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 ST-segment 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.
Résumé
Contexte
Le pronostic des patients en insuffisance cardiaque (IC) systolique aiguë post-infarctus 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.
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 . 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 . 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 . 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 , whereas long-term prognosis is described as better for STEMI patients .
Aldosterone is a mediator of the renin-angiotensin-aldosterone system, which is known to produce adverse cardiovascular effects in post-AMI patients, such as left ventricle remodelling and endothelial dysfunction . The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) 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 . 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 followed for up to 2.5 years, with a mean 16-month follow-up.
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 .
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 .
We examined the association of eplerenone treatment with primary outcomes of interest, depending on ST-segment 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 Mann-Whitney U test and Pearson’s Chi 2 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.
| NSTEMI ( n = 1758) | STEMI ( n = 4634) | P a | |||
|---|---|---|---|---|---|
| n | Mean ± SD or % | n | Mean ± SD or % | ||
| Region | |||||
| North America | 403 | 23 | 384 | 8 | < 0.0001 |
| Western Europe | 428 | 24 | 1198 | 26 | |
| Eastern Europe | 669 | 38 | 2210 | 48 | |
| Latin America | 100 | 6 | 456 | 10 | |
| Other | 158 | 9 | 386 | 8 | |
| Demographics | |||||
| Men | 1194 | 68 | 3350 | 72 | 0.0006 |
| Age (years) | 1758 | 66.9 ± 11.1 | 4634 | 62.6 ± 11.4 | < 0.0001 |
| Risk factors | |||||
| Body mass index (kg/m 2 ) | 1758 | 27 ± 5 | 4634 | 27 ± 4 | 0.86 |
| History of hypertension | 1196 | 68 | 2661 | 57 | < 0.0001 |
| Diabetes | 714 | 41 | 1330 | 29 | < 0.0001 |
| Prior history of AMI | 775 | 44 | 928 | 20 | < 0.0001 |
| Prior episode of HF | 496 | 28 | 394 | 9 | < 0.0001 |
| Haemodynamics | |||||
| Systolic blood pressure (mmHg) | 1758 | 122.5 ± 17.0 | 4634 | 117.7 ± 16.0 | < 0.0001 |
| Heart rate (bpm) | 1758 | 73 ± 12 | 4634 | 75 ± 12 | < 0.0001 |
| LVEF (%) | 1758 | 32.5 ± 6.5 | 4634 | 33.5 ± 7.7 | < 0.0001 |
| Biology | |||||
| Haemoglobin (g/dL) | 1758 | 13.3 ± 1.8 | 4634 | 13.3 ± 1.7 | 0.67 |
| Serum creatinine (mmol/L) | 1758 | 104.2 ± 31.7 | 4634 | 97.6 ± 27.4 | < 0.0001 |
| Treatments | |||||
| Revascularization | 464 | 26 | 2463 | 53 | < 0.0001 |
| ACEI | 1473 | 84 | 3945 | 85 | 0.18 |
| ARB | 72 | 4 | 128 | 3 | 0.006 |
| Beta-blocker | 1281 | 73 | 3510 | 76 | 0.018 |
| Aspirin | 1519 | 86 | 4143 | 89 | 0.0008 |
| Statin | 815 | 46 | 2146 | 46 | 0.97 |
| Study drug | |||||
| Eplerenone | 839 | 48 | 2365 | 51 | 0.018 |
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