Accepted Manuscript

Incidence and Prognostic Impact of Heart Failure Hospitalization During Follow

Up After Primary Percutaneous Coronary Intervention in ST-Segment Elevation
Myocardial Infarction

Tomohiko Taniguchi, MD, Hiroki Shiomi, MD, Takeshi Morimoto, MD, MPH, Hirotoshi
Watanabe, MD, Koh Ono, MD, Satoshi Shizuta, MD, Takao Kato, MD, Naritatsu
Saito, MD, Shuichiro Kaji, MD, Kenji Ando, MD, Kazushige Kadota, MD, Yutaka
Furukawa, MD, Yoshihisa Nakagawa, MD, Minoru Horie, MD, Takeshi Kimura, MD
PII: S0002-9149(17)30298-9
DOI: 10.1016/j.amjcard.2017.03.013
Reference: AJC 22474

To appear in: The American Journal of Cardiology

Received Date: 18 December 2016

Revised Date: 23 February 2017
Accepted Date: 1 March 2017

Please cite this article as: Taniguchi T, Shiomi H, Morimoto T, Watanabe H, Ono K, Shizuta S, Kato
T, Saito N, Kaji S, Ando K, Kadota K, Furukawa Y, Nakagawa Y, Horie M, Kimura T, Incidence and
Prognostic Impact of Heart Failure Hospitalization During Follow Up After Primary Percutaneous
Coronary Intervention in ST-Segment Elevation Myocardial Infarction, The American Journal of
Cardiology (2017), doi: 10.1016/j.amjcard.2017.03.013.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.
 1
ACCEPTED MANUSCRIPT

Incidence and Prognostic Impact of Heart Failure Hospitalization During Follow Up After

Primary Percutaneous Coronary Intervention in ST-Segment Elevation Myocardial Infarction

Short title: Heart failure after acute myocardial infarction

Tomohiko Taniguchi, MDa; Hiroki Shiomi, MDa; Takeshi Morimoto, MD, MPHb; Hirotoshi Watanabe, MDa;

Koh Ono, MDa; Satoshi Shizuta, MDa; Takao Kato, MDa; Naritatsu Saito, MDa; Shuichiro Kaji, MDc; Kenji

PT
Ando, MDd; Kazushige Kadota, MDe; Yutaka Furukawa, MDc; Yoshihisa Nakagawa, MDf; Minoru Horie,

RI
MDg; Takeshi Kimura, MDa

Institutions: aDepartment of Cardiovascular Medicine, Kyoto University Graduate School of Medicine,

SC
Kyoto, Japan; bDepartment of Clinical Epidemiology, Hyogo College of Medicine, Nishinomiya, Japan;
c
Division of Cardiology, Kobe City Medical Center General Hospital, Kobe, Japan; dDepartment of

U
Cardiology, Kokura Memorial Hospital, Kokura, Japan; eDepartment of Cardiovascular Medicine, Kurashiki
AN
Central Hospital, Kurashiki, Japan; fDivision of Cardiology, Tenri Hospital, Tenri, Japan; g Departments of
M

Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.

Corresponding author: Takeshi Kimura, MD

D

Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
TE

54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan

TEL: +81-75-751-4255 FAX: +81-75-751-3299

EP

Email: taketaka@kuhp.kyoto-u.ac.jp

Funding Sources: Ministry of Health, Labour and Welfare and the Pharmaceuticals and Medical Devices
C

Agency (PMDA) in Japan.

AC

1
 2
ACCEPTED MANUSCRIPT

Abstract

The incidence of heart failure (HF) hospitalization and its impact on long-term outcomes have not been well evaluated in

contemporary patients with ST-segment elevation myocardial infarction (STEMI) following primary percutaneous

PT
coronary intervention (PCI). The CREDO-Kyoto Acute Myocardial Infarction (AMI) Registry is a multicenter registry

enrolling 5429 consecutive AMI patients undergoing PCI from 2005 to 2007. The present study population consisted of

RI
3682 patients with STEMI who underwent primary PCI within 24 hours of symptom onset and discharged alive. The

SC
incidence rate of HF hospitalization was 4.4%/year during the first year after the index STEMI, which attenuated to

U
approximately 1.0%/year beyond 1-year to 5-year with the median follow-up period of 1956 days. The independent risk
AN
factors for HF hospitalization within 1 year included older age, prior myocardial infarction, heart failure at STEMI, left
M

ventricular dysfunction, anterior AMI, and onset to balloon time >3 hours, use of beta blocker and non-use of statin at
D

discharge. By the landmark analysis at 1-year, the cumulative incidences of all-cause death and HF hospitalization
TE

beyond 1-year and up to 5-year were significantly higher in patients with HF hospitalization within 1-year of STEMI

than in patients without (36.3% vs. 10.1%, P<0.001, and 40.4% vs. 4.3%, P<0.001, respectively). Even after adjusting for
EP

confounders, HF hospitalization within 1-year remained independently associated with a higher risk for death and HF
C

hospitalization beyond 1-year (hazard ratio [HR] 1.64, 95% confidence interval [CI] 1.02-2.52, P=0.04, and HR: 5.72,
AC

95% CI: 3.46-9.22, P<0.001, respectively). In conclusion, HF hospitalization within 1-year was independently associated

with a higher risk for all-cause death and HF hospitalization beyond 1-year.

Key words: myocardial infarction; heart failure; percutaneous coronary intervention

2
 3
ACCEPTED MANUSCRIPT

Mortality after ST-segment elevation myocardial infarction (STEMI) has been improved through widespread

and timely use of primary percutaneous coronary intervention (PCI),1,2 and through the optimal secondary prevention

therapies, with in-hospital mortality decreasing to about 5-10%.3-5 Primary PCI at early phase of STEMI reduces infarct

PT
size and decreases the risk of developing a substantial reduction of left ventricular ejection fraction (LVEF) and

subsequent development of heart failure (HF).6,7 On the other hand, improved survival of patients with myocardial

RI
infarction (MI) might have created a population with residual myocardial damage and a higher risk for developing HF.8,9

SC
Other factors such as an aging population and a decrease in sudden death due to penetration of implantable cardioverter

U
defibrillator (ICD) therapy might contribute to the increasing prevalence of HF after MI. In previous studies with and
AN
without primary PCI, HF hospitalization after MI was declining,7,10,11 and HF on admission and after discharge was
M

associated with increased short- and long-term mortality.12-14 However, the incidence of HF hospitalization and the
D

impact of HF hospitalization after discharge on long-term clinical outcomes in STEMI patients following primary PCI
TE

have not been well evaluated in a contemporary cohort of STEMI patients except for the post hoc analysis of randomized

HORIZONS-AMI trial, which included less severe HF such as New York Heart Association (NYHA) class 1 or 2.15
EP

Therefore, we sought to investigate the incidence and predictors of HF hospitalization and the impact of HF
C

hospitalization on long-term outcomes among STEMI patients treated with primary PCI in a large-scale multicenter acute
AC

myocardial infarction (AMI) registry in Japan.

Methods

The Coronary REvascularization Demonstrating Outcome Study in Kyoto (CREDO-Kyoto) AMI registry is a

physician initiated, non-company sponsored, multicenter registry enrolling consecutive patients with AMI having

3
 4
ACCEPTED MANUSCRIPT

coronary revascularization between January 2005 and December 2007 across 26 tertiary hospitals in Japan, excluding

those patients who underwent coronary revascularization after seven days of the onset of suspected AMI symptoms

(Supplementary Appendix A).16 The relevant review boards or ethics committees in all 26 participating centers approved

PT
the study protocol. Obtaining written informed consent from the patients was waived because of the retrospective study

design. Among 5429 patients enrolled in the CREDO-Kyoto AMI registry, 9 patients were excluded because of their

RI
refusal to participate in the study when contacted at follow-up. We also excluded 195 patients who had coronary artery

SC
bypass grafting surgery after the index AMI, 789 patients with non-STEMI, 494 patients who received PCI beyond 24

U
hours after onset, and 260 patients who died during the index hospitalization (Figure 1). Therefore, the study population
AN
for the current analysis consisted of 3682 STEMI patients who had primary PCI within 24 hours of onset and survived to
M

hospital discharge.
D

Experienced clinical research coordinators in the independent research organization (Research Institute for
TE

Production Development, Kyoto, Japan) collected demographic, angiographic, and procedural data from the hospital

charts or hospital databases according to the pre-specified definitions (Supplementary Appendix B)17. Collection of
EP

follow-up information was mainly conducted through review of the inpatient and outpatient hospital charts by the clinical
C

research coordinators, and additional follow-up information was collected through contact with patients, relatives and/or
AC

referring physicians by sending mail with questions regarding vital status and subsequent hospitalizations. Serious

adverse events such as death, MI, and HF hospitalization were adjudicated by the clinical event committee

(Supplementary Appendix C). HF hospitalization was defined as hospitalization due to worsening HF requiring

intravenous drug therapy. The detailed definitions of other baseline clinical characteristics were described previously.16,17

4
 5
ACCEPTED MANUSCRIPT

Primary outcome measures for the current analysis included all-cause death and HF hospitalization. As the secondary

outcome measure, we also evaluated cardiac death, sudden death, non-cardiac death, MI, stroke, and any coronary

revascularizaion. Death was regarded as cardiac in origin unless obvious non-cardiac causes could be identified.

PT
We present continuous variables as the mean and standard deviation or median and interquartile range (IQR)

and categorical variables as numbers and percentages. We compared continuous variables with Students t test or a

RI
Wilcoxon rank-sum test on the basis of the distributions. We compared categorical variables with the 2 test when

SC
appropriate; otherwise, we used Fishers exact test. We used the Kaplan-Meier method to estimate the cumulative

U
incidences of clinical event and assessed the differences with the log-rank test. We conducted a landmark analysis at 90
AN
days after the indexed STEMI to compare clinical outcomes between staged multivessel PCI strategy and culprit
M

vessel-only PCI strategy in STEMI patients with multivessel disease. Staged PCI was defined as PCI for non-culprit

lesion scheduled during the index hospitalization and performed within 90 days of the index STEMI.18 To evaluate the
D
TE

late events beyond 1-year, we used landmark analysis at 1-year. We used Cox proportional hazard models to identify

predictors associated with HF hospitalization within 1 year after discharge from the index AMI hospitalization. The
EP

effects of HF hospitalization within 1-year after index AMI hospitalization for the primary outcome measures beyond
C

1-year were expressed as hazard ratios (HR) with 95% confidence intervals (CI) by multivariable Cox proportional
AC

hazard models adjusting for the 35 clinically relevant factors indicated in Table 4. Consistent with our previous reports,

continuous variables were dichotomized using clinically meaningful reference values or median values. As a sensitivity

analysis, we conducted an adjusted analysis by the time-updated Cox regression model using heart failure hospitalization

as the time-updated variable together with other risk-adjusting 35 covariates at baseline to evaluate the impact of HF

5
 6
ACCEPTED MANUSCRIPT

hospitalization on long-term mortality during the entire follow-up period. We also conducted a sensitivity analysis

excluding those patients with prior HF, because they are a different category of patients with increased risk of subsequent

HF regardless of the impact of the index STEMI.

PT
All statistical analyses were conducted using JMP version 10.0.2 (SAS Institute Inc, Cary, NC, USA) or IBM

SPSS Statistics, version 19.0.0 (IBM Corp., Armonk, NY, USA). All reported P values were two-tailed, and P values less

RI
than 0.05 were considered statistically significant.

SC
Results

U
Baseline patient characteristics included 75% of men, 31% of diabetes mellitus, 9% of prior MI, and 27% of
AN
HF (prior and or current) (Table 1). The median length of follow-up was 1956 (IQR: 1668-2221) days. Cumulative
M

5-year incidences of all-cause death and HF hospitalization were 14.8% and 8.5%, respectively (Figure 2 and Table 2).
D

The annual incidence rate of HF hospitalization was 4.4%/year during the first year after the index STEMI, which
TE

attenuated to approximately 1.0%/year beyond 1-year and up to 5-year (Figure 2). Independent risk factors associated

with HF hospitalization within 1 year after STEMI identified by a multivariable Cox proportional hazard model were
EP

older age, prior MI, presence of HF at STEMI, thrombocytopenia, LVEF 40%, anterior AMI, onset-to balloon time >3
C

hours, use of beta blocker and non-use of statin at discharge (Table 3).
AC

There were 1854 patients with multivessel coronary artery disease. After excluding 549 patients (multivessel

PCI at acute phase, Killip class 3, death or HF hospitalization within 90 days, or age 90), 680 multivessel disease

patients underwent staged PCI for angiographically significant non-culprit lesions within 90 days (staged non-culprit

lesion PCI group), while 625 multivessel disease patients received primary PCI only (culprit lesion only PCI group). The

6
 7
ACCEPTED MANUSCRIPT

crude cumulative incidence of HF hospitalization was significantly lower in staged non-culprit lesion PCI group as

compared with culprit lesion only PCI group (5.1% versus 9.0%, P=0.006) (Supplementary Figure 1). During the entire

follow-up period, ICD/cardiac resynchronization therapy defibrillator (CRT-D) placement was more often performed in

PT
patients with HF hospitalization within 1 year than in those without (5/159 [3.1%] versus 22/3523 [0.6%]).

Among 3682 patients in the current study population, 157 patients died and 69 patients were lost to follow-up

RI
during 1-year after the index STEMI hospitalization. Among 159 patients with HF hospitalization within 1 year, 29

SC
patients died and 5 patients were lost to follow-up within 1-year after the index STEMI. Therefore, at the 1-year

U
landmark point, there were 125 patients with and 3333 patients without HF hospitalization within 1-year after the index
AN
STEMI hospitalization. Baseline characteristics were significantly different between those patients with and without HF
M

hospitalization within 1-year after the index AMI hospitalization (Table 4). Patients with HF hospitalization within 1-year
D

were much older and more often had left ventricular (LV) dysfunction (LVEF 40%), HF (prior or current), prior MI,
TE

end-stage renal disease, atrial fibrillation, anemia and malignancy than those without HF hospitalization within 1-year.

Regarding clinical presentation of STEMI, onset-to-admission time and total ischemic time were significantly longer in
EP

patients with HF hospitalization within 1-year than in those without, whereas door-to-balloon time was not different
C

between the 2 groups. Anterior MI, Killip class 2-4, and multivessel coronary artery disease were more often seen in
AC

patients with HF hospitalization within 1-year than in those without. The infarct size estimated by peak creatinine

phosphokinase value was significantly larger in patients with HF hospitalization within 1-year than in those without.

Regarding medications at hospital discharge, statins were more often prescribed in patients without HF hospitalization

within 1-year, while the prescription rates for beta-blockers and inhibitors of renin angiotensin system were not different

7
 8
ACCEPTED MANUSCRIPT

between the 2 groups (Table 4).

The cumulative incidences of all-cause death and HF hospitalization beyond 1-year and up to 5-year after the

index STEMI was significantly higher in patients with HF hospitalization within 1-year than in those without (36.3%

PT
versus 10.1%, P<0.001; 40.4% versus 4.3%, P<0.001, respectively) (Figure 3 and Table 5). After adjusting for

confounders, HF hospitalization within 1-year was independently associated with a higher risk for all-cause death and HF

RI
hospitalization beyond 1-year (adjusted HR: 1.64, 95% CI 1.02-2.52, P=0.04, and adjusted HR: 5.72, 95% CI: 3.46-9.22,

SC
P<0.001, respectively) (Table 5). The result from the sensitivity analysis to evaluate the impact of HF hospitalization on

U
long-term mortality during the entire follow-up period by the time-updated Cox regression model was fully consistent
AN
with those from the 1-year landmark analysis (adjusted HR: 3.46, 95% CI 2.63-4.56, P<0.001). HF hospitalization within
M

1-year was also associated with higher risk for cardiac death beyond 1-year, while the risk for non-cardiac death beyond
D

1-year was neutral. The cumulative incidence of sudden death beyond 1-year and up to 5-year after the index STEMI was
TE

significantly higher in patients with HF hospitalization within 1-year than in those without (4.7% versus 1.0%, P<0.001)

(Table 5).
EP

The cumulative 1-year incidence of HF hospitalization was significantly higher in patients with prior HF than
C

in patients with only current HF at time of the index STEMI (21.9% versus 4.1%, P<0.001). In the sensitivity analysis
AC

excluding those patients with prior HF, there were 117 patients and 3288 patients with and without HF hospitalization

within 1-year, respectively, at the 1-year landmark point. The cumulative incidences of all-cause death and HF

hospitalization beyond 1-year and up to 5-year after the index STEMI was significantly higher in patients with HF

hospitalization within 1-year than in those without (33.2% versus 9.8%, P<0.001; 38.2% versus 3.9%, P<0.001,

8
 9
ACCEPTED MANUSCRIPT

respectively).

Discussion

The main findings of the present study are as follows; (1) The risk for HF hospitalization was higher during the

PT
first year in STEMI patients who underwent primary PCI (4.4% at 1-year), which attenuated to 1.0%/year beyond 1-year

and up to 5-year; (2) HF hospitalization within 1-year was independently associated with a higher risk for all-cause death

RI
and HF hospitalization beyond 1-year.

SC
Several previous studies reporting an association between HF and mortality in patients with MI were based on

U
cohorts including relatively large proportion of patients without revascularization in the acute phase of MI.9,12,14,19-21 The
AN
management of AMI has dramatically changed during the past decades, and these advances might have a beneficial
M

impact on the incidence of HF and the prognosis of patients with post-discharge HF. The present study clearly
D

demonstrated the incidence of HF hospitalization and the significant prognostic impact of HF hospitalization within 1
TE

year in the contemporary cohort of consecutive STEMI patients with primary PCI. In the present study, the rate of HF

hospitalization remained high (8.5% at 5-year), particularly during the first year of the index STEMI (4.4% at 1-year),
EP

even though all the patients underwent PCI within 24 hours from the onset. In high-risk patients for HF, severe HF often
C

occurs relatively early after STEMI, if it does occur. The same trend was observed in post hoc analysis of the randomized
AC

HORIZONS-AMI trial, although the trial included relatively younger patients (mean age: approximately 60 years of age),

and patients with less severe HF at baseline (Killip class 3 at presentation: 0.4%).15 In the present study, HF

hospitalization within 1 year was independently associated with higher mortality risk beyond 1-year, suggesting that

prevention of HF hospitalization might lead to reduction in long-term mortality. Therefore, we should focus more on

9
 10
ACCEPTED MANUSCRIPT

prevention of HF hospitalization after discharge in high-risk patients. The predictors of HF identified in the current

analysis confirmed the findings in previous studies.12,13,15 Elderly patients with large anterior MI carried particularly

higher risk for HF hospitalization. Consistent with our previous report,16 delay from symptom onset to reperfusion was

PT
independently associated with higher risk for HF hospitalization within 1-year, suggesting the importance of prompt

revascularization for myocardial salvage to reduce infarct size and future risk for HF.

RI
Moreover, the landmark analysis at 1 year showed that the crude cumulative incidence of HF hospitalization at

SC
4 year was approximately 10 times higher in patients with HF hospitalization within 1 year as compared with those

U
without HF hospitalization within 1 year (40.4% versus 4.3%). More aggressive HF treatment of patients with HF
AN
hospitalization within 1 year may be warranted to improve prognosis. Furthermore, there also was a significant excess
M

risk for sudden death in patients with HF hospitalization within 1 year as compared with those without. Appropriate risk
D

stratification for sudden death and wider use of ICD might also be important to improve the mortality in patients with HF
TE

hospitalization after STEMI.

This study has several limitations. Firstly, HF hospitalization was an endpoint influenced by the judgment of
EP

physicians. We did not collect the data on less severe HF treated in outpatient settings. Secondly, the measured and
C

unmeasured differences in baseline characteristics between patients with and without HF hospitalization within 1 year
AC

might limit the comparability of the groups, although we tried to make statistical adjustment as extensively as possible to

minimize the influence of the differences in baseline characteristics. Third, the follow-up not conducted in person, but

through secondary data collection, might lead to a substantial amount of data loss. Fourth, we did not collect information

on peak troponin and brain natriuretic peptide. Fourth, the use of DES in STEMI patients was different from the current

10
 11
ACCEPTED MANUSCRIPT

standard. Finally, medical therapy at hospital discharge was not optimal from the current standard, and we could not

evaluate the adherence to the medications.

Acknowledgements
We appreciate the support and collaboration of the co-investigators participating in the CREDO-Kyoto AMI Registry. We

PT
are indebted to the outstanding effort of the clinical research coordinators for data collection.

RI
Funding Sources
This study was supported by Ministry of Health, Labour and Welfare and the Pharmaceuticals and Medical Devices
Agency (PMDA) in Japan.

SC
Disclosures

U
None. AN
M
D
TE
C EP
AC

11
 12
ACCEPTED MANUSCRIPT

1. Schiele F, Meneveau N, Seronde MF, Descotes-Genon V, Oettinger J, Ecarnot F, Bassand JP. Changes in management

of elderly patients with myocardial infarction. Eur Heart J 2009;30:987-994.

2. Nauta ST, Deckers JW, Akkerhuis KM, van Domburg RT. Age-dependent care and long-term (20 year) mortality of

PT
14,434 myocardial infarction patients: changes from 1985 to 2008. Int J Cardiol 2013;167:693-697.

3. Yeh RW, Sidney S, Chandra M, Sorel M, Selby JV, Go AS. Population trends in the incidence and outcomes of acute

RI
myocardial infarction. N Engl J Med 2010;362:2155-2165.

SC
4. Takii T, Yasuda S, Takahashi J, Ito K, Shiba N, Shirato K, Shimokawa H. Trends in acute myocardial infarction

U
incidence and mortality over 30 years in Japan: report from the MIYAGI-AMI Registry Study. Circ J 2010;74:93-100.
AN
5. Roe MT, Messenger JC, Weintraub WS, Cannon CP, Fonarow GC, Dai D, Chen AY, Klein LW, Masoudi FA, McKay C,
M

Hewitt K, Brindis RG, Peterson ED, Rumsfeld JS. Treatments, trends, and outcomes of acute myocardial infarction and
D

percutaneous coronary intervention. J Am Coll Cardiol 2010;56:254-263.

TE

6. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, Gonzalez-Juanatey JR, Harjola VP,

Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM,
EP

Ruschitzka F, Rutten FH, van der Meer P. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic
C

heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of
AC

Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart

J 2016;37:2129-2200.

7. Chen J, Hsieh AF, Dharmarajan K, Masoudi FA, Krumholz HM. National trends in heart failure hospitalization after

acute myocardial infarction for Medicare beneficiaries: 1998-2010. Circulation 2013;128:2577-2584.

12
 13
ACCEPTED MANUSCRIPT

8. Sutton MG, Sharpe N. Left ventricular remodeling after myocardial infarction: pathophysiology and therapy.

Circulation 2000;101:2981-2988.

9. Ezekowitz JA, Kaul P, Bakal JA, Armstrong PW, Welsh RC, McAlister FA. Declining in-hospital mortality and

PT
increasing heart failure incidence in elderly patients with first myocardial infarction. J Am Coll Cardiol 2009;53:13-20.

10. Hellermann JP, Jacobsen SJ, Redfield MM, Reeder GS, Weston SA, Roger VL. Heart failure after myocardial

RI
infarction: clinical presentation and survival. Eur J Heart Fail 2005;7:119-125.

SC
11. Shafazand M, Rosengren A, Lappas G, Swedberg K, Schaufelberger M. Decreasing trends in the incidence of heart

U
failure after acute myocardial infarction from 1993-2004: a study of 175,216 patients with a first acute myocardial
AN
infarction in Sweden. Eur J Heart Fail 2011;13:135-141.
M

12. Gerber Y, Weston SA, Enriquez-Sarano M, Berardi C, Chamberlain AM, Manemann SM, Jiang R, Dunlay SM, Roger
D

VL. Mortality Associated With Heart Failure After Myocardial Infarction: A Contemporary Community Perspective. Circ
TE

Heart Fail 2016;9:e002460.

13. Kaul P, Ezekowitz JA, Armstrong PW, Leung BK, Savu A, Welsh RC, Quan H, Knudtson ML, McAlister FA.
EP

Incidence of heart failure and mortality after acute coronary syndromes. Am Heart J 2013;165:379-385.e372.
C

14. Steg PG, Dabbous OH, Feldman LJ, Cohen-Solal A, Aumont MC, Lopez-Sendon J, Budaj A, Goldberg RJ, Klein W,
AC

Anderson FA, Jr. Determinants and prognostic impact of heart failure complicating acute coronary syndromes:

observations from the Global Registry of Acute Coronary Events (GRACE). Circulation 2004;109:494-499.

15. Kelly DJ, Gershlick T, Witzenbichler B, Guagliumi G, Fahy M, Dangas G, Mehran R, Stone GW. Incidence and

predictors of heart failure following percutaneous coronary intervention in ST-segment elevation myocardial infarction:

13
 14
ACCEPTED MANUSCRIPT

the HORIZONS-AMI trial. Am Heart J 2011;162:663-670.

16. Shiomi H, Nakagawa Y, Morimoto T, Furukawa Y, Nakano A, Shirai S, Taniguchi R, Yamaji K, Nagao K, Suyama T,

Mitsuoka H, Araki M, Takashima H, Mizoguchi T, Eisawa H, Sugiyama S, Kimura T. Association of onset to balloon and

PT
door to balloon time with long term clinical outcome in patients with ST elevation acute myocardial infarction having

primary percutaneous coronary intervention: observational study. BMJ (Clinical research ed) 2012;344:e3257.

RI
17. Kimura T, Morimoto T, Furukawa Y, Nakagawa Y, Kadota K, Iwabuchi M, Shizuta S, Shiomi H, Tada T, Tazaki J,

SC
Kato Y, Hayano M, Abe M, Tamura T, Shirotani M, Miki S, Matsuda M, Takahashi M, Ishii K, Tanaka M, Aoyama T, Doi

U
O, Hattori R, Tatami R, Suwa S, Takizawa A, Takatsu Y, Takahashi M, Kato H, Takeda T, Lee JD, Nohara R, Ogawa H,
AN
Tei C, Horie M, Kambara H, Fujiwara H, Mitsudo K, Nobuyoshi M, Kita T. Long-term safety and efficacy of
M

sirolimus-eluting stents versus bare-metal stents in real world clinical practice in Japan. Cardiovasc Interv Ther
D

2011;26:234-245.
TE

18. Toyota T, Shiomi H, Taniguchi T, Morimoto T, Furukawa Y, Nakagawa Y, Horie M, Kimura T. Culprit Vessel-Only vs.

Staged Multivessel Percutaneous Coronary Intervention Strategies in Patients With Multivessel Coronary Artery Disease
EP

Undergoing Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction. Circ J
C

2016;80:371-378.
AC

19. Lewis EF, Velazquez EJ, Solomon SD, Hellkamp AS, McMurray JJ, Mathias J, Rouleau JL, Maggioni AP, Swedberg

K, Kober L, White H, Dalby AJ, Francis GS, Zannad F, Califf RM, Pfeffer MA. Predictors of the first heart failure

hospitalization in patients who are stable survivors of myocardial infarction complicated by pulmonary congestion and/or

left ventricular dysfunction: a VALIANT study. Eur Heart J 2008;29:748-756.

14
 15
ACCEPTED MANUSCRIPT

20. Lewis EF, Moye LA, Rouleau JL, Sacks FM, Arnold JM, Warnica JW, Flaker GC, Braunwald E, Pfeffer MA.

Predictors of late development of heart failure in stable survivors of myocardial infarction: the CARE study. J Am Coll

Cardiol 2003;42:1446-1453.

PT
21. Hung J, Teng TH, Finn J, Knuiman M, Briffa T, Stewart S, Sanfilippo FM, Ridout S, Hobbs M. Trends from 1996 to

2007 in incidence and mortality outcomes of heart failure after acute myocardial infarction: a population-based study of

RI
20,812 patients with first acute myocardial infarction in Western Australia. J Am Heart Assoc 2013;2:e000172.

U SC
AN
M
D
TE
C EP
AC

15
 16
ACCEPTED MANUSCRIPT

Figure Legends

Figure 1. Study Flow Chart.

AMI=acute myocardial infarction; CABG=coronary artery bypass grafting; HF=heart failure; PCI=percutaneous

PT
coronary intervention; STEMI=ST-segment elevation myocardial infarction.

RI
Figure 2. Cumulative Incidences of All-cause Death (A) and Heart Failure Hospitalization (B) in the Entire Study

SC
Population.

U
AN
Figure 3. Cumulative Incidences of All-cause Death (A), and Heart Failure Hospitalization (B) Beyond 1-Year:
M

With versus Without Heart Failure Hospitalization Within 1-Year.

D
TE
C EP
AC

16
 ACCEPTED MANUSCRIPT

Tables

Table 1. Baseline Characteristics in the Entire Study Population

N=3682

PT
(A) Patient characteristics

RI
Age (years) 67.012.2

SC
Age 75 years 1080 (29%)

U
Men 2747 (75%)
AN
Body mass index (kg/m2) 23.73.5

Body mass index <25 kg/m2

M

2624 (71%)

Hypertension 2899 (79%)

D
TE

Diabetes mellitus 1157 (31%)

on insulin therapy 150 (4%)

EP

Current smoker 1532 (42%)

C

Prior myocardial infarction 315 (9%)

AC

Heart failure (prior and/or current) 1006 (27%)

History of heart failure 69 (2%)

Heart failure at STEMI 986 (27%)

Left ventricular ejection fraction (%) 5312

 ACCEPTED MANUSCRIPT

Left ventricular ejection fraction 40% 450/2940 (15%)

Left ventricular ejection fraction 30% 127/2940 (4%)

Severe mitral regurgitation 91 (2%)

PT
Prior stroke (symptomatic) 312 (8%)

RI
Peripheral vascular disease 105 (3%)

SC
eGFR <30 ml/min/1.73m2, without dialysis 121 (3%)

U
Hemodialysis AN 45 (1%)

Atrial fibrillation 334 (9%)

Anemia (Hemoglobin <11.0 g/dl) 304 (8%)

M

Thrombocytopenia (Platelet count <100*109/L) 55 (1%)

D

Chronic obstructive pulmonary disease 124 (3%)

TE

Liver cirrhosis 89 (2%)

EP

Malignancy 290 (8%)

C

(B) Presentation at STEMI

AC

Onset to presentation time (hours) 2.5 (1.1-5.1)

Onset to balloon time (hours) 4.2 (2.8-7.3)

3 867/3230 (27%)

3-6 1329/3230 (41%)

 ACCEPTED MANUSCRIPT

6-12 635/3230 (20%)

12-24 399/3230 (12%)

Door to balloon time (hours) 1.5 (1.0-2.2)

PT
Killip class

RI
1 2879 (78%)

SC
2 301 (8%)

U
3 AN 80 (2%)

4 422 (13%)

Location of myocardial infarction

M

Anterior 1696 (46%)

D

Inferior 1551 (42%)

TE

Lateral 109 (3%)

EP

Posterior 326 (9%)

C

Peak creatinine phosphokinase (IU/L) 2264 (1138-4094)

AC

(C) Angiographic and procedural characteristics

Multivessel coronary disease 1854 (50%)

Target of proximal LAD (including culprit and non-culprit lesions) 2002 (54%)

Target of unprotected LMCA (including culprit and non-culprit lesions) 90 (2%)

 ACCEPTED MANUSCRIPT

Target of CTO (non-culprit lesions) 109 (3%)

Target of bifurcation (including culprit and non-culprit lesions) 945 (26%)

Side-branch stenting 107 (3%)

PT
Total stent length >28 mm (including culprit and non-culprit lesions) 1456/3391 (43%)

RI
Minimum stent size <3.0 mm (including culprit and non- culprit lesions) 1063/3391 (31%)

SC
DES use (culprit lesions) 647 (18%)

U
DES use (including culprit and non-culprit lesions)
AN 1092 (30%)

Distal protection use 296 (8%)

Thrombectomy use 2348 (64%)

M

IVUS use 1126 (31%)

D

(D) Medications at discharge

TE

Thienopyridine 3256 (92%)

EP

Aspirin 3662 (99%)

C

Cilostazol 1308 (36%)

AC

Statin 2089 (57%)

Beta-blocker 1610 (44%)

ACE-I/ARB 2788 (76%)

Mineralocorticoid Receptor Antagonist 460 (12%)

 ACCEPTED MANUSCRIPT

Nitrates 1113 (30%)

Calcium channel blockers 761 (21%)

Nicorandil 1086 (29%)

PT
Warfarin 430 (12%)

RI
Proton pump inhibitors 1284 (35%)

SC
Histamine H2-receptor antagonists 1301 (35%)

U
Categorical variables were presented as number of patients (percentage), and continuous
AN
variables as mean standard deviation or median with interquartile range.

Body mass index was calculated as weight in kilograms divided by height in meters
M

squared.
D

eGFR was calculated by the Modification of Diet in Renal Disease formula modified
TE

for Japanese patients.

EP

The infarct size estimated by peak creatinine phosphokinase (CPK) value was evaluated
C

in 3670/3682 patients (99.7%).

AC
 ACCEPTED MANUSCRIPT

Table 2. Clinical Outcomes in the Entire Study Population.

Number of patients with at least

one event
Variable
(Cumulative 5-Year Incidence)

PT
(N=3682)
All-cause death 580 (14.8%)
Cardiac death 233 (6.0%)

RI
Sudden death 64 (1.6%)
Non-cardiac death 347 (9.4%)

SC
Myocardial infarction 218 (6.0%)
Stroke 211 (5.8%)
Heart failure hospitalization 306 (8.5%)

U
Any coronary revascularization 1309 (36.8%)
AN
The number of patients with at least 1 event was counted through the entire follow-up

period, while the cumulative incidence was truncated at 5-year.

M
D
TE
C EP
AC
 ACCEPTED MANUSCRIPT

Table 3. Risk Factors Associated With Heart Failure Hospitalization Within 1

Year After STEMI, Univariate and Multivariable Analysis

Univariate Multivariable

PT
Variable Unadjusted HR P value Adjusted HR P

RI
95%CI 95%CI value

SC
Age 75 years 3.54 (2.59-4.87) <0.001 1.64 (1.05-2.57) 0.03

U
Body mass index <25.0 1.52 (1.05-2.26) 0.02 0.95 (0.60-1.57) 0.84
AN
Men 0.57 (0.42-0.80) 0.001 0.73 (0.47-1.14) 0.16
M

Hypertension 1.21 (0.82-1.84) 0.35 1.20 (0.72-2.08) 0.50

Diabetes mellitus on insulin therapy 1.65 (0.81-2.96) 0.15 1.15 (0.47-2.40) 0.75
D
TE

Current smoker 0.51 (0.35-0.71) <0.001 0.76 (0.47-1.21) 0.25

Multivessel coronary disease 1.44 (1.05-1.99) 0.02 1.08 (0.72-1.63) 0.69

EP

Severe mitral regurgitation 2.72 (1.34-4.90) 0.008 1.13 (0.50-2.27) 0.75

C

Prior myocardial infarction 2.60 (1.72-3.81) <0.001 2.07 (1.18-3.47) 0.01

AC

Prior stroke (symptomatic) 1.18 (0.66-1.93) 0.56 0.90 (0.44-1.67) 0.75

Peripheral vascular disease 1.94 (0.88-3.70) 0.10 0.96 (0.29-2.37) 0.93

eGFR <30 ml/min/1.73m2,without 4.58 (2.75-7.21) <0.001 1.81 (0.85-3.52) 0.12

 ACCEPTED MANUSCRIPT

dialysis

Hemodialysis 2.18 (0.67-5.16) 0.17 0.55 (0.03-2.71) 0.53

Atrial fibrillation 2.50 (1.66-3.65) <0.001 1.42 (0.83-2.31) 0.19

PT
Anemia (Hemoglobin <11.0 g/dl) 2.14 (1.35-3.24) 0.002 0.65 (0.34-1.18) 0.16

RI
Thrombocytopenia (Platelet count 3.21 (1.36-6.34) 0.01 4.15 (1.70-8.66) 0.003

SC
<100*109/L)

U
Chronic obstructive pulmonary 1.17(0.46-2.42) 0.71 0.92 (0.27-2.27) 0.87
AN
disease
M

Liver cirrhosis 1.61 (0.63-3.33) 0.29 1.50 (0.52-3.42) 0.42

Malignancy 1.77 (1.07-2.76) 0.03 1.55 (0.85-2.65) 0.14

D
TE

Heart failure (prior and/or at the 5.32 (3.86-7.41) <0.001 3.03 (1.81-5.06) <0.001

index admission)
EP

Killip class 4 3.15 (2.24-4.38) <0.001 1.19 (0.72-1.97) 0.50

C

Left ventricular ejection fraction 4.80 (3.36-6.81) <0.001 2.44 (1.59-3.74) <0.001
AC

40%

Hours from onset to balloon 3 0.52 (0.33-0.79) 0.002 0.56 (0.33-0.89) 0.01

hours
 ACCEPTED MANUSCRIPT

Anterior myocardial infarction 1.64 (1.20-2.26) 0.002 1.54 (1.01-2.37) 0.04

Statin 0.52 (0.38-0.72) <0.001 0.64 (0.42-0.96) 0.03

Beta-blocker 1.31 (0.96-1.78) 0.09 1.57 (1.05-2.36) 0.03

PT
ACE-I/ARB 0.72 (0.52-1.02) 0.06 0.86 (0.54-1.41) 0.55

RI
Mineralocorticoid Receptor 3.46 (2.46-4.81) <0.001 1.51 (0.96-2.35) 0.07

SC
Antagonist

U
CI=confidence interval; HR=hazard ratio.
AN
M
D
TE
C EP
AC
 ACCEPTED MANUSCRIPT

Table 4. Baseline Characteristics: With versus Without HF Hospitalization

Within 1 Year.

Heart Failure Hospitalization 1 year

PT
Variable Yes No P value

RI
(N=125) (N=3333)

SC
(A) Baseline characteristics

U
Age (years) AN 74.011.0 66.311.9 <0.001

Age 75 years* 70 (56%) 879 (26%) <0.001

M

Men* 81 (65%) 2519 (76%) 0.006

Body mass index (kg/m2) 23.24.2 23.83.4 0.08

D

Body mass index <25 kg/m2 *

TE

96 (77%) 2334 (70%) 0.10

Hypertension* 101 (81%) 2626 (79%) 0.59

EP

Diabetes mellitus 35 (28%) 1036 (31%) 0.46

C

on insulin therapy* 5 (4%) 123 (4%) 0.81

AC

Current smoker* 36 (29%) 1430 (43%) 0.002

Prior myocardial infarction* 25 (20%) 266 (8%) <0.001

Heart failure (prior and/or current) * 78 (62%) 800 (24%) <0.001

History of heart failure 8 (6%) 45 (1%) <0.001

 ACCEPTED MANUSCRIPT

Heart failure at STEMI 76 (61%) 785 (24%) <0.001

Left ventricular ejection fraction (%) 4413 5412 <0.001

Left ventricular ejection fraction 40%* 42/100 (42%) 357/2695 (13%) <0.001

PT
Left ventricular ejection fraction 30% 19/100 (19%) 87/2695 (3%) <0.001

RI
Severe mitral regurgitation* 9 (7%) 77 (2%) 0.004

SC
Prior stroke (symptomatic) * 13 (10%) 258 (8%) 0.28

U
Peripheral vascular disease * AN 6 (5%) 85 (3%) 0.14

eGFR <30 ml/min/1.73m2, without dialysis* 14 (11%) 84 (3%) <0.001

Hemodialysis* 3 (2%) 32 (1%) 0.13

M

Atrial fibrillation* 23 (18%) 275 (8%) <0.001

D

Anemia (Hemoglobin <11.0 g/dl) * 18 (14%) 230 (7%) 0.001

TE

Thrombocytopenia (Platelet count <100*109/L) * 6 (5%) 42 (1%) 0.007

EP

Chronic obstructive pulmonary disease * 4 (3%) 107 (3%) 1.00

C

Liver cirrhosis* 5 (4%) 76 (2%) 0.22

AC

Malignancy* 17 (14%) 236 (7%) 0.006

(B) Presentation at STEMI

Onset to presentation time (hours) 3.3 (1.3-8.7) 2.4 (1.1-5.0) <0.001

Onset to balloon time (hours) 5.9 (3.6-11.0) 4.1 (2.8-7.0) <0.001

 ACCEPTED MANUSCRIPT

3 * 17/108 (16%) 806/2924 (28%)

3-6 38/108 (35%) 1215/2924 (42%)

<0.001
6-12 31/108 (29%) 565/2924 (19%)

PT
12-24 22/108 (20%) 338/2924 (12%)

RI
Door to balloon time (hours) 1.5 (1.0-2.3) 1.5 (1.0-2.2) 0.71

SC
Killip class

U
1 AN 63 (50%) 2700 (81%)

2 29 (23%) 238 (7%)

<0.001
3 10 (8%) 56 (2%)
M

4 (Cardiogenic shock) * 23 (18%) 339 (10%)

D

Location of myocardial infarction

TE

Anterior * 71 (57%) 1502 (45%)

EP

Inferior 42 (34%) 1428 (43%)

0.04
C

Lateral 1 (1%) 102 (3%)

AC

Posterior 11 (9%) 301 (9%)

Peak creatinine phosphokinase (IU/L) 3855 (1767-6226) 2225 (1125-3974) <0.001

(C) Angiographic and procedural characteristics

Multivessel coronary disease* 74 (59%) 1653 (50%) 0.04

 ACCEPTED MANUSCRIPT

Target of proximal LAD (including culprit and

76 (61%) 1795 (54%) 0.13
non-culprit lesions) *

Target of unprotected LMCA (including culprit

PT
6 (5%) 75 (2%) 0.06
and non-culprit lesions) *

RI
Target of CTO (non-culprit lesions) * 10 (8%) 94 (3%) <0.001

SC
Target of bifurcation (including culprit and non-
37 (30%) 844 (25%) 0.28

U
culprit lesions) * AN
Side-branch stenting (including culprit and
5 (4%) 95 (3%) 0.45
non-culprit lesions) *
M

Total stent length >28 mm (including culprit

D

50/112 (45%) 1320/3091 (43%) 0.68

and non-culprit lesions) *
TE

Minimum stent size <3.0 mm (including culprit

EP

32/112 (29%) 956/3091 (31%) 0.60

and non-culprit lesions) *
C

DES use (culprit lesions) * 22 (18%) 610 (18%) 0.84

AC

DES use (including culprit and non-culprit

36 (29%) 1024 (31%) 0.65
lesions)

Distal protection use * 6 (5%) 272 (8%) 0.17

Thrombectomy * 64 (51%) 2159 (65%) 0.002

 ACCEPTED MANUSCRIPT

IVUS use * 33 (26%) 1041 (31%) 0.25

(D) Medications at discharge

Thienopyridine 113 (96%) 2952 (91%) 0.10

PT
Aspirin 123 (98%) 3317 (99.5%) 0.09

RI
Cilostazol 50 (40%) 1191 (36%) 0.33

SC
Statin 51 (41%) 1955 (59%) <0.001

U
Beta-blocker AN 59 (47%) 1452 (44%) 0.42

ACE-I/ARB 91 (73%) 2566 (77%) 0.28

Mineralocorticoid Receptor Antagonist 35 (28%) 362 (11%) <0.001

M

Nitrates 40 (32%) 1007 (30%) 0.67

D

Calcium channel blockers 27 (22%) 691 (21%) 0.81

TE

Nicorandil 39 (31%) 981 (29%) 0.67

EP

Warfarin 25 (20%) 372 (11%) 0.002

C

Proton pump inhibitors 50 (40%) 1149 (34%) 0.20

AC

Histamine H2-receptor antagonists 40 (32%) 1189 (36%) 0.40

Categorical variables were presented as number of patients (percentage), and continuous

variables as mean standard deviation or median with interquartile range.

 ACCEPTED MANUSCRIPT

* Risk-adjusting variables incorporated into the multivariable Cox proportional hazard

models.

The infarct size estimated by peak CPK value was evaluated in 3449/3458 patients

PT
(99.7%).

RI
U SC
AN
M
D
TE
C EP
AC
 ACCEPTED MANUSCRIPT

Table 5. Clinical Outcomes by 1-Year Landmark Analysis: With versus Without

HF Hospitalization Within 1 Year

PT
Heart Failure Hospitalization 1 year

RI
Unadjusted Adjusted
P P
Yes HR HR
No value value

SC
Number of patients (95% CI) (95% CI)
Number of patients
with at least one
with at least one
event (Cumulative

U
event (Cumulative
Incidence)
Incidence) (N=3333)
AN
(N=125)

4.17 1.64
All-cause death 46 (36.3%) 379 (10.1%) <0.001 0.04
(3.03-6.00) (1.02-2.52)
M

11.0 5.72 <0.00

HF hospitalization 42 (40.4%) 147 (4.3%) <0.001
(7.70-15.37) (3.46-9.22) 1
D

5.63 2.45
Cardiac death 21 (19.1%) 128 (3.3%) <0.001 0.01
(3.45-8.74) (1.20-4.66)
TE

4.96
Sudden death 6 (4.7%) 42 (1.0%) 0.003 N/A -
(1.89-10.8)
3.42 1.19
EP

Non-cardiac death 25 (21.4%) 251 (7.1%) <0.001 0.60

(2.21-5.05) (0.60-2.14)

Myocardial 0.66 0.70

2 (2.0%) 102 (2.9%) 0.54 0.62
C

infarction (0.11-2.09) (0.11-2.43)

1.16 0.75
AC

Stroke 4 (4.8%) 114 (3.2%) 0.78 0.60

(0.36-2.76) (0.21-2.00)
Any coronary 0.66 0.67
12 (11.3%) 545 (16.0%) 0.13 0.25
revascularization (0.35-1.12) (0.30-1.29)

Number of patients with event was assessed through the entire follow-up period beyond

the 1-year landmark point, while cumulative incidence was truncated at 5-year from the

onset of STEMI.
 ACCEPTED MANUSCRIPT

N/A=not assessed.

PT
RI
U SC
AN
M
D
TE
C EP
AC
 ACCEPTED MANUSCRIPT

PT
RI
U SC
AN
M
D
TE
EP
C
AC
 ACCEPTED MANUSCRIPT

PT
RI
U SC
AN
M
D
TE
EP
C
AC
 ACCEPTED MANUSCRIPT

PT
RI
U SC
AN
M
D
TE
EP
C
AC
 ACCEPTED MANUSCRIPT

PT
RI
U SC
AN
M
D
TE
EP
C
AC
 ACCEPTED MANUSCRIPT

PT
RI
U SC
AN
M
D
TE
EP
C
AC