Comparison of Noninvasively and Invasively Managed

Patients, With or Without Revascularization in NoneST

Elevation Myocardial Infarction (from the Acute Coronary
Syndrome Israeli Survey)
Alex Blatt, MDa,b,*, Eran Kalmanovich, MDa,b, Orit Karny-Rahkovich, MDa,b, Svetlana Brener, MDa,b,
Meital Shlezinger, MScc, Nir Shlomo, MScc, Zvi Vered, MDa,b, Hanoch Hod, MDb,c,
Ilan Goldenberg, MDb,c, and Gabby Elbaz-Greener, MDa,b

Patients with noneST elevation myocardial infarction who are managed noninvasively at
presentation or are catheterized but without revascularization represent a heterogeneous
and understudied population. We evaluated the clinical characteristics, management
strategies, and outcomes of patients with noneST elevation myocardial infarction
(NSTEMI) who were enrolled in the prospective biannual Acute Coronary Syndrome Israeli
Surveys from 2004 to 2013. Patients were divided into 3 groups: no catheterization (no
angio), catheterization with revascularization (angio-revascularized), and catheterization
without revascularization (angio-nonrevascularized) groups. The study included 3,198
patients with NSTEMI. Coronary angiography was performed in 2,525 (79%) during the
index hospitalization, of whom 1899 (59%) underwent revascularization. Evidence-based
therapies were administered during the index hospitalization at a significantly higher
rate to those in the angio-revascularized group compared with the other 2 groups. Multi-
variate analysis showed that compared with those in the angio-revascularized and angio-
nonrevascularized groups, patients in the no angio group experienced a significantly
higher risk for 1-year mortality (hazard ratio 2.04 [p £0.0001] and 1.21 [p [ 0.01],
respectively). The risk associated with no revascularized was consistent in each risk subset
analyzed, including an older age, and increased creatinine levels. In conclusion, our data,
from a large real-world contemporary experience, suggest that patients with NSTEMI who
do not undergo coronary revascularization during the index hospitalization represent a
greater risk and undertreated group with increased risk for long-term mortality. Ó 2016
Elsevier Inc. All rights reserved. (Am J Cardiol 2016;118:1e5)

In patients with noneST elevation myocardial infarction
(NSTEMI) with moderate to high risk characteristics, cur-
rent guidelines recommend an invasive strategy with angi-
ography followed by percutaneous coronary intervention
(PCI) or coronary artery bypass grafting (CABG) if appro-
priate.1 In clinical practice, 27% to 48% and 45% to 69% of
this patient population do not undergo catheterization and
revascularization procedures respectively.2 Several studies
have highlighted the higher morbidity and mortality rates for
such patients.3e6 These findings suggest that this is a high-
risk population, yet these patients are undertreated with
evidence-based therapies.6 Patients with NSTEMI who are
managed without revascularization represent a heteroge-
neous and understudied population.7 Furthermore, currently,
there are limited data regarding the clinical characteristics
a
Department of Cardiology, Assaf Harofeh Medical Center, Zerifin,
Israel; bThe Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv,
Israel; and cThe Heart Center, Chaim Sheba Medical Center, Tel Hashomer,
Israel. Manuscript received January 21, 2016; revised manuscript received
and accepted March 31, 2016.
See page 5 for disclosure information.
*Corresponding author: Tel: þ972 537345906; fax: þ972 89779349.
E-mail address: alexb@asaf.health.gov.il (A. Blatt).
and outcomes of patients with NSTEMI who do not undergo
coronary revascularization during the index event in a
contemporary real-world setting. In this study, we evaluated
the clinical characteristics, medical management, and out-
comes of patients with NSTEMI who were enrolled in the
prospective Israeli Acute Coronary Syndrome Israeli sur-
veys (ACSIS). Patients were categorized as those who were
managed medically without intervention, compared with
those who were managed with an invasive strategy, with or
without revascularization.
Methods
The ACSIS is a national survey conducted in Israel since
1992. Details of these nationwide registries have been pre-
viously reported.8 Briefly, ACSIS is conducted during a
period of 2 months, once in 2 years. Data are prospectively
collected from all patients discharged with any diagnosis
corresponding to the acute coronary syndrome (ACS)
spectrum in each of the 25 coronary care units and cardi-
ology wards operating in Israel. Demographic and clinical
data are recorded on prespecified forms for all these patients.
The discharge diagnoses are recorded as determined by the
attending physicians based on clinical, electrocardiographic,
and biochemical criteria. In-hospital and 30-day outcome

0002-9149/16/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. www.ajconline.org
http://dx.doi.org/10.1016/j.amjcard.2016.03.054
2 The American Journal of Cardiology (www.ajconline.org)

Acute Coronary Syndrome Table 1

(n=6088) Patient baseline characteristics
Variable No-Angio Angio-No Angio-Revasc p
(n¼673) -Revasc (n¼1899)
(n¼ 626)

Age (years) 71. 98  12.9 64.02 12.4 63.69  12.2 < 0.001
(mean SD)
Non-ST elevaƟon myocardial
infarcƟon (NSTEMI) Women 30.9 26.6 20.3 < 0.001
(n=3198) Body Mass Index 28.72  8.0 29.18 17.8 28.69  13.61 0.01
(kg/m2)
(mean þSD)
Weight (kg) 77.1  15.7 79.9  16.9 80.9  15.6 <0.001
No Angiography Angiography (mean SD)
(n=673) (n=2525) Diabetes Mellitus 50.9 % 42.1 % 36.5 % <0.001
Hypertension 78.5 % 68.4 % 64.3 % <0.001
Dyslipidemia 68.0 % 72.5 % 74.1 % 0.08
Family history of 15.8 % 24.5 % 28.2 % <0.001
Coronary Artery
No RevascularizaƟon Any RevascularizaƟon
Disease
(n=626) (n=1899)
Current Smoker 21.0 % 33.5 % 36.6 % <0.001
Prior Myocardical 48.8 % 37.7 % 30.0 % <0.001
Figure 1. NSTEMI patient population subgroups analysis flow chart.
Infarction
Prior Percutaneous 38.3 % 34.3 % 32.8% 0.033
Coronary
data are ascertained by hospital chart review, telephone Intervention
contact, and clinical follow-up data. Patient management is Prior Coronary 22.8 % 13.2 % 11.2 % <0.001
at the discretion of the attending physicians. Mortality data Arterial By-Pass
during hospitalization and at 30 days and 1 year after Grafts
hospitalization are determined for all patients from hos- Chronic heart 25.3 % 8.3 % 7.7 % <0.001
failure
pital charts and by matching identification numbers of
Chronic Kidney 34.8 % 15.3 % 10.2 % <0.001
patients with the Israeli National Population Register. All Disease
parameters captured by the registry are defined by Past Cerebro- 15.5 % 9.8 % 7.5 % <0.001
protocol. Vascular
The population of the present study comprises patients Accident
included in ACSIS surveys from the years 2004 to 2013, Peripheral Vascular 18.6 % 10.4 % 7.9 % <0.001
who were admitted with NSTEMI, that is, clinical picture of Disease
ACS without STEMI and increase of cardiac biomarkers, Aspirin 61.9 % 55.6 % 52.0 % <0.001
principally troponin. Patients with STEMI and patients with Oral anticoagulants 10.5 % 4.6 % 3.7 % <0.001
an increase in cardiac biomarkers whose predominant clin- Beta blockers 55.9 % 41.3 % 40.3 % <0.001
Nitrates 24.6 % 11.6 % 10.0 % <0.001
ical picture was not of an ACS (i.e., heart failure, sepsis,
Diuretics 38.1 % 23.6 % 18.3 % <0.001
pulmonary embolism, arrhythmias) were not included. For Angiotensin- 54.3 % 46.8 % 40.2 % <0.001
this analysis, patients were categorized as who were treated Converting-
conservatively only without coronary angiography (“no Enzyme
angio group”). The angio group was further classified by Inhibitor /
patients who underwent revascularization, percutaneously or Angiotensin
bypass graft operation (“angio-revascularized group”), and Receptor Blocker
those who did not undergo intervention (“angio-non- Statins 55.9 % 53.0 % 50.7 % 0.05
revascularized group”). Patients admitted with STEMI or Insulin 14.8 % 10.4 % 7.4 % <0.001
discharged as unstable angina were not included in the Anti-hyperglycemic 29.9 % 28.2 % 24.2 % <0.01
drugs
current analysis. Major adverse cardiac events (MACE) at
Creatinine (mg%) 2.03  7.47 1.2 0.88 1.39  4.7 <0.001
30 days were defined by the composite outcome of death, (mean SD)
unstable angina, and reinfarction. Glomerular 57.2  66 78.176 87.0  309.3 <0.001
Characteristics of study participants were compared us- Filtration Rate
ing the chi-square test for categorical variables and the (ml/min)
Student t test or Wilcoxon rank tests, as appropriate for (mean SD)
continuous variables. The KruskaleWallis test was used for Hemoglobin (g/dL ) 12.2  2.2 13.4 1.8 13.8  3.6 <0.001
comparison of nonnormally distributed continuous vari- (mean SD)
ables. The probability of all-cause mortality during 30-day Creatine 500.9  1161 373.7 481 432.7  623 <0.001
and 1-year interval was graphically displayed using the Phosphokinase
(IU) (mean SD)
KaplaneMeier method. Cox proportional hazards
Glucose (mg%) 174  90 153  81 146  74 0.001
multivariate-adjusted survival models were used to evaluate (mean SD)
the independent effects of treatment groups on 7 days,
 Coronary Artery Disease/Comparison Managements in NSTEMI 3

40 18
<0.001
<0.001 16
35
<0.001
30 14
12
25
10
Angio-revasc. 20
Angio-revasc. 8
Angio-non-revasc. <0.001 15
Angio-non-revasc. 6
<0.001 <0.001 <0.001 <0.001
0.006
No-Angio 10 No-Angio 4
<0.001 <0.001
5 0.004
2
NS
0 0
n
n

tio
tio

ila
ita

nt
sc

Ve
su
Re

Figure 2. Clinical presentation.

Table 2 Figure 3. In-hospital complications.

In-hospital management
Variable No-Angio Angio-No-Revasc Angio-Revasc p Table 3
(n¼673) (n¼ 626) (n¼1899) Medications prescribed at hospital discharge
Coronary arterial 0 0 8.8 % <0.001 Variable Angio-Revasc Angio-No-Revasc No-Angio p
by-pass grafts (n¼1899) (n¼ 626) (n¼673)
Percutaneous 0 0 92.2 % <0.001
coronary Aspirin 84.4 % 94.3 % 97.7 % <0.001
intervention Beta blockers 75.4 % 81.0 % 81.5 % 0.002
Aspirin 90 % 96.2 % 98.4 % <0.001 P2Y12 receptor 48.3 % 44.0 % 78.3 % <0.001
Clopidogrel 61.8 % 73.6 % 88.1 % <0.001 inhibitors
Beta blockers 81.7 % 84.3 % 84.0 % 0.335 Angiotensin- 65.9 % 71.7 % 77.5 % <0.001
Angiotensin- 70.4 % 74.5 % 79.3 % <0.001 converting-
converting- enzyme inhibitor/
enzyme A Angiotensin
inhibitor / receptor blocker
Angiotensin Statins 77.4 % 89.4 % 94.3 % <0.001
receptor blocker Digoxin 4.4 % 1.0 % 0.9 % <0.001
Statins 79.1 % 91.7 % 93.3 % <0.001 Diuretic 44.7 % 25.7 % 21.4 % <0.001
Digoxin 5.5 % 1.4 % 1.1 % <0.001 Nitrates 24.7 % 13.3 % 8.6 % <0.001
Diuretic 53.4 % 31.2 % 24.5 % <0.001 Low molecular 19.1 % 14.1 % 6.5 % <0.001
Nitrates 34.4 % 28.2 % 23.9 % <0.001 weight heparin
Oral 7.4 % 4.4 % 3.3 % <0.001 Oral anticoagulants 8.5 % 5.2 % 3.6 % <0.001
Anticoagulants
Hospital duration 7.1  6.3 6.8  6.2 5.8  5.1 <0.001
(days)
patients with an admission diagnosis of NSTEMI, coronary
angiography was performed in 2,525 patients (79%) during
the index hospitalization, of whom, 1,899 (59%) underwent
30-day and 1-year all-cause mortality results presented as a revascularization intervention. The baseline clinical char-
hazard ratio (HR) and CI 95%. Logistic regression was used acteristics of study patients are presented in Table 1.
to evaluate the association between treatment group and Compared with the angio groups, patients in the no angio
MACE. All multivariate models were further adjusted for group was significantly older and with higher rates of
the additional prespecified covariates: gender, age, hyper- baseline clinical risk factors, known coronary artery disease,
tension, diabetes mellitus, dyslipidemia, chronic kidney chronic heart failure, symptomatic noncardiac atheroscle-
disease, current smoking, a family history of coronary artery rosis, and lower mean hemoglobin level. Accordingly were
disease (CAD), electrocardiogram at arrival, coronary artery prescribed higher rates of cardiovascular medications before
disease, previous MI, a history of heart failure, past PCI, admission.
past CABG, stroke, and peripheral vascular disease. Patients who underwent coronary angiography (with or
without intervention) were more likely to present
with typical angina (70%) as compared with those in the no
Results
angio group (51%; p <0.001) but had significant lower
A total of 6,088 patients were included in the last 5 frequency of high-risk admission clinical features
ACSIS. A total of 3,198 patients (54%) were admitted with (Figure 2). Hospital management of the study patients by the
a diagnosis of NSTEMI (Figure 1). Among the 3,198 study revascularization strategy is summarized in Table 2. The
4 The American Journal of Cardiology (www.ajconline.org)
Figure 4. KaplaneMeier mortality rates in the 3 prespecified angio
subgroups.
Direct Adjusted Survivor Functions
1.0
0.8
Survival Probability
0.6
0.4
0.2
0.0
0 100 200
DAYS
revascular_angio NO ANGIO
Figure 5. Adjusted survival curves for the 3 prespecified coronary angi-
ography groups. Findings are further adjusted for age, previous heart fail-
ure, creatinine >1.5 mg/dl, hemoglobin <12.0, acute heart failure, and
cardiogenic shock.
overall revascularization rate was 60%. Among patients who
underwent coronary revascularization, 92% were treated
with PCI and 8% underwent CABG. During hospital stay,
the medical management of ACS was more closely followed
per guidelines in the angio groups, as reflected in the higher
rate of dual antiplatelet treatment, Angiotensin converting
enzyme inhibitors/Angiotensin receptor blockers, and statins
administration than for the no angio group. Drugs to relieve
heart failure or angina symptoms, such as nitrates, furose-
mide, and digoxin, were given significantly more frequently
in the no angio group. Consistent with those findings, rates
of all cardiovascular and other in-hospital complications
were statistically higher in the no angio group, as illustrated
in Figure 3.
Hospital discharge medications for all groups are
described in Table 3. Similar to the management during
hospital stay, the optimal use of medical ACS treatment at
discharge was significantly greater in the angio groups,
whereas heart failure and angina relief symptom medica-
tions were prescribed significantly more frequently in the no
angio group.
The KaplaneMeier survival analysis showed that 1 year
of follow-up the cumulative probability of all-cause mor-
tality was significantly higher in patients who were not
referred to coronary angiography during the index hospi-
talization (5%) compared with the 2 groups who underwent
coronary angiography (1%, log-rank p value <0.001 for the
comparison among the 3 groups during follow-up
p <0.001
[Figure 4]). Multivariate analysis, after adjustment for age,
creatinine, and hemoglobin levels, showed consistent results
(Figure 5). Compared with those in the angio-revascularized
and angio-nonrevascularized groups, patients in the no
angio group experienced a significantly greater risk for 1-
year mortality (HR 2.04 95% [p 0.0001] and 1.21 95%
[p ¼ 0.01], respectively). The mortality in the no angio
group was more than double, compared with the angio-
revascularized group (HR 2.04), whereas the angio-
nonrevascularized has 20% higher mortality compared
with the same group (HR 1.21). Subgroup analysis showed
that the increased risk for 1-year mortality associated with
no coronary angiography was consistent in each high-risk
subset analyzed, including older patients (>75 years), and
those with higher creatinine levels (>1.5 mg/dl) during the
index admission (Figure 6).
Discussion
The present study provides contemporary data regarding
the clinical characteristics and outcomes of patients with
NSTEMI who are not referred for coronary angiography,
despite a recommendation for an invasive approach in this
population by current clinical practice guidelines. Our
findings provide real-world data regarding the high-risk
300 clinical and adverse clinical outcomes of patients with
NSTEMI who are not referred for coronary angiography in a
REV_ANGIO NON_REV_ANGIO
contemporary cohort who were enrolled in a prospective
survey over the past decade. We have shown that the de-
cision to catheterize is crucial because the “no angiography”
path is highly predictive of under treatment, high rates of in-
hospital and long-term complication and adverse events, and
higher mortality at one year.
Despite their high-risk profile and high prevalence,
medically managed patients are underrepresented in many
large-scale randomized clinical trials.9 Moreover, large-
scale randomized prospectively multicenter trial was per-
formed in this field. Prospective evaluation in the PLATelet
inhibition and patient Outcomes (PLATO) substudy of pa-
tients admitted with ACS showed higher rates of all-cause
death and MACE at 30 days, for patients who were pre-
specified as planned for noninvasive management than for
the entire PLATO population, in both the ticagrelor and
clopidogrel arms.10
In the clinical practice, Chan et al2 describe 27% to 48%
and 45% to 69% of this patient population does not undergo
catheterization and revascularization procedures respec-
tively. In our study, the proportions of patients who un-
derwent catheterization and angiography with
revascularization were relatively high (close to 80% and
60% respectively), higher than the proportions reported in
the studies.2 Our findings corroborate the highest rate of co-
morbidities, the worst clinical profile risk, and the worst
outcomes for patients who did not undergo coronary
 Coronary Artery Disease/Comparison Managements in NSTEMI
Impact of Period on 1-Year Survival
Hazard Ratio and 95% CI
No-Angio
NO_A NGIO
Angio-no-revasc
NO_REV_A NGIO
No-Angio
NO_A AgeBOVE
NGIO_A > 75 years
Angio-no-revasc
NO_REV_A NGIO_AAge > 75 years
BOVE
No-Angio Age < 75 years
NO_A NGIO_BELOW
Angio-no-revasc Age < 75 years
NO_REV_A NGIO_BELOW
No-Angio CreaƟnine > 1.5 mg%
NO_A NGIO_CREBELOW
Angio-no-revasc. CreaƟnine > 1.5 mg%
REV_A NGIO_CREBELOW
No-Angio CreaƟnine < 1.5 mg%
NO_A NGIO_CREA BOVE
Angio-no-revasc. CreaƟnine < 1.5 mg%
REV_A NGIO_CREA BOVE
0.1 1 10
Figure 6. Hazard ratios between no angio and angio-nonrevascularized groups, compared with angio-revascularized group.
angiography.3e6 This observation, combined with the
higher diagnosis of secondary MI in this group, leads to the
hypothesis that myocardial injury in this population is a
surrogate indicator of a worse clinical condition rather than
of a primary disease. This can explain and justify the
underuse of the invasive approach. In contrast, based on our
present findings, we can hypothesize that an invasive
approach in selected patients of this very high-risk NSTEMI
population may be possibly associated with reduced short-
and long-term adverse clinical outcomes and mortality.
Study limitations: This is an observational, retrospec-
tive study design to show the clinical characteristics and
outcomes of this population, but not to evaluate the benefit
management strategies in this population, for this purpose, a
prospective study would be required.
Disclosures
The authors have no conflicts of interest to disclose.
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