Download Heart failure with systolic dysfunction complicating acute myocardial

Archives of Cardiovascular Disease (2014) 107, 149—157
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CLINICAL RESEARCH
Heart failure with systolic dysfunction
complicating acute myocardial
infarction — differential outcomes but
similar eplerenone efficacy by ST-segment
or non-ST-segment elevation: A post hoc
substudy of the EPHESUS trial
Insuffisance cardiaque systolique post-infarctus du myocarde — un
pronostic différent mais une efficacité similaire de l’éplérénone
chez les patients avec ou sans sus-décalage du segment ST : une
sous-étude post hoc d’EPHESUS
Sylvain Carillo a,∗, Yan Zhang b, Renaud Fay a,
Michael Angioi c, John Vincent d,
Santosh C. Sutradhor d, Ali Ahmed b,
Bertram Pitt e, Faiez Zannad a
a
Inserm U961, cardiology, centre d’investigations cliniques CIC9501, institut Lorrain du cœur
et des vaisseaux, CHU de Nancy, 2, avenue du Morvan, 54500 Vandoeuvre-Lès-Nancy, France
b
University of Alabama at Birmingham and VA medical center, Birmingham, AL, USA
c
Clinic Louis-Pasteur, 54270 Essey-Lès-Nancy, France
d
Pfizer Inc., New York City, NY, USA
e
University of Michigan, Ann Arbor, MI, USA
Received 20 October 2013; received in revised form 18 January 2014; accepted 21 January 2014
Available online 11 March 2014
Abbreviations: ACS, Acute coronary syndrome; AMI, Acute myocardial infarction; CI, Confidence interval; EPHESUS, Eplerenone PostAcute Myocardial Infarction Heart Failure Efficacy and Survival Study; GRACE, Global Registry of Acute Coronary Events; HF, Heart failure;
HR, Hazard ratio; LVEF, Left ventricular ejection fraction; LVSD, Left ventricular systolic dysfunction; NSTEMI, Non-ST-segment elevation
myocardial infarction; PS, Propensity score; STEMI, ST-segment elevation myocardial infarction.
∗ Corresponding author.
E-mail address: [email protected] (S. Carillo).
1875-2136/$ — see front matter © 2014 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.acvd.2014.01.010
150
KEYWORDS
NSTEMI;
STEMI;
Heart failure;
Eplerenone
MOTS CLÉS
IDM ST— ;
IDM ST+ ;
Insuffisance
cardiaque ;
Éplérénone
S. Carillo et al.
Summary
Background. — Differential outcomes in patients with acute systolic heart failure (HF) complicating acute myocardial infarction (AMI) and the efficacy of mineralocorticoid receptor
antagonists according to non-ST-segment and ST-segment elevation myocardial infarction
(NSTEMI, STEMI) status has not been specifically investigated.
Methods. — In the EPHESUS study, 6632 patients with acute HF and left ventricular ejection fraction < 40% were randomized 3—14 days post-AMI (median 7.3 ± 3.0 days) to receive eplerenone
(n = 3319) or placebo (n = 3313). Among them, 6392 patients with available data on baseline STsegment status (4634 STEMI; 1758 NSTEMI) were compared using a Cox model analysis stratified
according to quintiles of propensity score (PS), taking into account major baseline risk factors,
including revascularization.
Results. — STEMI and NSTEMI patients differed significantly across a large variety of baseline characteristics. During 30 months of follow-up, all-cause death occurred in 19% and
13% (P < 0.0001), cardiovascular death in 16% and 12% (P < 0.0001), cardiovascular death and
hospitalization in 33% and 26% (P < 0.0001) and death from progression of HF in 5% and 3%
(P < 0.0001) of unadjusted NSTEMI and STEMI patients, respectively. After Cox model PS adjustment without revascularization, NSTEMI status still proved to be a risk factor for all-cause
death, cardiovascular death and death from progression of HF. After Cox model PS adjustment including revascularization, none of the outcomes differed between STEMI and NSTEMI
patients. Eplerenone morbidity and mortality benefits were consistent in the STEMI and NSTEMI
subgroups.
Conclusion. — In patients with acute systolic HF complicating AMI, eplerenone improves outcomes equally in STEMI and NSTEMI patients. Worse outcomes associated with NSTEMI could be
explained by more co-morbidities, less aggressive therapies and, mainly, less frequent revascularization.
© 2014 Elsevier Masson SAS. All rights reserved.
Résumé
Contexte. — Le pronostic des patients en insuffisance cardiaque (IC) systolique aiguë postinfarctus du myocarde (IDM), ainsi que l’efficacité des antagonistes des récepteurs aux
minéralocorticoïdes en fonction de l’élévation (ST + ) ou non (ST—) du segment ST n’a pas
encore été étudiée de manière spécifique.
Méthodes. — Dans l’étude EPHESUS, 6632 patients en IC aiguë avec une fraction d’éjection < 40 %
ont été randomisés entre j3 et j14 post-IDM (médiane de 7,3 ± 3,0 jours) pour recevoir de
l’éplérénone (n = 3319) ou un placebo (n = 3313). Parmi eux, les 6392 patients ayant des données exploitables sur l’état du segment ST à la phase aiguë de l’IDM (4634 ST+ et 1758 ST—) ont
été analysés selon le modèle de Cox stratifié par quintiles de score de propensité prenant en
compte les principales données, y compris le taux de revascularisation, différent de manière
significative entre les groupes ST+ et ST—.
Résultats. — Au terme des 30 mois de suivi de l’étude, l’analyse sans ajustement par score de
propensité retrouve un pronostic plus péjoratif pour les ST—, avec des taux de décès toute
cause de 19 % vs 13 % (p < 0,0001), de décès cardiovasculaire de 16 % vs 12 % (p < 0,0001), de
décès cardiovasculaire/hospitalisation cardiovasculaire de 33 % vs 26 % (p < 0,0001) et de décès
par IC de 5 % vs 3 % (p < 0,0001) observés respectivement chez les ST— et les ST+. Après ajustement par quintiles de score de propensité sans tenir compte du taux de revascularisation, le
statut ST— demeure plus péjoratif puisqu’il est un facteur de risque de décès toute cause, décès
cardiovasculaire et décès par insuffisance cardiaque. Le fait d’inclure le taux de revascularisation à l’analyse précédente abolit totalement la différence de pronostic entre les patients
ST— et ST+. Par ailleurs, les bénéfices de l’administration d’éplerénone mesurés en termes de
morbidité et de mortalité sont identiques chez les patients ST— et ST+.
Conclusions. — Chez les patients en IC systolique aiguë post-IDM, le bénéfice lié à
l’administration d’éplérénone est identique chez les ST— et les ST+. Le pronostic plus défavorable observé chez les ST— s’explique par des comorbidités plus importantes, des traitements
médicamenteux moins agressifs, mais surtout un taux de revascularisation plus faible.
© 2014 Elsevier Masson SAS. Tous droits réservés.
NSTEMI, eplerenone and outcomes
Background
Nearly half of all patients with acute myocardial infarction
(AMI) present left ventricular systolic dysfunction (LVSD) and
one quarter show symptoms of heart failure (HF), both of
which are associated with poor outcomes [1—6]. Nevertheless, the Global Registry of Acute Coronary Events (GRACE)
has shown that the spread of evidence-based therapies and
myocardial revascularization has halved the rate of HF during AMI [2]. Still, this complication remains challenging,
as 80% of morbidity and mortality in the acute phase of
myocardial infarction is to be found in this subgroup [7,8].
Regardless of LVSD or HF, there are clear prognostic differences between patients with non-ST-segment elevation
myocardial infarction (NSTEMI) and those with ST-segment
elevation myocardial infarction (STEMI). Indeed, hospital
prognosis is known to be better for NSTEMI patients [9—11],
whereas long-term prognosis is described as better for STEMI
patients [10,12,13].
Aldosterone is a mediator of the renin-angiotensinaldosterone system, which is known to produce adverse
cardiovascular effects in post-AMI patients, such as left ventricle remodelling and endothelial dysfunction [14]. The
Eplerenone Post-Acute Myocardial Infarction Heart Failure
Efficacy and Survival Study (EPHESUS) [15] conducted in
post-AMI patients complicated by acute HF and LVSD, showed
that the mineralocorticoid receptor antagonist eplerenone
improved morbidity and mortality outcomes.
Different outcomes in patients with acute HF and LVSD
complicating AMI and the efficacy of mineralocorticoid
receptor antagonists depending on NSTEMI and STEMI status has not been specifically investigated. In EPHESUS,
AMI patients complicated by LVSD and receiving standard
medical therapy were randomized to eplerenone versus
placebo. In the current analysis, we compared outcomes and
eplerenone benefits depending on NSTEMI and STEMI status,
using a propensity score (PS)-adjusted Cox model.
Methods
Study design
EPHESUS was an international randomized double-blind
placebo-controlled clinical trial, the design and results of
which have been previously reported [15]. Briefly, 6632
hospitalized post-AMI patients with left ventricular ejection fraction (LVEF) ≤ 40% were randomized within 3 to 14
days (median 7.3 ± 3.0 days) post-AMI to receive either
eplerenone (mean dose 43 mg/day) or placebo during the
2000—2001 period. LVEF was measured and analysed at the
study site by echocardiography, radionuclide angiography
or left angiography. Revascularization was performed using
thrombolysis, percutaneous coronary angioplasty and/or
coronary artery bypass grafting. All patients received
standard medical therapy and most had HF symptoms,
diagnosed clinically by the presence of pulmonary rales,
a third heart sound or pulmonary vascular congestion on
chest radiography. However, patients without HF symptoms
could be enrolled if they had diabetes. Overall, 2142 (33%)
patients had diabetes, among whom 659 (10% of all patients
and 31% of all diabetics) had no HF symptoms. Patients were
151
followed for up to 2.5 years, with a mean 16-month followup.
Study patients
Of the 6632 EPHESUS participants, 6510 (98%) had data on
ST-segment status. These patients were classified as having
NSTEMI or STEMI by the study investigators, based on their
interpretation of the electrocardiogram; 118 were excluded
from the analysis due to missing values for the 20 selected
baseline variables used for PS-matching. Therefore, observations from 6392 subjects (1758 [27%] NSTEMI; 4634 [73%]
STEMI) were used for the analysis. Data on sociodemographic, clinical, subclinical and laboratory variables were
collected at baseline and have been reported previously
[15].
Study outcomes
Primary outcomes of interest for the current analysis were
all-cause death, cardiovascular death, cardiovascular death
or hospitalization and death from progression of HF during
the 2.5 years of follow-up. These events were adjudicated
by a blinded EPHESUS critical events committee [15].
We examined the association of eplerenone treatment
with primary outcomes of interest, depending on STsegment status.
Statistical analyses
All analyses were performed using SAS 9.2 (SAS Institute
Inc., Cary, NC, USA). The two-tailed significance level
was set at P < 0.05. Continuous variables are expressed
as means ± standard deviations, categorical variables as
frequencies and percentages and hazard ratios (HRs) as estimates and 95% confidence intervals (CIs). Comparisons of
baseline characteristics were carried out using the MannWhitney U test and Pearson’s Chi2 test, as appropriate.
The association of eplerenone and NSTEMI with four
selected outcomes (all-cause death, cardiovascular death,
cardiovascular death or cardiovascular hospitalization and
death from progression of HF) was analysed using the Cox
proportional hazards model. STEMI and NSTEMI patients differed significantly in a number of features: using logistic
regression, a PS was constructed as the probability of an
individual to present NSTEMI based on the 20 selected baseline characteristics presented in Table 1. Two separate PSs
were computed separately, including or not including revascularization, in order to investigate its effect on prognosis.
A sensitivity analysis was done using PS-matching, according
to all 64 available baseline characteristics.
Time-to-event analyses were then carried out with
eplerenone and NSTEMI as exposition factors and PS quintiles as stratification variables, which allowed the number
of factors in the model to be reduced and prevented any
issue of log-linearity between PS and outcomes. The validity
assumptions of the Cox models (proportionality of hazards,
absence of interaction and co-linearity) were thoroughly
checked and any violation was ruled out. The association of
eplerenone with outcomes according to ST-segment status
was illustrated using Kaplan—Meier curves.
152
Table 1
S. Carillo et al.
Baseline characteristics.
NSTEMI (n = 1758)
n
Region
North America
Western Europe
Eastern Europe
Latin America
Other
403
428
669
100
158
Pa
STEMI (n = 4634)
Mean ± SD or %
n
Mean ± SD or %
23
24
38
6
9
384
1198
2210
456
386
8
26
48
10
8
< 0.0001
Demographics
Men
Age (years)
1194
1758
68
66.9 ± 11.1
3350
4634
72
62.6 ± 11.4
0.0006
< 0.0001
Risk factors
Body mass index (kg/m2 )
History of hypertension
Diabetes
Prior history of AMI
Prior episode of HF
1758
1196
714
775
496
27 ± 5
68
41
44
28
4634
2661
1330
928
394
27 ± 4
57
29
20
9
0.86
< 0.0001
< 0.0001
< 0.0001
< 0.0001
Haemodynamics
Systolic blood pressure (mmHg)
Heart rate (bpm)
LVEF (%)
1758
1758
1758
122.5 ± 17.0
73 ± 12
32.5 ± 6.5
4634
4634
4634
117.7 ± 16.0
75 ± 12
33.5 ± 7.7
< 0.0001
< 0.0001
< 0.0001
Biology
Haemoglobin (g/dL)
Serum creatinine (mmol/L)
1758
1758
13.3 ± 1.8
104.2 ± 31.7
4634
4634
13.3 ± 1.7
97.6 ± 27.4
0.67
< 0.0001
Treatments
Revascularization
ACEI
ARB
Beta-blocker
Aspirin
Statin
464
1473
72
1281
1519
815
26
84
4
73
86
46
2463
3945
128
3510
4143
2146
53
85
3
76
89
46
< 0.0001
0.18
0.006
0.018
0.0008
0.97
839
48
2365
51
0.018
Study drug
Eplerenone
ACEI: angiotensin-converting enzyme inhibitor; AMI: acute myocardial infarction; ARB: angiotensin II receptor antagonist; bpm: beats
per minute; HF: heart failure; LVEF: left ventricular ejection fraction; NSTEMI: non-ST-segment elevation myocardial infarction; SD:
standard deviation; STEMI: ST-segment elevation myocardial infarction.
a P value from Mann-Whitney and Chi2 tests for continuous and categorical variables, respectively.
Results
revascularized.
(Table 1).
NSTEMI
patients
received
eplerenone
Patient characteristics
A significant proportion of the patients had NSTEMI (1758
of 6392 patients, 27%). Before matching, compared with
STEMI patients, those with NSTEMI came from different
regions, were older, were more frequently women and
had a higher burden of co-morbidities, such as hypertension, diabetes, prior history of AMI and prior episode of
HF (Table 1). NSTEMI patients had a lower heart rate,
higher systolic blood pressure and a lower LVEF and more
frequently had impaired renal function (Table 1). Concerning therapies, NSTEMI patients less frequently received
aspirin and beta-blockers, were more frequently given
angiotensin receptor therapy and were far less frequently
Outcomes according to ST segment status
Over the 30-month follow-up period, compared with STEMI
patients, NSTEMI patients experienced more adverse outcomes (all-cause death, 19% vs 13%; cardiovascular death,
16% vs 12%; cardiovascular death/hospitalization, 33% vs
26%; and death from progression of HF, 5% vs 3%) (Table 2).
After Cox model PS adjustment without revascularization, NSTEMI status still proved to be a risk factor for
all-cause death (HR 1.18, 95% CI 1.03—1.37; P = 0.022), cardiovascular death (HR 1.17, 95% CI 1.00—1.37; P = 0.048) and
death from progression of HF (HR 1.36, 95% CI 1.01—1.82;
P = 0.042) (Table 3).
NSTEMI, eplerenone and outcomes
Table 2
153
Outcomes.
NSTEMI (na = 1758)
All-cause death
Cardiovascular death
Cardiovascular death or hospitalization
Death from progression of HF
STEMI (na = 4634)
Pb
nc
%
nc
%
340
290
583
92
19
16
33
5
621
538
1188
122
13
12
26
3
< 0.0001
< 0.0001
< 0.0001
< 0.0001
HF: heart failure; NSTEMI: non-ST-segment elevation myocardial infarction; STEMI: ST-segment elevation myocardial infarction.
a Total frequency.
b P value from Chi2 test.
c Outcome frequency.
After Cox model PS adjustment including revascularization, none of the outcomes differed between STEMI and
NSTEMI patients (Table 4).
Eplerenone efficacy
The beneficial effect of eplerenone was constant among all
primary outcomes of interest (Table 5) and was observed
whatever the ST segment status (Fig. 1).
Table 3 Association of ST-segment status with outcomes (propensity score without revascularization).
NSTEMI
All-cause death
Cardiovascular death
Cardiovascular death or
hospitalization
Death from progression
of HF
Pa
HR (95% CI)
0.022
0.048
0.29
1.18 (1.03—1.37)
1.17 (1.00—1.37)
1.06 (0.95—1.18)
0.042
1.36 (1.01—1.82)
CI: confidence interval; HF: heart failure; HR: hazard ratio;
NSTEMI: non-ST-segment elevation myocardial infarction.
a P value from Cox regression.
Table 4 Association of ST-segment status with outcomes (propensity score with revascularization).
Discussion
To our knowledge, this study is the first to focus on the prognostic differences between NSTEMI and STEMI specifically
in patients with systolic acute HF complicating AMI, a subset of patients at the highest risk of short- and long-term
death [5,6,8]. Consistent with the main findings of previous
reports in non-HF patients [8,10,13,16,17], worse outcomes
associated with NSTEMI could mainly be explained by more
frequent co-morbidities, less aggressive therapies and, most
importantly, less frequent revascularization. A second major
finding of our analysis is that eplerenone improved outcomes in both STEMI and NSTEMI patients. Although STEMI
and NSTEMI go through the same pathophysiological process,
namely acute atherothrombosis [18—20], there are differences between the two presentations.
STEMI is the consequence of complete thrombotic occlusion of a major coronary artery, mainly by plaque disruption
[21], whereas NSTEMI is a subtotal coronary occlusion,
mainly by plaque erosion [22]. Thrombus is described as
fibrin rich in STEMI and platelet rich in NSTEMI. Thrombotic
load is often higher in STEMI than in NSTEMI [23,24].
Regarding HF, myocyte loss leading to acute contractile
dysfunction is not the only mechanism leading to acute
HF in acute coronary syndrome (ACS) patients, as the
GRACE registry showed that 11.2% of patients with unstable angina also showed signs of HF [3]. Thus, myocardial
stunning/hibernation [6], ventricular remodelling, acute
mitral regurgitation and ischaemia-induced impairment in
Table 5
Association of study drug with outcomes.
NSTEMI
P
All-cause death
Cardiovascular death
Cardiovascular death or
hospitalization
Death from progression
of HF
a
Eplerenone
HR (95% CI)
0.28
0.45
0.79
1.08 (0.94—1.25)
1.06 (0.91—1.24)
1.02 (0.91—1.13)
0.15
1.25 (0.93—1.68)
CI: confidence interval; HF: heart failure; HR: hazard ratio;
NSTEMI: non-ST-segment elevation myocardial infarction.
a P value from Cox regression.
All-cause death
Cardiovascular death
Cardiovascular death or
hospitalization
Death from progression
of HF
Pa
HR (IQR)
0.004
0.003
0.004
0.83 (0.73—0.94)
0.81 (0.71—0.93)
0.87 (0.79—0.96)
0.049
0.76 (0.58—1.00)
HF: heart failure; HR: hazard ratio; IQR: interquartile range.
a P value from Cox regression.
154
Figure 1.
S. Carillo et al.
Association of eplerenone with outcomes according to ST-segment status.
myocardial relaxation [5] have been reported to cause HF in
acute ischaemic conditions.
Poor prognosis of post-AMI patients with acute
systolic HF
HF complicating AMI is known to increase cardiovascular
risk in equal proportions among STEMI and NSTEMI patients,
while HF AMI patients are known to benefit from revascularization less frequently than non-HF patients [3]. In the
GRACE [3], NRMI-2 [8], Euro Heart Survey [11] and Gulf RACE
[25] registries, conducted in unselected ACS patients, the
death rate in patients with HF was 2—4 times higher than
in those without HF. Our results obtained in acute systolic
HF patients show once again that acute HF seriously compounds the prognosis of AMI patients and illustrates very well
the concept of ‘‘deadly intersection’’ between ACS and HF
mentioned by Velasquez and Pfeffer [5].
Acute clinical HF and LVSD are two phenomena that do
not necessarily co-exist in post-AMI patients. Indeed, in the
SAVE study [26], 60% of LVSD patients showed no HF, whereas
in the VALIANT study [27], 42% of patients with acute HF
did not have LVSD. In our study, post-AMI patients with both
clinical signs of HF and LVSD were enrolled, thus we targeted
the highest risk patients.
As could be expected, the prognosis of our post-AMI
patients with acute systolic HF was very poor, with a 19%rate of all-cause death for NSTEMI patients and a 16%-rate
for STEMI patients over the 2.5-year follow-up period. The
majority of these deaths were due to cardiovascular causes.
Given that the patients in our study had a poor outcome, we must wonder about the medical and reperfusion
therapies that could have improved their prognosis. Concerning medical therapies, both our NSTEMI and STEMI
groups were quite adequately treated, in compliance with
the guidelines at the time of the study: 73—86% were
treated with beta-blockers, angiotensin-converting enzyme
inhibitors and aspirin. The relatively low use of statins is
consistent with their low level of evidence in post-AMI HF
patients at the time of the trial. Indeed, so far, all statin
trials in ACS patients have excluded those with HF and/or
LVSD.
Although at the time of the study NSTEMI and STEMI with
HF were both a class 1 indication for urgent revascularization [28,29], only 26% and 53%, respectively, received
NSTEMI, eplerenone and outcomes
reperfusion therapy — a low rate in line with a worldwide
study and with clinical practice in the early 2000s [13,30].
The recent spread of reperfusion therapies is the main factor associated with the recent improvement in outcomes
among AMI patients [2]. In comparison, the latest registry
in Europe has shown that 90% of STEMI patients and 70%
of NSTEMI patients benefit from revascularization nowadays [31]. Consequently, more frequent use of reperfusion
therapies among our high-risk AMI HF patients would have
improved outcome in both our NSTEMI and STEMI subgroups.
Differences between NSTEMI and STEMI among
HF patients
Although in unselected ACS patients NSTEMI is as common as
STEMI [11], our study enrolled fewer NSTEMI patients than
STEMI patients, probably because of the per-protocol selection criterion of LVSD and HF, which is indeed more frequent
in STEMI patients [9,12,13].
Previous studies have already shown that although
NSTEMI causes less severe ischaemia and myocardial damage, it is usually associated with a worse outcome than STEMI
[10,12,13]; a combination of five factors may account for
this.
First, as shown in Tables 1 and 4, revascularization is the
most discriminating factor between STEMI-HF and NSTEMIHF patients, with twice as many reperfusion therapies in
STEMI patients. Indeed, our analysis showed that the prognostic difference between the two groups was no longer
statistically significant when revascularization was taken
into account in the adjustment strategy. However, even if
NSTEMI patients benefit more frequently from revascularization nowadays, they still are more unlikely to be reperfused
than STEMI patients (70% vs 90%) [31]. This persistent difference is probably due to a combination of technical and
individual factors. Indeed, a significant proportion of NSTEMI
patients are not technically suitable for revascularization,
as they more frequently present a diffuse coronary disease
with fewer fresh thrombi and more calcified lesions than
STEMI patients. Moreover, NSTEMI patients are still less frequently revascularized than STEMI patients because of a
perceived lower benefit in such patients. A more frequent
use of revascularization among our specific very-high-risk
NSTEMI-HF patients at the time of the study might have
improved their prognosis [2] and decreased the difference
in outcomes between NSTEMI and STEMI.
Second, due to study design, patients who died within
3 days after AMI (i.e. before enrolment in the trial) were
not included in our study. Unlike NSTEMI patients, > 50% of
deaths in STEMI patients occur very early after the onset
of symptoms, especially during the first 2 hours [33]. The
selection bias related to enrolment time might have underestimated the mortality rate in the STEMI subgroup, which
partly explains the mortality difference between NSTEMI and
STEMI patients in our report.
Third, our NSTEMI patients were less likely to receive
appropriate medical therapies, such as aspirin and betablockers, when hospitalized for AMI. This less rigorous
medical treatment of NSTEMI patients has been consistently
reported in previous studies as a factor that might explain
their worse prognosis compared with STEMI patients [34].
155
Fourth, compared with STEMI patients, those with NSTEMI
had a greater burden of co-morbidities, such as old age,
diabetes and hypertension. Studies carried out regardless of
HF status, such as EHS-ACS II [11] and the series reported by
Terkelsen et al. [13], came to strictly similar findings.
Fifth, compared with STEMI patients, our NSTEMI patients
were three times more likely to have a history of HF, a
condition that is known to triple the long-term risk of death
after myocardial infarction [13] and inevitably affected the
prognosis of NSTEMI patients in our series.
Consequently, as can be seen in unselected AMI patients
[35], it seems that the poor long-term outcome in our
NSTEMI-HF patients can be explained by more frequent
co-morbidities and less aggressive treatment (mainly less
frequent revascularization), rather than by the type of acute
ST-segment variation per se.
Thus, the imbalances in baseline characteristics mentioned above account for the less favourable unadjusted
prognosis among NSTEMI patients, as illustrated by the
results of our PS-matching analysis, which abolished all differences in primary outcomes between NSTEMI and STEMI
patients.
Eplerenone efficiency
In the EPHESUS study, eplerenone benefited patients with
NSTEMI and STEMI equally. Indeed, whatever the ST-segment
status, high-risk AMI survivors with LVSD or HF, receiving optimal treatment with angiotensin-converting enzyme
inhibitors or angiotensin receptor blockers and a betablocker benefit from further neurohormonal blockade with
eplerenone.
Although post hoc, this new subgroup analysis extends
the findings of previous reports of prespecified or post hoc
subgroup analyses, such as diabetics [36], hypertensives [37]
and patients with LVEF < 30% [38], which consistently showed
a marked clinical benefit for eplerenone across a variety of
AMI presentations.
Study limitations
Several limitations to our study must be acknowledged.
Baseline electrocardiographical findings of STEMI or NSTEMI
were reported by investigators and were not centrally adjudicated, therefore misclassification is possible. It is also
possible that patients with STEMI developed NSTEMI, or vice
versa, during follow-up. However, this phenomenon, also
known as regression dilution, is known to underestimate true
associations [39].
Based on pathophysiological hypothesis and prognostic
literature data, we selected 20 baseline characteristics
that differed most between the two groups to run our PS
adjustment. Using all available characteristics would have
eliminated all identifiable baseline confounders, but would
have seriously lowered the power of our analysis. A sensitivity analysis using PS-matching all 64 available baseline
variables yielded similar results.
We had no data on death during the first 48 hours nor on
delay to reperfusion after index AMI. These data would have
helped us to better fine-tune the difference in prognosis
between NSTEMI and STEMI.
156
Conclusion
In conclusion, as far as we know, our study is the first report
comparing outcomes and eplerenone efficiency among postAMI acute systolic HF patients with STEMI and NSTEMI.
The study shows that in that specific high-risk populations, NSTEMI remains a useful marker for identifying a group
of patients with more adverse long-term outcomes. Among
those patients, eplerenone improves outcomes equally in
STEMI patients and NSTEMI patients. However, because
NSTEMI carries a worse prognosis, additional therapeutic
interventions must be carried out in such high-risk LVSD
patients, including more aggressive medical therapies and
more frequent revascularization.
Disclosure of interest
Sylvain Carillo, Renaud Fay and Mickael Angioi: none. Yan
Zhang: affiliation with UAB. John Vincent and Santosh
C. Sutradhor: Pfizer Inc. employees. Ali Ahmed: affiliation with UAB and VA. Bertram Pitt: consultant for Pfizer,
Merck, Novartis, Bayer, Takeda, AstraZeneca, Lilly, BMS,
BG Medicine (stock options), Relypsa (stock options), Cytopherx, Amorcyte, Aurasence (stock options) and Ardelyx;
grants from Novartis, Medtronic and Forrest Laboratories.
Faiez Zannad: grants to institution from BG Medicine and
Roche Diagnostics; consultant/member of steering committees, event committees and data safety monitoring boards
for Bayer, Biomérieux, Biotronik, BostonScientific, CVCT,
Novartis, Pfizer, Resmed, Servier and Takeda.
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