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 standard 300- to 600-mg loading dose of clopidogrel. If a coronary stent was implanted, clopidogrel was prescribed 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. 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 intervention (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.

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 Consortium criteria for MI (a detailed description can be found in the online Supplemental Material ).

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 characterized 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 subsequent 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. Bleeding complications were defined according to the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries (GUSTO) criteria. Stroke was defined as an irreversible neurologic deficit, as classified by the treating neurologist, on the basis of supporting information, 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 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 selection Cox proportional hazards models to determine independent 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, noncardiac, 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 relevant predictors of the clinical outcomes. Relevant predictors were determined by performing backward selection stepwise 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 analyses, 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 imputations. The imputation procedure and subsequent Cox proportional hazards regression estimation were performed according to Rubin’s protocol. Pooled estimates of the imputed data were considered primary analyses. As a sensitivity 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 presented 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%).

Cumulative incidence of recurrent MI.

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 independent 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 Supplement display predictors of recurrent MI with and without persistent ST-segment elevation and predictors of recurrent MI caused by stent thrombosis. None of the factors associated 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 associated with recurrent NSTEMI.

Table 3

Multivariable predictors of recurrent myocardial infarction

	HR	95% CI	p Value
30 day recurrent MI
Multivessel disease without CTO	2.98	1.62–5.49	<0.001
Multivessel disease with CTO	2.91	1.43–5.90	0.003
Calcification of the culprit vessel	1.74	1.19–3.55	0.052
History of stroke or TIA	2.17	1.02–4.63	0.045
Family history of CAD	1.64	0.97–2.78	0.066
Intracoronary thrombus	1.69	0.95–3.00	0.076
Vessel diameter (per 1-mm decrease)	1.96	1.08–3.57	0.028
Total ischemic time (per 30 min)	1.03	1.01–1.04	0.003
Recurrent MI between 31 days and 1 yr
Diabetes mellitus
NIDDM	2.47	1.32–4.61	0.005
IDDM	3.63	1.64–8.00	0.001
Peripheral artery disease	3.83	1.94–7.58	<0.001
Ostial lesion	2.68	1.53–4.71	0.001
Previous MI	2.20	1.20–4.03	0.011
Vessel diameter (per 1-mm decrease)	1.60	0.95–2.68	0.075
Recurrent MI after 1 yr
Diabetes mellitus
NIDDM	1.92	1.49–2.47	0.009
IDDM	1.49	0.94–2.37	0.50
Previous MI	1.70	1.33–2.18	0.030
Calcification of the culprit vessel	1.53	1.25–1.89	0.039
Stent length (per 1-mm increase)	1.02	1.02–1.03	0.001
All recurrent MIs
Diabetes mellitus
NIDDM	1.69	1.18–2.41	0.004
IDDM	2.29	1.38–3.81	0.001
History of bleeding	1.89	1.09–3.27	0.024
Peripheral vascular disease	1.89	1.22–2.92	0.004
GP IIb–IIIa inhibitors	1.53	1.17–2.00	0.002
Total ischemic time (per 30 min)	1.02	1.00–1.03	0.026
Multivessel disease without CTO	1.52	1.12–2.06	0.007
Multivessel disease with CTO	1.61	1.13–2.31	0.009
Previous MI	1.47	1.03–2.10	0.032
Calcification of the culprit vessel	1.55	1.16–2.06	0.003
Vessel diameter (per 1-mm decrease)	1.47	1.12–1.94	0.006
Total ischemic time (per 30 min)	1.01	1.00–1.03	0.042

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