JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
19, 2018
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VOL. 71, NO.
ª 2018 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN
COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER
THE CC BY-NC-ND LICENSE (http://creativecommons.org/licenses/by-nc-nd/4.0/).
4-Step Protocol for Disparities in
STEMI Care and Outcomes in Women
Chetan P. Huded, MD, MSC,a,b Michael Johnson, MD,a,b Kathleen Kravitz, MBA, RN,b Venu Menon, MD,b
Mouin Abdallah, MD,a,b Travis C. Gullett, MD,c Scott Hantz, RN,b Stephen G. Ellis, MD,b Seth R. Podolsky, MD,c
Stephen W. Meldon, MD,c Damon M. Kralovic, DO,c Deborah Brosovich, RN,b Elizabeth Smith, MPH,c
Samir R. Kapadia, MD,b Umesh N. Khot, MDa,b
ABSTRACT
BACKGROUND Women with ST-segment elevation myocardial infarction (STEMI) receive suboptimal care and have
worse outcomes than men. Whether strategies to reduce STEMI care variability impact disparities in the care and
outcomes of women with STEMI is unknown.
OBJECTIVES The study assessed the care and outcomes of men versus women with STEMI before and after imple-
mentation of a comprehensive STEMI protocol.
METHODS On July 15, 2014, the authors implemented: 1) emergency department catheterization lab activation; 2)
STEMI Safe Handoff Checklist; 3) immediate transfer to an immediately available catheterization lab; and 4) radial first
approach to percutaneous coronary intervention (PCI). The authors prospectively studied consecutive patients with
STEMI and assessed guideline-directed medical therapy (GDMT) before PCI, median door-to-balloon time (D2BT), in-
hospital adverse events, and 30-day mortality stratified by sex before (January 1, 2011 to July 14, 2014; control group)
and after (July 15, 2014 to December 31, 2016) implementation of the STEMI protocol.
RESULTS Of 1,272 participants (68% men, 32% women), women were older with more comorbidities than men. In the
control group, women had less GDMT (77% vs. 69%; p ¼ 0.019) and longer D2BT (median 104 min; [interquartile range
(IQR): 79 to 133] min vs. 112 [IQR: 85 to 147] min; p ¼ 0.023). Women had more in-hospital stroke, vascular complica-
tions, bleeding, transfusion, and death. In the comprehensive 4-step STEMI protocol, sex disparities in GDMT (84% vs.
80%; p ¼ 0.32), D2BT (89 [IQR: 68 to 106] min vs. 91 [IQR: 68 to 114] min; p ¼ 0.15), and in-hospital adverse events
resolved. The absolute sex difference in 30-day mortality decreased from the control group (6.1% higher in women;
p ¼ 0.002) to the comprehensive 4-step STEMI protocol (3.2% higher in women; p ¼ 0.090).
CONCLUSIONS A systems-based approach to STEMI care reduces sex disparities and improves STEMI
care and outcomes in women. (J Am Coll Cardiol 2018;71:2122–32) © 2018 The Authors. Published by Elsevier on
behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
S T-segment
guideline-directed
elevation
medical
myocardial
(STEMI) care provided to women lags behind
the care provided to men, with lower rates of
therapy
infarction
(GDMT) and
longer door-to-balloon times (D2BT) observed in
women (1–8). Moreover, women with STEMI have
worse clinical outcomes with
in-hospital adverse events and higher mortality
higher rates of
From the aHeart and Vascular Institute Center for Healthcare Delivery Innovation, Cleveland, Ohio; bHeart and Vascular Institute,
Cleveland Clinic, Cleveland, Ohio; and the cEmergency Services Institute of the Cleveland Clinic, Cleveland, Ohio. The funding
source was unrestricted philanthropic support to the Heart and Vascular Institute Center for Healthcare Delivery Innovation,
Cleveland Clinic. The funding source had no role in the design or conduct of the study; collection, management, analyses, or
interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publi-
cation. Dr. Ellis has served as a consultant for Abbott Vascular, Boston Scientific, and Medtronic. Dr. Khot has served as a
consultant for AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of this paper
to disclose.
Manuscript received February 22, 2018; accepted February 25, 2018.
ISSN 0735-1097 https://doi.org/10.1016/j.jacc.2018.02.039
JACC VOL. 71, NO. 19, 2018
MAY 15, 2018:2122–32
(4,7,9–14). In a recent meta-analysis of 68,536 pa-
tients with STEMI, female sex was independently
associated with a 48% higher relative risk of in-
hospital death (15). The American Heart Association
(AHA) has identified “closing knowledge gaps on
acute myocardial infarction.treatments for women”
as a “public health [priority]” (16). The 2017 European
Society of Cardiology STEMI guidelines acknowledge
that “women tend to receive.evidence-based treat-
ments less frequently.than men” and that women
“must be managed equally” (17). However, successful
strategies to improve STEMI care in women are
needed to achieve these goals.
SEE PAGE 2133
It is unknown whether a systems-based approach
to STEMI care that minimizes care variability can
achieve similar care and outcomes for men and
women. The purpose of this study was to describe the
care processes and clinical outcomes of men versus
women with STEMI before and after implementation
of a comprehensive 4-step STEMI protocol at our
institution.
METHODS
STUDY POPULATION. We performed a prospective,
observational registry-based study of consecutive
patients with STEMI treated with primary percuta-
neous coronary intervention (PCI) at our center from
January 1, 2011, to December 31, 2016. No patients
were excluded. Baseline characteristics, procedural
data, and in-hospital outcomes were collected pro-
spectively and adjudicated by the standards of the
American College of Cardiology National Cardiovas-
cular Data Registry (ACC NCDR) CathPCI data registry
(18).
CLEVELAND CLINIC COMPREHENSIVE 4-STEP STEMI
PROTOCOL. The Cleveland Clinic main campus hos-
pital is a 1,437-bed quaternary care center with 24/7
primary PCI capability. Our STEMI network includes
10 Cleveland Clinic hospitals and 3 free-standing
emergency departments (EDs) up to 60 miles in dis-
tance by ground transport. Our protocol for interfa-
cility transfer of patients with STEMI has been
previously published (19). On July 15, 2014, we
implemented a comprehensive 4-step STEMI protocol
to minimize STEMI care variability. We defined pa-
tients treated from January 1, 2011, to July 14, 2014, as
the control group, and patients treated from July 15,
2014, to December 31, 2016, as the comprehensive 4-
step STEMI protocol group.
In the control group, the decision to activate the
cardiac catheterization lab was made jointly between
Huded et al. 2123
Sex Disparities in STEMI Care and Outcomes
the ED physician, on-call cardiology fellow, ABBREVIATIONS
and cardiac catheterization lab physician. AND ACRONYMS
The initial triage and management including
ACC = American College of
administration of GDMT varied based on the Cardiology
expertise and preferences of the treating ED
AHA = American Heart
and cardiology physicians. Patients were Association
transferred from the ED or inpatient unit to D2BT = door-to-balloon time
the cardiac catheterization lab once an initial ED = emergency department
assessment was completed and the cardiac
GDMT = guideline-directed
catheterization lab was deemed ready to medical therapy
accept the patient, which occasionally PCI = percutaneous coronary
entailed a brief delay. At the time of primary intervention
PCI, the choice of radial versus femoral STEMI = ST-segment elevation
vascular access was operator dependent with myocardial infarction
some operators preferring radial and other operators
preferring femoral access.
By contrast, the comprehensive 4-step STEMI
protocol included the following 4 key process
changes. First, we improved the efficiency of cardiac
catheterization lab activation by implementing ED
physician cardiac catheterization lab activation
criteria without requiring delay for consultation with
cardiology. Second, we standardized the early triage
and management of STEMI patients including the
administration of GDMT by using a STEMI Safe
Handoff Checklist. The STEMI Safe Handoff Checklist:
1) outlines key roles of ED and cardiology nurses and
physicians to allow for each team member to perform
high acuity assessments simultaneously; 2) provides
guidance on the appropriate choice and route of
administration of GDMT; and 3) notifies the cardiac
catheterization lab team of factors, which may in-
crease the risk of PCI-related complications. Third, we
instituted a policy of immediate transfer to an
immediately available cardiac catheterization lab at
all times to avoid patient delays in awaiting readiness
of the cardiac catheterization lab (20). Only patients
with uncertain diagnosis or active resuscitation are
delayed in the ED or inpatient unit in our hospital.
Fourth, we transitioned to a radial first approach for
vascular access in primary PCI among suitable pa-
tients (21). Although individual operators were
allowed to choose the best site of vascular access for
each patient, use of the radial artery was highly
encouraged as the initial strategy in patients without
contraindications.
Multiple strategies previously associated with
D2BT performance improvements (22,23) were well
established at our institution during the control and
comprehensive 4-step STEMI protocol. These
included the transmission of pre-hospital electrocar-
diograms by emergency medical services, a single-call
to activate the catheterization lab team, in-house
cardiology fellows, performance data monitoring
2124 Huded et al. JACC VOL. 71, NO. 19, 2018

Sex Disparities in STEMI Care and Outcomes MAY 15, 2018:2122–32

T A B L E 1 Baseline and Procedural Characteristics

Control Group Comprehensive 4-Step STEMI Protocol

Men (n ¼ 490) Women (n ¼ 233) p Value Men (n ¼ 378) Women (n ¼ 171) p Value

Demographics and comorbidities

Age, yrs 59.6  11.5 63.5  14.1 <0.001 59.9  11.8 64.5  12.8 <0.001
Body mass index, kg/m2 28.8  5.4* 29.9  7.2 0.020 29.6  5.6* 30.8  8.1 0.062
Caucasian 69.0 (338) 60.5 (141)* 0.024 70.9 (268) 71.9 (123)* 0.819
Smoking history 47.6 (233) 43.8 (102) 0.342 45.2 (171) 41.5 (71) 0.399
Hypertension 69.7 (340) 81.1 (189) 0.001 75.1 (284) 83.6 (143) 0.024
Dyslipidemia 71.7 (350) 78.4 (181) 0.059 73.2 (276) 78.1 (132) 0.206
Family history of coronary artery disease 23.7 (116) 22.7 (53) 0.783 20.6 (78) 19.3 (33) 0.739
Prior congestive heart failure 13.1 (64) 12.9 (30) 0.929 12.4 (47) 15.8 (27) 0.281
Prior PCI 19.2 (94) 19.7 (46) 0.859 22.8 (86) 23.3 (40) 0.856
Prior coronary artery bypass surgery 5.1 (25) 5.2 (12) 0.978 3.7 (14) 5.8 (10) 0.252
End-stage renal disease on dialysis 1.6 (8) 1.3 (3) 1.000 1.3 (5) 2.3 (4) 0.470
Prior cerebrovascular disease 10.8 (53) 16.3 (38) 0.037 9.3 (35) 17.5 (30) 0.005
Prior peripheral artery disease 7.8 (38) 12.0 (28) 0.063 9.0 (34) 11.1 (19) 0.431
Chronic lung disease 10.2 (50) 14.2 (33) 0.119 9.0 (34) 21.1 (36) <0.001
Diabetes mellitus 25.7 (126) 40.3 (94) <0.001 31.2 (118) 42.7 (73) 0.008
Presenting location
Primary ED 22.7 (111) 27.9 (65) 0.020 25.4 (96) 24.6 (42) 0.973
Inter-hospital transfer 72.0 (353) 62.7 (146) 69.0 (261) 69.6 (119)
In-hospital 5.3 (26) 9.4 (22) 5.6 (21) 5.8 (10)
Procedural details
Nonsystem delay before PCI 20.0 (98) 29.2 (68) 0.006 18.3 (69) 21.6 (37) 0.352
Cardiogenic shock within 24 h before PCI 11.6 (57)* 15.9 (37)* 0.113 7.4 (28)* 8.8 (15)* 0.576
Out-of-hospital cardiac arrest 4.3 (21) 3.4 (8) 0.585 2.6 (10) 3.5 (6) 0.578
Baseline hemoglobin, mg/dl 14.7  2.0 13.1  2.0 <0.001 14.9  1.7 13.4  1.9 <0.001
Salvage PCI status 2.2 (11) 4.3 (10) 0.126 1.1 (4) 4.1 (7) 0.018
Transradial access for PCI 19.2 (94)† 17.2 (40)† 0.531 68.8 (260)† 62.6 (107)† 0.152
Peak troponin T, ng/ml 5.44  5.23 4.63  4.66 0.050 5.11  4.84 4.76  4.76 0.436
Intra-aortic balloon pump status
None 89.2 (437)* 84.1 (196) 0.100 90.4 (342)* 87.7 (150) 0.554
Prior to PCI 1.2 (6)* 0.4 (1) 0.5 (2)* 0.0 (0)
During PCI 5.5 (27)* 8.6 (20) 2.4 (9)* 2.9 (5)
After PCI 4.1 (20)* 6.9 (16) 6.6 (25)* 9.4 (16)
Mechanical ventilator status
None 97.3 (477) 95.7 (223) 0.071 98.9 (374) 98.8 (169) 0.373
Prior to PCI 1.0 (5) 3.0 (7) 0.5 (2) 0.0 (0)
During PCI 1.0 (5) 0.0 (0) 0.3 (1) 0.0 (0)
After PCI 0.6 (3) 1.3 (3) 0.3 (1) 1.2 (2)
Culprit artery
Left main 0.4 (2) 2.1 (5) 0.331 0.3 (1) 0.6 (1) 0.459
Left anterior descending 40.6 (199) 42.1 (98) 42.1 (159) 42.1 (72)
Left circumflex 18.0 (88) 16.7 (39) 18.0 (68) 17.5 (30)
Ramus intermedius 0.8 (4) 0.9 (2) 1.9 (7) 0.0 (0)
Right coronary 40.0 (196) 38.2 (89) 37.8 (143) 39.8 (68)
Bypass graft 0.2 (1) 0.0 (0) 0.0 (0) 0.0 (0)
Procedural medications (before or during PCI)
Bivalirudin 77.1 (378)† 75.5 (176)† 0.600 4.0 (15)† 1.2 (2)† 0.109
Glycoprotein 2b/3a inhibitor 27.8 (136)† 17.2 (40) 0.002 19.6 (74)† 17.0 (29) 0.467
Unfractionated heparin 81.2 (398)† 79.8 (186)† 0.618 98.7 (373)† 99.4 (170)† 0.671
Low-molecular weight heparin 0.6 (3) 1.3 (3) 0.394 0.8 (3) 1.2 (2) 0.649
Direct thrombin inhibitor 0.6 (3) 0.4 (1) 1.000 0 (0) 0.6 (1) 0.311
Fluoroscopy dose, Gy 2.03  1.45† 1.61  1.16 <0.001 1.60  1.01† 1.40  1.16 0.041
Contrast medium, ml 194  84† 177  74† 0.007 159  58† 151  59† 0.121

Values are mean  SD or % (n). Baseline hemoglobin was available in 1,262 patients, fluoroscopy dose in 1,268 patients, and contrast volume in 1,269 patients. *p < 0.05 for comparison of
control group versus Comprehensive 4-Step STEMI Protocol within sex. †p < 0.01 for comparison of control group versus Comprehensive 4-Step STEMI Protocol within sex.
ED ¼ emergency department; PCI ¼ percutaneous coronary intervention; STEMI ¼ ST-segment elevation myocardial infarction.
JACC VOL. 71, NO. 19, 2018 Huded et al. 2125
MAY 15, 2018:2122–32 Sex Disparities in STEMI Care and Outcomes

F I G U R E 1 Administration of GDMT

A Administration of GDMT Prior to Arterial Sheath Insertion for Primary PCI

100%

P = 0.320
90% P = 0.019
83.6%
80.1%
80% 76.7%

70% 68.5%

60%

50%
Control Group Comprehensive 4-Step STEMI Protocol

B Administration of GDMT Prior to Completion of Primary PCI

P = 0.028 P = 0.525

97.4% 98.2%
100% 96.7%
93.1%
90%

80%

70%

60%

50%
Control Group Comprehensive 4-Step STEMI Protocol

Men Women

GDMT for STEMI was defined as administration of aspirin, an oral P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor), and an anticoagulant
(low-molecular weight or unfractionated heparin before sheath insertion for PCI; low-molecular weight heparin, unfractionated heparin, or
bivalirudin before completion of PCI). (A) The % of patients in whom GDMT was administered before arterial sheath insertion for PCI was
significantly lower in women in the control group but was similar between sexes in the comprehensive 4-step STEMI protocol group. Among
men (p ¼ 0.013) and women (p ¼ 0.009), administration of GDMT before arterial sheath insertion for PCI increased after implementation of
the comprehensive 4-step STEMI protocol. The absolute magnitude of increase in GDMT administration was substantially greater in women.
(B) The % of patients in whom GDMT was administered before completion of PCI was significantly lower in women in the control group but
was similar between sexes in the comprehensive 4-step STEMI protocol group. Among women (p ¼ 0.017), but not men (p ¼ 0.595),
administration of GDMT before completion of PCI increased after implementation of the comprehensive 4-step STEMI protocol.
GDMT ¼ guideline-directed medical therapy; PCI ¼ percutaneous coronary intervention; STEMI ¼ ST-segment elevation myocardial
infarction.

and feedback, and interdisciplinary collaboration
between ED and cardiology providers.
STUDY ENDPOINTS. We studied the care processes
and clinical outcomes of men versus women in the
control group and the comprehensive 4-step STEMI
protocol. The care processes assessed were: 1)
administration of GDMT for STEMI; and 2) D2BT. We
assessed the timing of GDMT: 1) in relation to arterial
sheath insertion at the start of PCI; and 2) in relation
to the completion of the PCI procedure. GDMT was
defined as administration of aspirin, a P2Y12 inhibitor
(clopidogrel, prasugrel, or ticagrelor), and an antico-
agulant (low-molecular weight or unfractionated
heparin before sheath; low-molecular weight heparin,
unfractionated heparin, or bivalirudin before
completion of PCI). D2BTs were defined according to
ACC NCDR standards.
The clinical outcomes assessed were: 1) in-hospital
adverse events; and 2) 30-day mortality. In-hospital
2126 Huded et al. JACC VOL. 71, NO. 19, 2018

Sex Disparities in STEMI Care and Outcomes MAY 15, 2018:2122–32

F I G U R E 2 D2BT Performance

A Median Door-to-Balloon Time (Control Group)

350
Women +25 min
P = 0.352
300
Door-to-Balloon Time (min)

250

200
Women +8 min Women +12 min
P = 0.023 P = 0.022
150 Women +19 min
P = 0.006

100

50
104 112 62 81 111 123 105 130
0
Overall Primary ED Interhospital Transfer In-Hospital

B Median Door-to-Balloon Time (Comprehensive 4-Step STEMI Protocol)

350

300
Door-to-Balloon Time (min)

250

200

Women +2 min Women +4 min

150
P = 0.150 P = 0.089
Women –8 min
Women +3 min
100 P = 0.693
P = 0.561

50

89 91 53 56 99 103 66 58
0
Overall Primary ED Interhospital Transfer In-Hospital

Men Women

(A) In the control group, D2BT was significantly longer in women overall, among primary ED presenting patients, and among interhospital
transfer patients. Among patients with in-hospital presentation, D2BT was numerically longer in women than men but did not reach sta-
tistical significance. Median D2BT is shown with error bars indicating interquartile range. (B) In the comprehensive 4-step STEMI protocol
group, D2BT was similar between sexes overall and within each presenting location group. After implementation of the comprehensive 4-
step STEMI protocol, we observed shorter D2BT in men (overall p < 0.001; primary ED p ¼ 0.001; interhospital transfer p < 0.001; in-
hospital p < 0.001) and women (overall p < 0.001; primary ED p ¼ 0.004; interhospital transfer p < 0.001; in-hospital p ¼ 0.001)
compared with the control group. Median D2BT is shown with error bars indicating interquartile range. D2BT ¼ door-to-balloon time;
ED ¼ emergency department; STEMI ¼ ST-segment elevation myocardial infarction.

adverse events (post-PCI cardiogenic shock, stroke,
vascular complication, and bleeding) were each
adjudicated by the ACC NCDR CathPCI registry defi-
nitions by trained data abstractors. Survival status
at 30 days was ascertained by review of the medical
record and follow-up phone calls to patients in
whom survival status was not available in the
medical record. Survival status was complete in
98.7% (n ¼ 1,255) of the population, with 1.3% lost to
follow-up at 30 days.
STUDY DESIGN AND STATISTICAL ANALYSIS. Cate-
gorical variables are presented as n (%). Continuous
variables are presented as mean  SD. We used the
chi-square test and Fischer exact test as appropriate
to compare categorical variables and the independent
JACC VOL. 71, NO. 19, 2018 Huded et al. 2127
MAY 15, 2018:2122–32 Sex Disparities in STEMI Care and Outcomes

samples Student’s t-test to compare continuous var-

T A B L E 2 In-Hospital Adverse Events
iables. D2BT is presented as median with interquartile
range, and we used the nonparametric Mann- Comprehensive
Control Group 4-Step STEMI Protocol
Whitney U test to compare D2BT distributions be-
Men Women p Men Women p
tween groups. We used Kaplan-Meier life tables and (n ¼ 490) (n ¼ 233) Value (n ¼ 378) (n ¼ 171) Value
the log-rank test to compare 30-day mortality. We Post-PCI cardiogenic shock 7.3 (36) 8.2 (19) 0.684 4.5 (17) 4.7 (8) 0.925
performed additional sensitivity analyses of: 1) un- New heart failure 7.6 (37) 9.9 (23) 0.279 9.3 (35) 9.4 (16) 0.971
adjusted 30-day mortality with patients lost to Stroke 0.2 (1) 3.0 (7)* 0.002 0.8 (3) 0 (0)* 0.556

follow-up imputed as deceased; and 2) risk-adjusted Tamponade 0.4 (2) 0.4 (1) 1.000 0.8 (3) 0 (0) 0.556
New dialysis 1.4 (7) 0.4 (1) 0.447 1.6 (6) 1.2 (2) 1.000
30-day mortality (Online Figures 1 and 2). We used
Vascular complication 0.2 (1) 2.6 (6) 0.005 0.3 (1) 0.6 (1) 0.526
logistic regression models to study the association of
Bleeding 8.6 (42) 18.9 (44) <0.001 9.3 (35) 13.5 (23) 0.139
each STEMI system improvement and in-hospital
Nonaccess site 45.2 (19) 36.4 (16) 0.402 25.7 (9) 26.0 (6) 0.975
mortality. All analyses were performed using SPSS Access site 54.8 (23) 63.6 (28) 74.3 (26) 74.0 (17)
version 25 software (IBM, Armonk, New York). This Transfusion 8.4 (41) 13.3 (31) 0.037 7.1 (27) 9.4 (16) 0.371
study was approved by the institutional review board Coronary artery 4.3 (21) 2.1 (5) 0.149 3.4 (13) 1.8 (3) 0.412
bypass surgery
at the Cleveland Clinic, and waiver of written
LVEF #35% 22.9 (112)† 18.5 (43) 0.178 15.1 (57)† 16.4 (28) 0.698
informed consent was provided.
In-hospital 3.7 (18) 8.2 (19) 0.011 2.1 (8) 4.7 (8) 0.098
cardiovascular death
RESULTS In-hospital any death 4.5 (22) 10.3 (24)* 0.003 2.4 (9) 4.7 (8)* 0.150

The study population included 1,272 consecutive pa-
tients of which men were 868 (68.2%) and women
were 404 (31.8%) (Table 1). Patients presenting with
STEMI to our primary ED were 314 (24.7%), patients
presenting as interhospital transfers were
(69.1%), and the remaining 79 (6.2%) had in-hospital
STEMI. In both the control group and comprehen-
sive 4-step STEMI protocol group, women were on
average 4 years older with higher rates of cardiovas-
cular comorbidities compared with men. In the con-
Values are % (n). *p < 0.01 for comparison of control group vs. Comprehensive 4-Step STEMI Protocol within
sex. †p < 0.05 for comparison of control group vs. Comprehensive 4-Step STEMI Protocol within sex.
LVEF ¼ left ventricular ejection fraction; other abbreviations as in Table 1.
879
GDMT before arterial sheath insertion (p ¼ 0.009) and
before completion of PCI (p ¼ 0.017) both increased
after implementation of the comprehensive 4-step
STEMI protocol compared with the control group.
CARE PROCESS #2: D2BT. In the control group, me-

trol group, the rate of radial access for primary PCI
was similarly low between men and women (19.2% vs.
17.2%; p ¼ 0.531), and after implementation of the
comprehensive 4-step STEMI protocol, the rate of
radial access for primary PCI was similarly high
among men and women (68.8% vs. 62.6%; p ¼ 0.152)
demonstrating successful adoption of a radial first
approach to primary PCI in both sexes.
CARE PROCESS #1: GDMT. In the control group,
women received GDMT significantly less often than
men (Figure 1). The administration of GDMT was
lower in women both before arterial sheath insertion
for PCI as well as before completion of the PCI pro-
cedure. In the comprehensive 4-step STEMI protocol,
we observed no significant difference in the admin-
istration of GDMT between men and women either
before arterial sheath insertion or before completion
of PCI procedure. Among men, administration of
GDMT before arterial sheath insertion increased
(p ¼ 0.013) after implementation of the comprehen-
sive 4-step STEMI protocol, whereas there was no
significant change in administration of GDMT before
completion of PCI (p ¼ 0.595) compared with the
control group. Among women, administration of
dian D2BT was 8 min longer in women overall, 19 min
longer in women presenting to the primary ED, and
12 min longer in women presenting as interhospital
transfer with STEMI. Among patients with in-hospital
STEMI, median D2BT was 25 min longer in women,
but the difference did not reach statistical signifi-
cance. After implementation of the comprehensive
4-step STEMI protocol, we observed no significant
difference between men and women in D2BT overall
or among primary ED, interhospital transfer, or
in-hospital STEMI subgroups (Figure 2). After imple-
mentation of the comprehensive 4-step STEMI
protocol, we observed shorter D2BT in men (overall
p < 0.001; primary ED p ¼ 0.001; interhospital
transfer p < 0.001; in-hospital p < 0.001) and women
(overall p < 0.001; primary ED p ¼ 0.004; inter-
hospital transfer p < 0.001; in-hospital p ¼ 0.001)
compared with the control group.
CLINICAL OUTCOME #1: IN-HOSPITAL ADVERSE
EVENTS. Women suffered from higher rates of post-
PCI stroke, vascular complication, bleeding, trans-
fusion, and in-hospital death than men in the control
group. After implementation of the comprehensive
4-step STEMI protocol, we observed no significant
2128 Huded et al. JACC VOL. 71, NO. 19, 2018

Sex Disparities in STEMI Care and Outcomes MAY 15, 2018:2122–32

significant (Figure 3). Additional sensitivity analyses

F I G U R E 3 30-Day Mortality
of unadjusted 30-day mortality with missing patients
imputed as deceased and risk-adjusted 30-day mor-
A 30-Day Mortality (Control Group) tality provided similar results (Online Figures 1 and 2).
20% When patients were stratified by sex, we observed
numerically lower unadjusted all-cause mortality
All-Cause Mortality

15% from the control group to the comprehensive

Women 10.7%
4-step STEMI protocol (men 4.6% vs. 3.3%; log-
10% rank p ¼ 0.328; women 10.7% vs. 6.5%; log-rank
P = 0.002
Men 4.6%
p ¼ 0.128), which did not meet statistical significance.
5%
ASSOCIATION OF INDIVIDUAL STEMI SYSTEM
IMPROVEMENTS AND IN-HOSPITAL MORTALITY. In
0%
men, achievement of D2BT within national practice
0 5 10 15 20 25 30
goals (#90 min for primary ED/in-hospital STEMI
Follow-Up (Days)
or #120 min for interhospital transfer STEMI), GDMT
B 30-Day Mortality (Comprehensive 4-Step STEMI Protocol)
administration before arterial sheath insertion for
PCI, and radial access for PCI were each significantly
20%
associated with >50% reduction in the odds of in-
hospital mortality. In women, achievement of D2BT
All-Cause Mortality

15%
within national practice goals and radial access were
each significantly associated with >50% reduction in
10%
P = 0.090 Women 6.5% the odds of in-hospital mortality, whereas GDMT
administration before arterial sheath insertion for PCI
5% Men 3.3%
was associated with a 50% reduction in the odds of in-
hospital mortality, which did not reach statistical
0%
0 5 10 15 20 25 30 significance (Figure 4).
Follow-Up (Days)
DISCUSSION

Time-to-event analysis for all-cause mortality within 30 days of primary PCI is shown.
Survival status at 30 days was complete in 98.7% (n ¼ 1,255) of the population, with
1.3% lost to follow-up at 30 days. (A) In the control group, 30-day mortality was
significantly higher in women compared with men. (B) In the comprehensive 4-step
STEMI protocol group, 30-day mortality was numerically higher in women compared
with men, but did not reach statistical significance. Among men and women, 30-day
mortality decreased from the comprehensive 4-step STEMI protocol to the control group,
but did not meet statistical significance (men log-rank p ¼ 0.344, women log-rank
p ¼ 0.099). Abbreviations as in Figure 1.
difference between men and women in the rates of
any in-hospital adverse events (Table 2). After
implementation of the comprehensive 4-step STEMI
protocol, we observed a lower rate of left ventricular
ejection fraction #35% in men compared with the
control group, and lower rates of stroke and in-
hospital death in women compared with the control
group.
CLINICAL OUTCOME #2: 30-DAY MORTALITY. In the
control group, unadjusted all-cause mortality was
significantly higher in women compared with men,
with an absolute difference of 6.1%. In the compre-
hensive 4-step STEMI protocol, the absolute differ-
ence in mortality between women
diminished to 3.2% and was no longer statistically
Women in our series presented at an older age and
with a higher burden of cardiovascular comorbidities
compared with men. In the control group, the STEMI
care processes and clinical outcomes of women
were significantly worse than those of men,
consistent with the prior published reports
(1,5,8,10,12,14–16,24). Implementation of a compre-
hensive 4-step STEMI protocol was associated with
improved STEMI care and outcomes in men and
women, with greater absolute improvements in
women contributing to reduced sex disparities. The
resolution of sex disparities in use of GDMT and D2BT
performance translated into improved clinical out-
comes, with men and women having similarly low
rates of in-hospital adverse events and similar re-
ductions in 30-day mortality (Central Illustration).
Despite the higher risk profile of women with
STEMI compared with men, use of a systems-based
approach minimizing STEMI care variability led to
reduced sex disparities in care processes and clinical
outcomes.
The rate of GDMT use in STEMI is known to be less
in women compared with men. In an analysis of
and men 237,225 patients in the AHA GWTG-CAD (Get With
the Guidelines–Coronary Artery Disease) registry,
JACC VOL. 71, NO. 19, 2018 Huded et al. 2129
MAY 15, 2018:2122–32 Sex Disparities in STEMI Care and Outcomes

F I G U R E 4 Association of STEMI System Improvement and In-Hospital Mortality

D2BT at Goal GDMT Before Sheath Radial Access

0%

–10%
% Mortality Odds Reduction

–20%

–30%

–40%

–50%
–50%
–53% (+4%, –76%)
–60% –58% (–2%, –77%) P = 0.064
P = 0.043 –59%
(–12%, –79%) (–3%, –82%) –62%
–70% P = 0.021 –67% P = 0.042 (–6%, –85%)
(–30%, –84%) P = 0.036
P = 0.003

Men Women

In men, D2BT within national practice goals, GDMT before arterial sheath insertion for PCI, and radial access for PCI were each associated with
significant reduction in the odds of in-hospital mortality. In women, D2BT within national practice goals and radial access for PCI were each
associated with significant reduction in the odds of in-hospital mortality, whereas GDMT before arterial sheath insertion for PCI showed a
trend toward reduced odds of in-hospital mortality, which was not statistically significant. Percent reduction in odds of in-hospital mortality
(95% confidence intervals) and p values are shown. D2BT at goal defined as D2BT #90 min for primary ED/in-hospital STEMI and
D2BT #120 min for interhospital transfer STEMI. Abbreviations as in Figures 1 and 2.

women with acute myocardial infarction of all ages
were less likely to receive aspirin within 24 h of
arrival (3). Disparity in the administration of GDMT
suggests major systems-based deficiencies because
these differences are less likely to be attributed
to differing patient risk factor profiles. The early
management of STEMI patients requires rapid deci-
sion making on pharmacotherapy in the emergency
setting while also performing critical competing tasks
such as timely transport to the catheterization lab.
We resolved disparities in the use of GDMT in women
by use of a STEMI Safe Handoff Checklist, which
provides real-time clinical support to guide clinicians
in the choice and standard dosing of appropriate
pharmacotherapy during the early triage and man-
agement of STEMI patients.
The treatment delay in women with STEMI is well
established. Despite major improvements in D2BT
performance nationally in the United States, sex
disparity in D2BT performance has persisted. Among
42,149 patients with D2BT reported to the Center for
Medicare & Medicaid Services in 2010, women were
less often treated with D2BT #90 min (89.1% vs.
92.2%) and D2BT #75 min (66.3% vs. 71.9%) compared
with men (25). In recent years, studies of large
regional STEMI systems have demonstrated narrow
treatment delays between men and women, but no
prior study has demonstrated resolution of D2BT
delays in women (2,26). In a contemporary report of
23,809 patients treated within the AHA Mission:
Lifeline STEMI Systems Accelerator program, Hino-
hara et al. (27) observed consistently slower D2BT
in women versus men over time and no improvement
in D2BT in women despite significant improvements
in men in that study. Our findings suggest that
minimizing care variability across sexes in the deci-
sion and timing of catheterization lab activation and
immediate transfer to an immediately available
catheterization lab may translate into similar D2BT
performance in men and women.
Presentation with STEMI and female sex are both
known independent risk factors for bleeding after PCI
(28), and bleeding is known to be associated with
significantly increased mortality after STEMI (29–31).
The upfront medical therapies for STEMI include
highly potent antiplatelet and antithrombotic medi-
cines, and one of the challenges in treating women
with STEMI is achieving the right balance between
providing adequate antiplatelet/antithrombotic
treatment without increasing bleeding risk. Despite
major improvements in the prompt administration of
early potent antiplatelet/antithrombotic treatment
among women in our study, we observed a 5.4% ab-
solute decrease in bleeding rate and a 3.9% absolute
decrease in transfusion rate in women, confirming
the safety of a systems-based approach with a
2130 Huded et al. JACC VOL. 71, NO. 19, 2018

Sex Disparities in STEMI Care and Outcomes MAY 15, 2018:2122–32

C E NT R AL IL L U STR AT IO N Impact of a Comprehensive 4-Step STEMI Protocol on Sex Disparities in

STEMI Care and Outcomes

Comprehensive 4-Step STEMI Protocol

1. Standardized emergency department physician catheterization lab activation criteria
2. STEMI Safe Handoff Checklist
3. Immediate transfer to an immediately available catherization lab
4. Radial first approach for PCI

Men Fare Better than Women (%) Without Protocol With Protocol

10 10.3
9
8 8.2
7
7.1
6 6.1
5.8
5
4.9
4 4.2
3 3.5 3.2
2.8
2 2.2 2.3 2.4 2.3
1
0.3
0
0.8*
–1
Patients Door-to- Bleeding Transfusion Vascular Stroke In-hospital 30-day
receiving balloon events injury *With mortality mortality
guideline- time protocol,
directed women fare
medical therapy better
than men
Huded, C.P. et al. J Am Coll Cardiol. 2018;71(19):2122–32.

On July 15, 2014, we implemented a comprehensive 4-step STEMI protocol at our institution based on the 4 key principles as shown. Before this, women were treated
with lower-rates of GDMT and longer D2BT, contributing to higher rates of in-hospital adverse events and higher rates of 30-day mortality. After implementation of
the comprehensive 4-step STEMI protocol, sex disparities in STEMI care (administration of GDMT and D2BT performance) resolved, and sex disparities in clinical
outcomes (in-hospital adverse events and 30-day mortality) were mitigated. GDMT indicates administration of aspirin, a P2Y12 inhibitor, and an anticoagulant before
arterial sheath insertion for primary PCI. PCI ¼ percutaneous coronary intervention; STEMI ¼ ST-segment elevation myocardial infarction.

checklist to guide the administration of prompt
GDMT in women.
Compared with men, women are less likely to be
treated with transradial PCI for STEMI in the United
States (32) despite the fact that women are known to
derive major benefits from radial access for primary
PCI. Radial access offers fewer bleeding complica-
tions and improved survival compared with trans-
femoral access in STEMI patients (21,33). Moreover, a
recent analysis of 8,404 patients with acute coronary
syndromes in the MATRIX-Access (Minimizing
Adverse Haemorrhagic Events by Transradial Access
Site and Systemic Implementation of AngioX) trial
demonstrated that the benefit of transradial versus
transfemoral access was relatively greater in women
than in men (34). However, adoption of transradial
PCI for STEMI has been slow and is currently used
in <25% of patients with STEMI in the United States,
JACC VOL. 71, NO. 19, 2018 Huded et al. 2131
MAY 15, 2018:2122–32 Sex Disparities in STEMI Care and Outcomes

with considerable interoperator and interfacility
variability (32). Adoption of transradial PCI for STEMI
in women in particular may be limited because female
sex is an independent predictor of transradial PCI
failure (35). Despite this concern, we illustrate that
radial access for primary PCI can be successfully
adopted in women and men alike with concomitant
major reductions in D2BT in both sexes.
STUDY LIMITATIONS. First, this is an observational
study at a single STEMI referral center, and our
findings warrant validation across other centers.
However, no patients with STEMI treated with pri-
mary PCI were excluded from this prospective anal-
ysis, and our population should reflect the STEMI
population of any large urban STEMI referral center in
the United States. Second, we used a historical con-
trol group, and patients were not randomly assigned
to STEMI treatment protocols, which introduces the
possibility of undetected confounding. However,
women were higher risk than men, with older age and
higher burden of comorbidities in both the control
and comprehensive 4-step STEMI protocol groups.
Third, our study is underpowered to detect differ-
ences in mortality by sex. Although we did observe
promising reductions in 30-day mortality in both men
and women after implementation of the comprehen-
sive 4-step STEMI protocol, these changes did not
reach statistical significance and warrant validation
in a larger population.
CONCLUSIONS
Sex disparities in the care processes and clinical
outcomes of STEMI patients are well established.
Adoption of systems-based solutions for minimizing
STEMI care variability led to marked improvements in
care processes and clinical outcomes in women with
STEMI. This strategy offers the promise to provide
equal care of men and women, resolving the long-
standing sex gap in STEMI outcomes.
ACKNOWLEDGMENTS The authors wish to acknowl-
edge the important contributions of many personnel
from the Cleveland Clinic Emergency Services Insti-
tute, Critical Care Transport, and the Sones Cardiac
Catheterization Lab.
ADDRESS FOR CORRESPONDENCE: Dr. Umesh N.
Khot, Cleveland Clinic Heart and Vascular Institute
Center for Healthcare Delivery Innovation, 9500
Euclid Avenue, Desk J2-4, Cleveland, Ohio 44195.
E-mail: khotu@ccf.org.
PERSPECTIVES
COMPETENCY IN SYSTEMS-BASED PRACTICE: Strategies
are needed to reduce sex disparities in care and clinical outcomes
for patients with STEMI. A comprehensive protocol that includes:
1) standardized emergency department criteria for rapid referral
to the cardiac catheterization laboratory; 2) a safe handoff
checklist; 3) immediate patient transfer to the catheterization
laboratory; and 4) a radial first approach to primary PCI, im-
proves outcomes among both men and women with STEMI,
reducing sex disparity.
TRANSLATIONAL OUTLOOK: More work is needed to
implement systems of care for patients with acute STEMI based
on these principles and to identify other processes that further
enhance clinical outcomes for patients of either sex.

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KEY WORDS acute myocardial infarction,
door-to-balloon time, sex disparity, women,
percutaneous coronary intervention, STEMI
A PPE NDI X For supplemental figures, please
see the online version of this paper.