Accepted Manuscript

Impact of NonInfarct-Related Artery Disease on Infarct Size and Outcomes (from the
CRISP-AMI Trial)
Rohan Shah, BS, Robert M. Clare, MS, Karen Chiswell, PhD, W. Schuyler Jones,
MD, A. Sreenivas Kumar, MD, DM, Holger Thiele, MD, Richard W. Smalling, MD,
PhD, Praveen Chandra, MD, Marc Cohen, MD, Divaka Perera, MD, Derek P. Chew,
MD, John K. French, MBChB, PhD, Jonathan Blaxill, MB BS, E. Magnus Ohman, MD,
Manesh R. Patel, MD
PII:

S0002-9343(16)30788-4

DOI:

10.1016/j.amjmed.2016.07.011

Reference:

AJM 13636

To appear in:

The American Journal of Medicine

Received Date: 25 February 2016

Revised Date:

25 July 2016

Accepted Date: 25 July 2016

Please cite this article as: Shah R, Clare RM, Chiswell K, Jones WS, Kumar AS, Thiele H, Smalling RW,
Chandra P, Cohen M, Perera D, Chew DP, French JK, Blaxill J, Ohman EM, Patel MR, Impact of Non
Infarct-Related Artery Disease on Infarct Size and Outcomes (from the CRISP-AMI Trial), The American
Journal of Medicine (2016), doi: 10.1016/j.amjmed.2016.07.011.
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Impact of NonInfarct-Related Artery Disease on Infarct Size and

Outcomes (from the CRISP-AMI Trial)

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Running Head: NonIRA Disease

Rohan Shah, BSa; Robert M. Clare, MSa; Karen Chiswell, PhDa; W. Schuyler Jones, MDa,b; A. Sreenivas
Kumar, MD, DMc; Holger Thiele, MDd; Richard W. Smalling, MD, PhDe; Praveen Chandra, MDf; Marc
Cohen, MDg; Divaka Perera, MDh; Derek P. Chew, MDi; John K. French, MBChB, PhDj; Jonathan Blaxill,

Clinical Research Institute, Durham, NC; bDivision of Cardiology, Department of Medicine,

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aDuke

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MB BSk; E. Magnus Ohman, MDa,b; Manesh R. Patel, MDa,b

Duke University Medical Center, Durham, NC; cDepartment of Cardiovascular Sciences, Citizens
Hospitals, Hyderabad, India; dMedical Clinic II, University Heart Center Lbeck, Lbeck, Germany;
eDivision

of Cardiology, Memorial Hermann Heart and Vascular Institute, University of Texas,

Houston, TX; fDivision of Cardiology, Medanta the Medicity, Haryana, India; gDivision of

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Cardiology, Newark Beth Israel Medical Center, Newark, NJ; hCardiovascular Division, Kings
College, London, England; iDepartment of Cardiovascular Medicine, Flinders Medical Center,
Bedford Park, Australia; jDepartment of Cardiology, Liverpool Hospital, Liverpool, Australia;
of Cardiology, Leeds General Infirmary, Leeds, England

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kDepartment

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All authors had access to the data and a role in writing the manuscript.

Corresponding Author: Manesh R. Patel, MD, Duke Clinical Research Institute, Duke University
Medical Center, PO Box 17969, 2400 Pratt St, Durham, NC 27715.
Phone: (919) 668-8917, Fax: (919) 668-7026, Email: manesh.patel@duke.edu.
Word Count: 5330 (all-inclusive)

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ABSTRACT
Background: Noninfarct-related artery (non-IRA) disease is prevalent in patients with STsegment elevation myocardial infarction (STEMI). We aimed to assess the impact of non-IRA

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disease on infarct size and clinical outcomes in patients with acute STEMI.

Methods: The Counterpulsation to Reduce Infarct Size Pre-PCI Acute Myocardial Infarction (CRISPAMI) trial randomized patients to intra-aortic balloon counterpulsation (IABC) vs. no IABC before

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percutaneous coronary intervention in patients with acute STEMI. Infarct size (% left ventricular
mass) at 35 days post percutaneous coronary intervention and 6-month clinical outcomes were

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compared between patients with and without non-IRA disease (defined as 50% stenosis in at least
1 non-IRA).

Results: A total of 324 (96.1%) patients had anterior STEMI, of whom 34.9% had non-IRA disease.
There was no difference in infarct size (% left ventricular mass) between patients with and without
non-IRA disease (median 39% vs. 39%; p=0.73). At 6 months, there was no difference in rates of

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recurrent myocardial infarction (0.9% vs. 0.9%; p=0.78), major TIMI bleeding (0.9% vs. 0.5%;
p=0.77), or all-cause death (3.5% vs. 2.4%; p=0.61) in patients with and without non-IRA disease,
respectively. Patients with non-IRA disease had a higher rate of new/worsening heart failure with

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hospitalization (8.8% vs. 1.9%; p=0.0050).

Conclusions: More than one-third of patients with anterior STEMI in the CRISP-AMI study had non-

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IRA disease. These patients had similar infarct sizes and rates of recurrent myocardial infarction,
major bleeding, and all-cause death. Patients with non-IRA disease did have a higher rate of
new/worsening heart failure with hospitalization. Further study is needed to understand the
mechanisms of outcomes of patients with non-IRA disease.
Clinical Trial Registration: ClinicalTrials.gov number NCT00833612
Key Words: ST-segment elevation myocardial infarction; infarct-related artery; noninfarct-related
artery; heart failure

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INTRODUCTION
The prevalence and significance of acute ST-segment elevation myocardial infarction (STEMI) has
been well described in the literature, as has the prevalence of noninfarct-related artery (non-IRA)

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disease, which has been shown to be approximately 40% to 51%. However, the clinical impact of
non-IRA disease has not been well established.1,2 Evidence of the impact of non-IRA disease on
clinical outcomes has been inconclusive, with some studies reporting an increase in recurrent

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percutaneous coronary intervention but no difference in mortality in patients with non-IRA disease
at 30 days or 1 year1,3 when compared with patients without non-IRA disease. More recent

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evidence suggests that non-IRA disease may in fact be associated with worse prognosis, including
higher 30-day mortality, compared with patients without non-IRA disease.4 In addition, there is a
lack of consensus about the treatment approach (aggressive vs. conservative) that should be
implemented in these patients with non-IRA disease.4-7 More data are required on how non-IRA
disease may affect primary infarct size and patient outcomes to help guide treatment choices in the

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future. As a result, in this substudy of the Counterpulsation to Reduce Infarct Size Pre-PCI for Acute
Myocardial Infarction (CRISP-AMI) trial, we aimed to investigate the differences in baseline
characteristics, specific procedural characteristics, treatment metrics, and outcomes in patients

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with acute myocardial infarction, with and without significant non-IRA disease.

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MATERIALS AND METHODS

The methods used in the CRISP-AMI trial have been previously described.8,9 Briefly, CRISP-AMI was
a prospective, open, international, multicenter (N=30 centers), randomized controlled trial to
determine whether a routine strategy of intra-aortic balloon counterpulsation (IABC) insertion
prior to primary percutaneous coronary intervention leads to a reduction in infarct size as
measured by cardiac magnetic resonance imaging (MRI) in patients with acute anterior STEMI

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without cardiogenic shock. Patients in the standard-of-care group within the trial received primary
percutaneous coronary intervention without planned IABC support.
To determine whether IABC reduces infarct size, a population of adult patients within 6

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hours of onset of chest pain and planned primary percutaneous coronary intervention for acute
anterior STEMI with significant myocardium at risk were included in the study. Patients with prior
myocardial infarction or coronary artery bypass graft procedures were excluded from the study as

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the primary endpoint assessed infarct size. Patients with indications for planned IABC insertion
such as cardiogenic shock, inability to undergo IABC implantation, fibrinolysis within 72 hours of

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presentation, or known contraindication for cardiac MRI for endpoint assessment were also
excluded from the study.

The interventions and procedures used in the CRISP-AMI trial have also been previously
described.8,9 Patients were randomized to pre-reperfusion initiation of IABC and mechanical
reperfusion with percutaneous coronary intervention or primary percutaneous coronary

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intervention alone. For study participants randomized to receive IABC plus percutaneous coronary
intervention, balloon counterpulsation was recommended for at least 12 hours with a maximum of
24 hours after percutaneous coronary intervention. If patients were hemodynamically unstable,

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balloon counterpulsation could be continued for longer periods at the discretion of the
investigators. Study participants randomized to receive percutaneous coronary intervention alone

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may have had subsequent insertion of IABC if there was clinical deterioration. To ensure rapid
reperfusion, sites with demonstrated ability to meet guideline standards were chosen (median
door-to-device time of <90 minutes). Furthermore, data about the timing of first medical contact,
randomization, IABC insertion, and first device were captured and monitored by the steering
committee and the data and safety monitoring board during the trial to ensure continued high
quality of care. Cardiac MRI was performed between 3 and 5 days after percutaneous coronary
intervention to assess the primary endpoint of infarct size.

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Institutional review boards and ethics committees approved the trial, and all enrolled
patients provided written informed consent. The Duke Clinical Research Institute (Durham, NC)
coordinated the trial and carried out data management and analyses with oversight from a steering

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committee. The safety and efficacy of the trial was overseen by an independent data and safety
monitoring board.

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Population Included in the Substudy

The present substudy included all randomized patients in the CRISP-AMI study. For this analysis,

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non-IRA disease was defined as 50% stenosis in at least 1 non-IRA. In examining the differences
between patients with and without non-IRA disease, the analysis population included all subjects
enrolled in the CRISP-AMI study for whom an IRA was designated on the case report form. Patients
with an unidentified IRA were excluded from this analysis. In addition, since only one of the
remaining patients had an IRA other than the left anterior descending, only patients with the left

Cardiac MRI Protocol

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anterior descending artery as the IRA were included in this study.

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The cardiac MRI protocol to determine infarct size has been previously described.8,10-12 Cardiac MRI
using standard sequences was performed for microvascular obstruction, area at risk, and left

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ventricle dimensions and function. A central cardiac MRI laboratory at the University of Leipzig
Heart Center (Leipzig, Germany) performed both quality assessment of the images collected in the
study as well as manual, blinded assessment of the MRIs for left ventricular myocardial mass,
microvascular obstruction, area at risk, and infarct size.

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Clinical Endpoints
The clinical endpoints evaluated were: (1) infarct size (% left ventricle) 3 to 5 days post
percutaneous coronary intervention or at discharge, whichever comes first; (2) Canadian

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Cardiovascular Society angina classification at discharge, 30 days, and 6 months; (3) all-cause death
through 6 months post randomization; (4) recurrent myocardial infarction through 6 months post
randomization; (5) new/worsening heart failure with hospital admission through 6 months post

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randomization; (6) major bleeding per Global Utilization of Streptokinase and Tissue Plasminogen
Activator for Occluded Coronary Arteries (GUSTO I) and Thrombolysis In Myocardial Infarction

through 6 months post randomization.

Statistical Analyses

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(TIMI) definitions through 6 months post randomization; and (7) major vascular complications

Baseline characteristics, procedural characteristics, and clinical outcomes were described with

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frequencies and percentages for categorical variables, and median values with 25th and 75th
percentiles and minimum and maximum values for continuous variables. P-values were provided
for group comparisons using chi-squared or Fishers mid-p exact tests for categorical variables, and

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the Wilcoxon test for continuous variables.

Linear regression was used to estimate the effect of non-IRA disease on infarct size (% left

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ventricle) 3 to 5 days post percutaneous coronary intervention. Factors associated with infarct size
were identified by stepwise selection from a pre-specified list of candidate covariates (age, sex,
complete ST-segment resolution, time from symptom onset to first device [min], door-to-balloon
time, pre- and post-procedural TIMI score, non-distal left anterior descending artery, diabetes,
hypertension, creatinine, nicotine use, aspirin [before procedure], heparin, enoxaparin, clopidogrel
[before procedure], ticlopidine, prasugrel [before procedure], bivalirudin, glycoprotein IIb/IIIa
inhibitor, statin [before procedure], beta-blocker [before procedure], region, and treatment with

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IABC vs. standard of care), as previously reported.13 These factors were included as covariates in
the regression model to adjust for possible confounding of the effect of non-IRA disease.
A level of significance of p<0.05 was pre-specified. All statistical analyses were performed at

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Duke Clinical Research Institute using SAS Version 9.2 (SAS Institute, Cary, NC).

RESULTS

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Study Population

A total of 337 patients with anterior STEMI without cardiogenic shock were enrolled and

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randomized in the CRISP-AMI trial at 30 sites in 9 countries from June 2009 to February 2011
(Figure 1). After excluding patients with no IRA (n=5), an unidentified IRA (n=7), or an IRA other
than the left anterior descending artery (n=1), 324 patients met the criteria for inclusion in this
substudy. A total of 211 (65.1%) patients had no non-IRA disease, while 113 (34.9%) patients had
non-IRA disease.

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Patient Characteristics

Baseline characteristics of patients in the study with and without non-IRA disease are shown in
Table 1. Patients with non-IRA disease were older, with a median age of 59 years compared with 54

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years for patients without non-IRA disease (p=0.0005). Patients with non-IRA disease had higher
rates of comorbidities compared with patients without non-IRA diseaseincluding hypertension

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(38.1% vs. 25.1%; p=0.0185), dyslipidemia (22.1% vs. 7.1%; p=0.0001), renal insufficiency (3.5%
vs. 0.0%; p=0.0071), and diabetes (29.2% vs. 12.3%; p=0.0002)but lower rates of current
smoking (24.8% vs. 35.7%; p=0.0396). Other characteristics, including peripheral artery disease,
presenting blood pressure, heart rate, and degree of ST-segment elevation in anterior leads, were
statistically similar across both groups.

Angiographic Findings and Procedural Characteristics

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Patients with non-IRA disease were more likely to have disease in the mid-left anterior descending
artery (49.6% vs. 35.5%; p=0.0151) and less likely to have disease in the distal left anterior
descending artery (1.8% vs. 8.1%; p=0.0179) compared with patients without non-IRA disease,

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respectively. Patients with non-IRA disease were also less likely to have 100% stenosis (53.1% vs.
70.6%) and more likely to have 75% to 99% stenosis (46.0% vs. 28.4%) (p=0.0036) in the left
anterior descending artery. Of the 113 patients with non-IRA disease, 7 patients (6.2%) had >50%

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stenosis in the left main (LM) artery, 66 patients (58.4%) had >50% stenosis in the left circumflex
(LCx) artery, and 74 patients (65.5%) had >50% stenosis in the right coronary artery (RCA).

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Similar numbers of patients in both groups were randomized into the IABC and non-IABC
groups and had an intra-aortic balloon pump placed (Table 2). Percutaneous coronary intervention
was performed in fewer patients with non-IRA disease (92.0% vs. 98.6%), while coronary artery
bypass grafting was more frequently performed (5.3% vs. 0.0%) (p=0.003). In total, 6 interventions
were performed on non-IRAs, including 2 to the LM, 1 to the LCx, and 3 to the RCA. Patients with

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non-IRA disease were more likely to receive drug-eluting stents (57.4% vs. 43.8%; p=0.046) and
less likely to receive bare metal stents (44.6% vs. 57.6%; p=0.021). No statistically significant
difference was observed in the first device used (atherectomy/thrombectomy vs. balloon vs. stent)

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on the IRA between the 2 groups. Pre-intervention TIMI flow was less likely to be grade 0 (54.9%
vs. 71.1%) and more likely to be grades 1, 2, and 3 in patients with non-IRA disease (p=0.002),

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while post-intervention TIMI flows were not statistically significantly different.

Processes of Care

No statistically significant difference was observed in the total ischemic time (time from symptom
onset to first device) or in the time from hospital contact to first device in the IRA between the 2
groups (Table 2). The median total ischemic time was 194 minutes for patients with non-IRA
disease and 196 minutes for patients without non-IRA disease. The median time for hospital

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contact to first IRA device was 68 minutes for patients with non-IRA disease and 74 minutes for
patients without non-IRA disease.

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Outcomes

The median infarct size (% of left ventricular mass by cardiac MRI) was 39% for patients with and
without non-IRA disease (Table 3). Presence of non-IRA disease did not contribute significantly in

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either an unadjusted linear model of infarct size ( = -1.9, 95% CI -6.9 to 3.13, p=0.46) or in an
adjusted linear model ( = -2.0, 95% CI -7.1 to 2.98, p=0.43), incorporating total ischemic time and

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pre-procedural TIMI score (Table 4). Other covariates (as described in the methods) were analyzed
and found to be non-contributory to infarct size.

There were no significant differences in medication use at hospital discharge. There was
some evidence of an increase in angina per Canadian Cardiovascular Society classification postprocedure in patients with non-IRA disease (p=0.0530), but this difference became insignificant at

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30 days (p=0.8001) and at 6 months (p=0.4200), and most patients (>90%) both with and without
non-IRA disease had no angina at each time point (Table 3). At 6 months, there was no significant
difference in the rate of all-cause death (2.4% vs. 3.5%; p=0.6141), recurrent myocardial infarction

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(0.9% vs. 0.9%; p=0.7771), vascular complications (2.4% vs. 3.5%; p=0.6141), or major bleeding
(per TIMI definition) (0.5% vs. 0.9%; p=0.7722) in patients without non-IRA disease and with non-

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IRA disease, respectively. Data on subsequent revascularizations in patients with and without nonIRA disease were not available. Patients with non-IRA disease showed higher rates of
new/worsening heart failure with hospitalization (8.8% vs. 1.9%; p=0.0050) at 6 months. This
included patients with new/worsening heart failure at index hospitalizations or subsequent
hospitalizations within 6 months.

DISCUSSION

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The main finding from this study is that the presence of non-IRA disease does not affect the infarct
size as assessed by cardiac MRI in patients with acute anterior STEMI. Patients with non-IRA
disease, present in approximately one-third of the patients, also did not have a significant difference

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in angina classification, recurrent myocardial infarction, or all-cause death at 6 months when

compared with patients without non-IRA disease. Finally, patients with non-IRA disease were more
likely to develop new/worsening heart failure with hospitalization in the first 6 months after their

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myocardial infarction when compared with patients without non-IRA disease.

Previous work on the impact of non-IRA disease on infarct size is limited. While the impact

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of chronic total occlusion in non-IRAs has been studied, the impact of significant non-IRA disease on
infarct size has not been reported. One of the strengths of this study is that it provides novel insight
into the fact that non-IRA disease does not affect infarct size as measured by cardiac MRI in patients
with acute anterior STEMI. Thus, infarct size is similar in patients with acute anterior STEMI
regardless of whether they have significant disease only in a single vessel or in multiple vessels. Our

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study was powered to assess the difference in this endpoint.

Data on the impact of non-IRA disease on the clinical outcomes of STEMI patients have been
inconclusive. Goldstein et al1 previously noted that the presence of non-IRA disease in patients with

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acute myocardial infarction is associated with a higher rate of recurrent acute coronary syndrome
and repeat angioplasty, but found no difference in the rate of mortality within 1 year. Similar

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findings were reported by Kim et al3 in a study of 439 patients that showed higher rates of heart
failure (16.4% vs. 6.3%) but no difference in mortality rates at 30 days in patients with non-IRA
disease. On the other hand, in a study of 312 patients, while Moreno et al2 similarly reported higher
rates of revascularization with multivessel disease, they also noted higher rates of in-hospital
mortality (21% vs. 7%), with multivessel disease being an independent risk factor for mortality.
Jaski et al14 also reported a trend toward increased in-hospital mortality for patients with non-IRA
disease in a study of 151 patients, while also reporting increased occurrence of a multitude of

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complications in these patients. A recent pooled analysis of 8 trials by Park et al,4 including a total
of 28,282 patients (14,929 [52.8%] of whom had non-IRA disease), found the presence of non-IRA
disease to be associated with an overall increased risk of 30-day mortality (4.3% vs. 1.7%).

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The results of this analysis concur with the finding of increased incidence of heart failure in
patients with non-IRA disease reported by Kim et al, although overall rates of heart failure are
lower in our study. Similar to Goldstein et al and Kim et al, our study did not find an increase in

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mortality due to the presence of non-IRA disease, although we also did not find an increase in rates
of recurrent myocardial infarction within the first 6 months. It should be noted that MRI variable

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data, in addition to that previously mentioned, or data about subsequent revascularizations were
not available, which may have otherwise helped determine the reason for the difference in
incidence of heart failure between the groups noted above. Furthermore, it should also be noted
that this study was not powered to assess difference in clinical outcomes, and as such, these
findings from our study should be considered hypothesis generating.

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A significant difference between the present study and the ones mentioned previously is
that this study exclusively included patients with a first myocardial infarction, while the other
studies included patients with a recurrent case of myocardial infarction as well. Furthermore, our

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analysis included patients exclusively with anterior STEMI and the left anterior descending artery
as the IRA, resulting in none of the patients having the left anterior descending artery as the non-

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IRA. These 2 factors, combined with the differences in time points at which clinical outcomes were
measured, may help explain some of the variation in results seen between this analysis and the
previous studies. Finally, it should be noted that the patients included in this analysis spanned
multiple continents, and results were not segregated by geographic region.
The results of the present study suggest that infarct size may not be the mechanism by
which non-IRA disease has an adverse impact on patient outcomes. It also appears that any effect
that non-IRA disease may have on recurrent myocardial infarction as suggested by previous studies

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is likely limited during the first 6 months, although some previous analyses suggest otherwise.
Detailed further study is required to investigate the link between non-IRA disease and the
increased incidence of heart failure with a focus on possible mechanisms by which this may occur.

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In order to guide effective treatment choices in the future, results of this study should be taken into
consideration along with the latest research on treatment strategies in patients with and without

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non-IRA disease.

Limitations

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This current study has the following limitations. First, the small sample size prevents us from
drawing concrete conclusions; only 324 patients were included in this analysis, of whom 113
patients had non-IRA disease. Second, since this was a retrospective analysis in the CRISP-AMI trial
population, the study was not powered to specifically demonstrate the differences between patients
with and without non-IRA disease. As such, the results of this study should be seen as hypothesis-

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generating. Third, since this analysis included patients with only anterior STEMI, and only patients
with their first myocardial infarction, the generalizability to all patients with STEMI is questionable.
Finally, since the outcomes were all measured at 6 months, effects that may manifest over a longer

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CONCLUSION

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period of time may be missed by this analysis.

In this substudy of the CRISP-AMI trial, approximately one-third of the patients with anterior
STEMI had non-IRA disease. There was no difference in infarct size as measured by cardiac MRI in
patients with and without non-IRA disease. When compared with patients without non-IRA disease,
patients with non-IRA disease also had a similar rate of recurrent myocardial infarction, major
bleeding, and all-cause death at 6 months. However, patients with non-IRA disease did have a
higher rate of new/worsening heart failure with hospitalization at 6 months. To guide effective

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treatment choices, future studies should aim at investigating the association between non-IRA
disease and heart failure as well as the mechanisms by which non-IRA disease may lead to adverse

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outcomes in patients with STEMI.

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Acknowledgements:
The authors would like to thank Morgan deBlecourt for editorial assistance, which was provided as

Funding:
The CRISP-AMI trial was funded by Maquet (formerly Datascope).

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Disclosures:

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part of her regular duties as an employee of the Duke Clinical Research Institute.

RM Clare: None.
K Chiswell: None.

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R Shah: None.

WS Jones: Research Grants AstraZeneca, Boston Scientific Corporation, Bristol-Myers

Squibb, American Heart Association; Consultant/Honoraria American College of

AS Kumar: None.
H Thiele: None.

P Chandra: None.

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RW Smalling: None.

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Physicians, American Physician Institute.

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M Cohen: Maquet: advisory board.

D Perera: Research funding and speaker fees from Maquet (<$10,000 in past 3 years).
DP Chew: None.

JK French: None.
J Blaxil: None.

EM Ohman: Available at https://dcri.org/about-us/conflict-of-interest.

MR Patel: Research Grants Johnson & Johnson, Pluristem, AstraZeneca; Consultant
Baxter, Genzyme, Bayer, Ortho McNeil Jansen.

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9. Patel MR, Thiele H, Smalling RW, Chandra P, Zhou Y, Cohen M, Perera D, Ohman EM. A

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multicenter, randomized, controlled study of mechanical left ventricular unloading with

counterpulsation to reduce infarct size prepercutaneous coronary intervention for acute
myocardial infarction: rationale and design of the Counterpulsation Reduces Infarct Size
Acute Myocardial Infarction trial. Am Heart J. 2011;162:47-55. e41.
10. Thiele H, Kappl MJ, Conradi S, Niebauer J, Hambrecht R, Schuler G. Reproducibility of

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chronic and acute infarct size measurement by delayed enhancement-magnetic resonance

imaging. J Am Coll Cardiol. 2006;47:1641-1645.
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M, Thiele H, Gutberlet M. Right ventricular injury in ST-elevation myocardial infarction: risk

stratification by visualization of wall motion, edema, and delayed-enhancement cardiac

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magnetic resonance. Circ Cardiovasc Imaging. 2012;5:60-68.

12. Kim RJ, Albert TS, Wible JH, Elliott MD, Allen JC, Lee JC, Parker M, Napoli A, Judd RM;
Gadoversetamide Myocardial Infarction Imaging Investigators. Performance of delayedenhancement magnetic resonance imaging with gadoversetamide contrast for the detection
and assessment of myocardial infarction: an international, multicenter, double-blinded,
randomized trial. Circulation. 2008;117:629-637.

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13. Vemulapalli S, Zhou Y, Gutberlet M, Kumar AS, Mills JS, Blaxill J, Smalling R, Ohman EM, Patel
MR. Importance of total ischemic time and preprocedural infarct-related artery blood flow

CRISP-AMI Trial). Am J Cardiol. 2013; 112:911-917.

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in predicting infarct size in patients with anterior wall myocardial infarction (from the

14. Jaski BE, Cohen JD, Trausch J, Marsh DG, Bail GR, Overlie PA, Skowronski EW, Smith SC Jr.
Outcome of urgent percutaneous transluminal coronary angioplasty in acute myocardial

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FIGURE LEGEND
Figure 1. Inclusion and exclusion criteria for patients with ST-segment elevation myocardial
infarction, with and without noninfarct-related artery disease, in the current analysis.

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Definitions: Noninfarct-related artery disease was defined as 50% stenosis in at least 1 non
infarct-related artery.

Abbreviations: IRA, infarct-related artery; CRF, case report form; LAD, left anterior descending;

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MRI, magnetic resonance imaging; HF, heart failure; MI, myocardial infarction.

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Table 1: Baseline (including angiographic) characteristics by presence of non-IRA disease

Age, y, median (25th, 75th percentiles)

Female, %

Total
(N=324)

Non-IRA Disease
(N=113)

No Non-IRA Disease
(N=211)

p-value

57 (48, 66)

59 (52, 66)

54 (46, 64)

0.0005

17.9%

16.8%

18.5%

0.7057

46.3%

35.4%

0.0081

Asian
Black or African American

4.3%

8.0%

White

46.9%

54.0%

Medical History, %
Prior percutaneous coronary intervention

1.5%

2.7%

Hypertension

29.6%

38.1%

Current smoking

31.9%

24.8%

Dyslipidemia

12.4%

Prior atrial fibrillation

1.2%

Renal insufficiency

1.2%

Diabetes

18.2%

52.1%
2.4%

43.1%

0.9%

0.2571

25.1%

0.0185
0.0396

7.1%

0.0001

0.9%

1.4%

0.8069

3.5%

0.0%

0.0071

29.2%

12.3%

0.0002

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35.7%

22.1%

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Presenting systolic blood pressure, mm Hg, median (25th,

75th percentiles)

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Race, %

130 (118, 150)

131 (119, 154)

130 (116, 150)

0.4899

Presenting diastolic blood pressure, mm Hg, median (25 ,

th
75 percentiles)

80 (71, 92)

80 (70, 91)

80 (71, 93)

0.3814

Heart rate, bpm, median (25th, 75th percentiles)

81 (71, 94)

80 (70, 94)

81 (72, 93)

0.8626

0.0%

0.0%

0.0%

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Degree of ST-segment elevation in anterior leads, mm, %

0 to <2 mm
2 to <4 mm

0.7098

0.3%

0.0%

0.5%

40.1%

42.5%

38.9%

59.6%

57.5%

60.7%

62.7%

61.1%

63.5%

0.6745

40.4%

49.6%

35.5%

0.0151

5.9%

1.8%

8.1%

0.0179

64.5%

53.1%

70.6%

34.6%

46.0%

28.4%

0.9%

0.9%

0.9%

0.0%

0.0%

0.0%

0.0%

0.0%

0.0%

0.3%

0.9%

0.0%

75 to 99%

0.3%

0.9%

0.0%

50 to 74%

1.5%

4.4%

0.0%

1 to 49%

11.4%

14.2%

10.0%

0%

86.4%

79.6%

90.0%

2.2%

6.2%

0.0%

75 to 99%

8.0%

23.0%

0.0%

50 to 74%

10.2%

29.2%

0.0%

1 to 49%

29.9%

24.8%

32.7%

0%

49.7%

16.8%

67.3%

4 to <6 mm

Proximal left anterior descending

Mid left anterior descending
Distal left anterior descending

100%
75 to 99%
50 to 74%
1 to 49%
0%

100%

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Maximum % stenosis in LM

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Maximum % stenosis in left anterior descending

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6 mm
Infarct-Related Artery Location, %

0.0036

NA

Maximum % stenosis in LCx

100%

Maximum % stenosis in RCA

NA

NA

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Non-IRA Disease
(N=113)

No Non-IRA Disease
(N=211)

100%

3.1%

8.8%

0.0%

75 to 99%

10.8%

31.0%

0.0%

50 to 74%

9.0%

25.7%

0.0%

1 to 49%

32.7%

20.4%

39.3%

0%

44.4%

14.2%

60.7%

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Total
(N=324)

p-value

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Definitions: Proximal left anterior descending = Before first diagonal; Mid left anterior descending = Between first and second diagonal; Distal left
anterior descending = After second diagonal.
Abbreviations: LCx, left circumflex; LM, left main; IRA, infarct-related artery; RCA, right coronary artery.

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Table 2: Procedural characteristics and peri-procedural medications by non-IRA disease

Total
(N=324)

Non-IRA Disease
(N=113)

No
Non-IRA Disease
(N=211)

IABC

48.8%

45.1%

50.7%

No IABC

51.2%

54.9%

50.9%

49.6%

Performed

96.3%

92.0%

Not performed

3.7%

8.0%

CABG instead

1.9%

5.3%

No infarct artery identified

0.0%

0.0%

Technical limitations

1.9%

2.7%

1.4%

Grade 0

65.4%

54.9%

71.1%

Grade 1

10.2%

11.5%

9.5%

Grade 2

15.1%

19.5%

12.8%

Grade 3

9.3%

14.2%

6.6%

Grade 0

1.3%

1.8%

1.0%

Grade 1

1.9%

2.7%

1.4%

Grade 2

2.2%

5.5%

0.5%

Grade 3

94.7%

90.0%

97.1%

1.9%

5.6%

0.0%

33.3%

33.3%

0.0%

16.7%

16.7%

0.0%

50.0%

50.0%

0.0%

36.4%

32.4%

38.5%

47.6%

52.4%

45.2%

16.0%

15.2%

16.3%

96.8%

95.3%

97.6%

0.270

48.4%

57.4%

43.8%

0.046

53.3%

44.6%

57.6%

0.021

299 (25)
86.3 (62.83)
72.0 (48.0, 105.0)

98 (15)
83.9 (70.71)
68.0 (45.0, 97.0)

201 (10)
87.5 (58.77)
74.0 (50.0, 108.0)

301 (23)
218.1 (113.64)
195.0 (140.0, 275.0)

99 (14)
227.9 (141.98)
194.0 (136.0, 275.0)

202 (9)
213.3 (96.83)
196.0 (142.0, 275.0)

Intra-aortic balloon pump placement, %

Infarct-related artery TIMI flow, %

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Pre-intervention grade

Post-intervention grade

Interventions performed on non-IRAs, %

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Left main
Left circumflex
Right coronary
First device used on IRA, %
Atherectomy/thrombectomy
Balloon

Drug-eluting stent used, %

Bare metal stent used, %

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Hospital contact to first (IRA) device

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Stent

N (missing)
Mean (SD)
Median (25th , 75th percentiles)

49.3%
51.7%

0.719

98.6%

0.003

1.4%
0.0%
0.0%

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Percutaneous coronary intervention, %

Patients with any stent used, %

p-value
0.339

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Randomized treatment, %

0.002

0.054

0.550

0.356

Symptom onset to first device (Tot.Isch.Time)

N (missing)
Mean (SD)
Median (25th , 75th percentiles)

0.956

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Total
(N=324)

Non-IRA Disease
(N=113)

No
Non-IRA Disease
(N=211)

P-value

Unfractionated heparin

78.7%

73.5%

81.5%

0.092

Bivalirudin

17.3%

24.8%

13.3%

0.009

GP IIb/IIIa inhibitor

47.2%

48.7%

46.4%

0.702

Aspirin

57.1%

59.3%

55.9%

0.560

Nitroglycerin

48.0%

53.1%

45.2%

0.178

Enoxaparin

9.0%

11.5%

7.6%

0.239

Clopidogrel

51.2%

55.8%

48.8%

0.235

Ticlopidine

0.0%

Prasugrel

13.3%

Statin

38.6%

Beta-blocker

26.2%

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Periprocedure medications, %

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Anticoagulant use, %

0.0%

14.2%

12.8%

0.731

38.9%

38.4%

0.923

26.5%

0.864

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0.0%

25.7%

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Abbreviations: CABG, coronary artery bypass graft; GP, glycoprotein; IABC, intra-aortic balloon counterpulsation; IRA, infarct-related artery; SD,
standard deviation; TIMI, thrombolysis in myocardial infarction.

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Table 3: Clinical outcomes by presence of non-IRA disease
Total
(N=324)

Non-IRA Disease
(N=113)

No Non-IRA Disease
(N=211)

p-value

39 (27, 53)

39 (26, 53)

39 (28, 53)

0.7342

No angina

97.8%

95.5%

99.0%

Class I

0.3%

0.0%

Class II

0.3%

0.9%

Class III

0.6%

1.8%

Class IV

0.9%

1.8%

No angina

92.3%

91.5%

Class I

5.5%

5.7%

Class II

0.3%

Class III

1.0%

Class IV

1.0%

Infarct size, % left ventricle, median (25th, 75th percentiles)

0.0530

No angina
Class I
Class II
Class III
Class IV
All-cause death, %
Recurrent myocardial infarction, %
New/worsening HF with hospitalization, %

Major bleeding (per TIMI definition), %

Vascular complications, %

0.0%
0.0%
0.5%

0.8001

92.6%
5.4%
0.5%

1.9%

0.5%

0.9%

1.0%
0.4200

93.5%

90.6%

95.1%

2.6%

2.8%

2.5%

2.6%

4.7%

1.5%

0.6%

0.9%

0.5%

0.6%

0.9%

0.5%

2.8%

3.5%

2.4%

0.6141

0.9%

0.9%

0.9%

0.7771

4.3%

8.8%

1.9%

0.0050

0.3%

0.9%

0.0%

0.1744

0.6%

0.9%

0.5%

0.7722

2.8%

3.5%

2.4%

0.6141

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Major bleeding (per GUSTO I definition), %

0.5%

0.0%

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CCS classification at 6 months, %

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CCS classification at 30 days, %

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CCS classification post-procedure, %

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Abbreviations: CCS, Canadian Cardiovascular Society; GUSTO I, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded
Coronary Arteries; HF, heart failure; IRA, infarct-related artery; TIMI, Thrombolysis In Myocardial Infarction.

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Table 4: Non-IRA disease in unadjusted and adjusted* linear models of infarct size (% LV)
Model

Beta (95% CI)

P-Value

Unadjusted

268

-1.9 (-6.9 to 3.13)

0.46

Adjusted

248

-2.0 (-7.1 to 2.98)

0.43

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Adjusted model includes: (1) total ischemic time, and (2) pre-procedural TIMI = 0 or 1.
Abbreviations: CI, confidence interval; IRA, infarct-related artery; LV, left ventricle; TIMI, thrombolysis in myocardial infarction.

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337 patients randomized

in the CRISP-AMI trial

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324 patients with IRA

disease in LAD included
in this analysis

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5 with no IRA on CRF

7 with unidentified IRA
1 with IRA other than LAD

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113 patients with non-IRA disease

211 patients with no non-IRA

disease

117 included in analysis for infarct

size:
34 excluded from analysis
(either MRI not performed, or
performed but not evaluable)

113 included in analysis of

new/worsening HF with
hospitalization, major bleeding,
recurrent MI, and all-cause death

211 included in analysis of

new/worsening HF with
hospitalization, major bleeding,
recurrent MI, and all-cause death

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91 included in analysis for infarct

size:
22 excluded from analysis
(either MRI not performed, or
performed but not evaluable)

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Clinical Significance

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Nearly 35% of patients with anterior STEMI had non-IRA disease.

There was no difference in infarct size in patients with and without non-IRA disease at
time of acute MI.
There were similar rates of recurrent MI in patients with and without non-IRA disease at
6 months.
Patients with non-IRA disease did have a higher rate of new/worsening heart failure
with hospitalization.

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