the factors asso-
ciated with recurrent STEMI were predictive of recurrent
NSTEMI. A history of previous MI, peripheral artery
disease, dyslipidemia, previous CABG, anterior infarction,
coronary calcification, young age, and a 300-mg clopidogrel
loading dose (rather than 600 mg) were predictive of
recurrent STEMI. By contrast, body mass index, diabetes,
a history of bleeding, lower creatinine clearance, multivessel
disease, total ischemic time, and ostial lesions were asso-
ciated with recurrent NSTEMI.
Table 4 lists unadjusted and adjusted hazard ratios for
clinical outcome after recurrentMI. In time-updated, covariate
adjusted Cox models, the occurrence of recurrent MI was
associatedwithahigher risk ofsubsequent outcome,including
all-cause mortality, cardiac mortality, noncardiac mortality,
stroke, and GUSTO criteria severe and moderate bleeding.
To investigate whether the magnitude of risk of subse-
quent cardiac mortality was dependent on the presence of
ST-segment elevation during recurrent MI, we performed
additional time-dependent Cox models simultaneously,
including recurrent STEMI and NSTEMI as time-dependent
covariates. By univariate analysis, a NSTEMI during
follow-up was associated with a higher risk of subsequent
mortality compared with recurrent STEMI (NSTEMI: haz-
ard ratio [HR] 6.55; 95% confidence interval [CI] 4.62 to
9.29, p <0.001 vs STEMI: HR 4.43; 95% CI 2.94 to 6.68,
p <0.001). After multivariable adjustment, the difference in
prognostic value between STEMI and NSTEMI weakened.
Both were strong predictors of subsequent cardiac mortality
(STEMI: HR 4.41; 95% CI 2.90 to 6.72, p <0.001;
NSTEMI HR 5.07; 95% CI 3.56 to 7.22, p <0.001).
Figure 2 shows cumulative cardiac mortality after
recurrent MI as a function of the time from initial PPCI to
recurrent MI. Early recurrent MI ( 1 day from initial PPCI)
was associated with the highest mortality rate (64.4%).
Thereafter the mortality rates declined; the lowest subse-
quent mortality rate was noted when the recurrent MI
occurred between 31 and 365 days after the initial PPCI
(34.8%). Figure 3 illustrates unadjusted and adjusted HRs
for subsequent cardiac mortality after recurrent MI stratified
by the timing of recurrent MI. By univariate analysis, the
magnitude of mortality risk associated with early recurrent
MIs was twice that of recurrent MIs occurring between 2
and 365 days after initial PPCI. By multivariate analysis,
however, the difference in prognostic value of the early and
late recurrent MIs was attenuated. Early recurrent MI was
associated with a high subsequent mortality risk (HR 6.55),
followed by a nadir mortality risk when the recurrent MI
took place 2 to 7 days after initial PPCI (HR 5.16). There-
after there was an upward trend in mortality risk with
increasing time since PPCI.
All of these results (including predictors of and outcome
after recurrent MI) were similar when the analyses were
performed in the original data set (data not shown).
Discussion
The main findings of this study can be summarized as
follows. We found correlates of recurrent MI to be a combi-
nation of conventional risk factors and markers of athero-
sclerotic burden. Recurrent MI is associated with an increased
risk of cardiac- and noncardiac mortality, stroke, and
bleeding. The degree of subsequent risk of mortality was
independent of the presence of persistent ST-segment eleva-
tion during recurrent MI. Finally, there was a mild difference
Table 4
Clinical outcome after recurrent myocardial infarction
Outcome No. of Events Unadjusted Adjusted*
Re-MI No Re-MI HR 95% CI p Value HR 95% CI p Value
Death 84 267 5.88 4.51 7.66 <0.001 5.10 3.88 6.71 <0.001
Cardiac 70 198 7.92 5.84 10.72 <0.001 6.86 5.03 9.35 <0.001
Noncardiac 14 69 2.53 1.41 4.53 0.002 2.02 1.10 3.69 0.023
Stroke 15 59 4.18 2.29 7.62 <0.001 3.68 2.02 6.72 <0.001
Ischemic 14 58 4.00 2.16 7.43 <0.001 3.49 1.88 6.49 <0.001
Hemorrhagic 2 2 9.70 1.36 69.32 0.024 —†
— — —
GUSTO severe or moderate bleeding 15 197 3.71 2.10 6.56 <0.001 3.17 1.79 5.60 <0.001
GUSTO severe bleeding 11 79 3.15 1.89 5.27 <0.001 3.66 1.78 7.51 <0.001
GUSTO moderate bleeding 8 128 3.23 1.50 6.97 0.003 2.54 1.18 5.48 0.017
Re-MI ¼ recurrent MI.
* Adjusted HRs were calculated using Cox regression analyses including the occurrence of re-MI as a time-dependent covariate adjusting for predictors of
the clinical outcomes. Predictors of clinical outcomes were determined by performing stepwise backward selection Cox regression analyses.
†
Multivariable analysis was not possible because of the low number of events.
Figure 2. Cumulative cardiac mortality after recurrent MI as a function of
the time to recurrence. Bars indicate Kaplan-Meier estimates and 95%
confidence intervals. Mortality is highest when the recurrent MI occurs
early after the initial PPCI.
Coronary Artery Disease/Recurrent MI After PPCI for STEMI 233

6. in magnitude of risk of subsequent cardiac mortality
depending on the timing of recurrent MI. Early recurrent MI
(within the first day after initial PPCI) and late recurrent MI
(after a month) conferred a slightly greater risk of subsequent
cardiac mortality.
The correlates of recurrent MI identified in this analysis
were in accordance with previous studies conducted in the
prestenting era.12e14
Thus, risk factors for recurrence seem
not to have changed with introduction of routine coronary
stenting and triple or quadruple antithrombotic therapy.
Predictors of recurrent MI consisted of angiographic lesion-
specific correlates, clinical factors associated with severe
atherosclerotic burden such as diabetes or previous athero-
sclerotic events, and factors associated with heart failure.
Our study thus demonstrates that subjects with conventional
risk factors for atherosclerotic disease remain at high risk of
recurrent MI despite improvements in secondary prevention.
Therefore, continuing progress in secondary prevention may
further improve outcomes of STEMI survivors by reducing
the rates of recurrent ischemic events.
In accordance with previous studies, we found recurrent MI
to be associated with a marked increase in cardiac mortality.
We found no difference in prognostic value between recurrent
MIwithandwithout persistentST-segmentelevation.Thisisin
accordance with the results of the Observatoire sur la Prise en
charge hospitalière, l’Evolution à un an et les caRactéristiques
de patients présentant un infArctus du myocarde avec ou sans
onde Q (OPERA) registry, in which it was demonstrated that
patients with STEMI and NSTEMI have comparable 1-year
mortality rates.15
Although the infarct size is generally larger in
STEMI,16
NSTEMI patients are generally older and in worse
condition, have had more previous myocardial damage, and
have more severe (noncardiac) co-morbidities. Moreover,
NSTEMI patients are less consistently treated with secondary
prevention.15
Consistent with observations in the VALsartan In Acute
myocardial INfarction Trial (VALIANT), early recurrent MI
(occurring within 1 day of the initial PPCI) was associated
with the highest unadjusted mortality rate.14
After multivar-
iable adjustment, the risk of subsequent mortality associated
with recurrent MI within the first day was only slightly
elevated compared with recurrent MI after the first day. This
implies that the excess mortality after early recurrent MI
was largely attributable to other high-risk features present in
patients with early recurrent MI, such as cardiogenic shock,
renal failure, and multivessel disease. We also observed
a trend toward higher subsequent mortality with late recurrent
MIs. One explanation for the higher mortality risk of late
recurrent MI could be that late recurrent MI is associated with
heart failure.
In this analysis, recurrent MI was associated with an
increased risk of subsequent stroke and severe and moderate
bleeding complications. Because both these complications
are by themselves determinants of mortality, the occurrence
of stroke and bleeding after recurrent MI may have further
contributed to the higher mortality after recurrent MI.17,18
It
is conceivable that aggressive antithrombotic therapy after
recurrent MI in conjunction with invasive procedures such
as repeat PCI and CABG augmented the risk of bleeding
complications. Several mechanisms may be responsible for
the higher risk of stroke after recurrent MI. First, atrial
fibrillation frequently complicates MI and is associated with
systemic embolism and stroke.19
Second, MI contributes to
loss of ventricular function and development of mural
thrombi secondary to focal akinesia, which is associated
with the occurrence of stroke.20,21
Third, patients with
recurrent MI are exposed to a greater atherosclerotic burden,
thus increasing the risk of ischemic stroke. Finally, antith-
rombotic therapy after recurrent MI facilitates the occur-
rence of hemorrhagic stroke.22
There are several potential limitations to the present
study. First, the patients were selected from a series of
consecutive STEMI patients on the basis of the availability
of at least 1 aPTT measurement. However, the clinical and
procedural characteristics of patients included in the study
were typical of a European STEMI cohort, and there was no
difference in 30-day mortality rates between patients
included in and excluded from the study. Therefore it is
unlikely that the selection of patients affected the general
conclusions of our study. Second, the angiographic data
presented in this study were not core-lab adjudicated, and
prespecified definitions for some angiographic variables
were unavailable. This may have an impact on the repro-
ducibility of some parameters.
Acknowledgment: The authors thank the staff of the
departments of cardiology of the following hospitals for
Figure 3. Influence of recurrent MI on subsequent cardiac mortality as a function of time from PPCI to recurrence. Shown are unadjusted HRs (upper panel)
and adjusted HRs (lower panel) for subsequent cardiac mortality determined with Cox regression analysis including recurrent MI as time-dependent covariate.
After multivariable adjustment, both early recurrent MI (occurring in the first day after the initial PPCI) and late recurrent MI were associated with a greater HR
for subsequent cardiac mortality.
234 The American Journal of Cardiology (www.ajconline.org)

7. their assistance during data collection (alphabetical order):
BovenIJ Ziekenhuis, Bronovo, Diakonessenhuis Utrecht,
Flevoziekenhuis, Gelre Ziekenhuizen, Gemini Ziekenhuis,
HagaZiekenhuis, Kennemer Gasthuis, MC Zuiderzee,
Meander Medisch Centrum, Medisch Centrum Alkmaar,
Medisch Centrum Haaglanden, Onze Lieve Vrouwe Gasthuis,
Rode Kruis Ziekenhuis Beverwijk, Sint Lucas Andreas
Ziekenhuis, Slotervaartziekenhuis, Spaarne Ziekenhuis, St.
Antonius Ziekenhuis, Tergooiziekenhuizen, Vrije Universiteit
Medisch Centrum, Westfriesgasthuis, Ziekenhuis Amstelland,
and Zuwe Hofpoort Ziekenhuis.
Disclosures
The authors have no conflicts of interest to disclose.
Supplementary Data
Supplementary data related to this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.amjcard.2013.
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