• „ Original article

Prediction of early death after myocardial infarction in patients with reduced left ventricular ejection fraction. The search for new indications for cardioverter-defibrillator implantation (ICD)

Damian Pres1, Mateusz Tajstra1, Przemysław Mitkowski2, Aneta Ciślak1, Kamil Bujak1, Jarosław Kaźmierczak3, Maciej Sterliński4, Katarzyna Mizia-Stec5, Radosław Sierpiński6 , Mariusz Gąsior1, Łukasz Szumowski6, Zbigniew Kalarus7

13rd Department of Cardiology, Silesian Center for Heart Diseases, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland

21st Department of Cardiology, Poznan University of Medical Sciences, Poznan, Poland

3Department of Cardiology, Pomeranian Medical University, Szczecin, Poland

4Department of Arrhythmia, National Institute of Cardiology, Warszawa, Poland

51st Department of Cardiology, Medical University of Silesia, Katowice, Poland

6Department od Arrhythmia, Institute of Cardiology, Warszawa, Poland

71st Department of Cardiology, Congenital Heart Diseases, and Electrotherapy, Silesian Center for Heart Diseases, Zabrze, Poland

Introduction

Over the last two decades, there has been a significant increase in the number of implantable cardioverter-defibrillator (ICD) implantation procedures. It has been proven that this therapy reduces mortality in patients with heart failure [1]. The current European Society of Cardiology (ESC) guidelines recommend ICD implantation as the standard treatment of patients with reduced left ventricular ejection fraction (LVEF) [2]. However, in patients who have recently had a myocardial infarction (MI), the assessment of indications for primary prevention ICD implantation should be postponed until at least 40 days after the acute coronary syndrome [3]. The IRIS (The Immediate Risk Stratification Improves Survival) and DINAMIT (the Defibrillator in Acute Myocardial Infarction Trial) studies showed that ICD implantation does not reduce all-cause mortality in this period but decreases the rate of death due to arrhythmia. However, the latter is offset by an increase in nonarrhythmic mortality [4, 5]. According to the ESC guidelines, primary prevention ICD implantation in this period should be considered in case of incomplete revascularization and reduced LVEF prior to MI [3]. Despite the high prevalence of the invasive management strategy in the treatment of acute coronary syndromes, which has led to an improvement in in-hospital outcomes, long-term mortality in post-MI patients is still unsatisfactory, especially in those with reduced LVEF. It has been shown that 7% of patients with MI who survive until hospital discharge die or experience nonfatal cardiac arrest within 6 months. Additionally, in the subgroup of MI patients with LVEF lower than 30%, the risk of death significantly increases during the first month after the event [6]. It must be noted that the most frequent cause of death in this group is ventricular arrhythmia [7]. Therefore, considering the highest rate of death and causes of death in the first few weeks after MI, we aimed to identify the group of high-risk patients with reduced LVEF who would benefit from primary prevention ICD implantation within 40 days of MI.

Methods

SILCARD, PL-ACS, AMI-PL

In the present study, we analyzed data from 205 606 MI patients (both ST-segment elevation and non-ST-segment elevation myocardial infarction) derived from three combined medical registries: SILCARD (The Silesian Cardiovascular Database), PL-ACS (Polish Registry of Acute Coronary Syndromes), and AMI-PL (Acute Myocardial Infarction in Poland).

SILCARD was developed under the agreement between the Silesian Center for Heart Disease in Zabrze and the Regional Department of National Health Fund (NHF) in Katowice, Poland to conduct epidemiological analyzes and prepare scientific elaborations on the group of patients with cardiovascular diseases (CVD) in the Silesia Province. The design and rationale of the SILCARD database were described previously [8]. The reported data come from 310 hospital wards and 1863 outpatient clinics and contain information on 487 518 patients, 956 634 cardiovascular hospitalizations, and 61 906 964 outpatient visits.

The PL-ACS is a clinically driven registry established in 2003, gathering detailed data on in-hospital management, treatment modalities, and outcomes. Its design and introduction were a joint effort of the Silesian Center for Heart Diseases in Zabrze and the Polish Ministry of Health. Currently, over 630 000 hospitalizations for acute coronary syndrome are listed in the PL-ACS registry. Its detailed design has been described elsewhere [9].

The AMI-PL is a registry of administrative data gathered from all MI hospitalizations, containing data from the national healthcare provider. The database currently comprises information on over 550 000 hospitalizations from 2009. The detailed design of AMI-PL has been presented previously [10].

According to letter no. PCN/0022/KB/49/21, keeping the register is not a medical experiment and does not require the consent of the ethics committee.

Study population

A flowchart of the study population is shown in Figure 1. Patients who were included in the study were hospitalized with MI treated invasively, had LVEF <40%, and survived until hospital discharge. The exclusion criteria were as follows: MI treated with fibrinolysis or conservatively, ICD or cardiac resynchronization therapy defibrillator (CRT-D) implanted before the index hospitalization or within 40 days after MI, elective coronary artery revascularization within 40 days after MI, and missing data on LVEF. In total, 18 736 patients were included. Patients were divided into two groups according to the survival status at 40 days — patients who died within this period (n = 1331) and patients who survived (n = 17 405). Selected clinical characteristics and angiographic parameters, as well as causes of rehospitalizations, were analyzed in both groups.

Qualitative parameters are presented as percentages while continuous parameters are presented as the median and interquartile range. Differences in categorical variables between the groups were tested using the χ2 test with Pearson modification, whereas differences in continuous variables were tested using the U Mann-Whitney test. To assess the impact of particular parameters on 40-day mortality, a multivariable analysis was performed using step-down Cox proportional hazards regression modeling. The multivariable model included the following variables: age, sex, LVEF, sudden cardiac arrest before admission or during hospitalization, cardiogenic shock, a history of arterial hypertension, diabetes mellitus, chronic kidney disease, tobacco smoking, diagnosis of ST-segment elevation myocardial infarction (STEMI), multivessel coronary artery disease, and final thrombolysis in myocardial infarction (TIMI) flow 0–2 vs. 3. The results of the multivariable analysis are expressed as a hazard ratio (HR) with the corresponding 95% confidence interval (CI). For mortality at 12 months, the analysis with the Kaplan-Meier method with the log-rank comparison of curves was performed. The level of statistical significance was P <0.05 (two-tailed). Statistica 10 software (StatSoft Inc., Tulsa, OK, USA) was used for all calculations.

Patients who died during a 40-day follow-up were older and more frequently female. Moreover, they were more likely to have cardiac arrest before admission or within the first 48 hours of hospital admission, as well as pulmonary edema, cardiogenic shock, hypertension, diabetes mellitus, a previous stroke, peripheral arterial disease, and had both lower blood pressure on admission and LVEF. Patients who died were less frequently current smokers and were less likely to have previous coronary artery revascularization in comparison with individuals who survived 40 days (Table 1).

In the group of patients who died, there was a higher percentage of patients with multivessel disease and the left main artery as an infarct-related artery. Patients who survived 40 days had more likely the left anterior descending artery as an infarct-related artery and a higher success rate of percutaneous coronary intervention (PCI) (Table 2). The success rate in the whole study population (TIMI 3 flow after PCI) was 89.03%.

In patients who died in 40 days following MI, major bleeding and recurrent MI were more often observed. These patients were more likely to require inotropic support and intra-aortic balloon pumps (Table 2). Moreover, they were less likely to be prescribed antiplatelets, β-blockers, ACE inhibitors/angiotensin II receptor antagonists, statins, and nitrates. On the other hand, patients who survived 40 days were less frequently discharged on anticoagulants (Table 3).

Forty-day mortality and its predictors

Forty-day and 1-year mortality in patients with MI and LVEF <40% who survived until hospital discharge was 7.1% and 18.81%, respectively. The cumulative mortality rate in this group is shown in Figure 2.

In the multivariable analysis, the independent predictors of 40-day mortality were as follows: cardiac arrest before hospital admission or within the first 48 hours of hospitalization, cardiogenic shock before admission or during hospitalization, unsuccessful PCI, lower LVEF, age >65 years, and chronic kidney disease (Table 4).

Table 4. Predictors for 40-day mortality — a multivariable analysis

	HR (95% CI)	P-value
Sudden cardiac arrest before admission or within the first 48 hours of hospital admission	3.35 (2.82–3.98)	<0.0001
Unsuccessful PCI	2.42 (2.11–2.84)	<0.0001
Cardiogenic shock before admission or during hospitalization	3.06 (2.62–3.59)	<0.0001
LVEF <20%a	2.75 (2.25–3.36)	<0.0001
LVEF 20%–30%a	1.90 (1.68–2.16)	<0.0001
Age >65 years	1.82 (1.59–2.07)	<0.0001
Chronic kidney disease	1.25 (1.07–1.47)	0.0053

aVs. LVEF ≥30%

Abbreviations: CI, confidence interval; HR, hazard ratio; other — see Table 1 and Figure 1

Cumulative mortality rate curves for patients stratified according to independent predictors of death are depicted in Figures 2 and 3.

Figure 3. A. Kaplan-Meier curves for patients stratified by final TIMI flow. B. Kaplan-Meier curves for patients stratified by left ventricular ejection fraction. C. Kaplan-Meier curves for patients stratified by age. D. Kaplan-Meier curves for patients with and without CKD

Abbreviations: CKD, chronic kidney disease, other — see Table 4

We found ca. three-fold higher 40-day mortality in patients with cardiac arrest, cardiogenic shock, or unsuccessful percutaneous coronary intervention compared to patients without these complications.

Rehospitalizations within 40 days

There were significantly higher overall and cardiovascular 40-day readmission rates in patients who died during this period. Cardiac arrest was significantly more frequent, while stable coronary artery disease and unstable angina were significantly less frequent causes of readmission in this group, compared to patients who survived 40 days (Table 5). The median time from hospital discharge to readmission in patients who died and survived 40 days was 10 (5.25–18) and 24 (14–33) days, respectively.

Table 5. 40-day readmissions and procedures during follow-up

	Patients who survived 40 days (n = 17 405)	Patients who died within 40 days (n = 1331)	P-value
Readmission rate, n (%)	3563 (20.47)	695 (52.25)	<0.0001
Readmission for cardiovascular disease, n (%)	3084 (17.72)	617 (46.38)	<0.0001
Causes of readmissions, n (%)
Atrial fibrillation	75 (2.43)	8 (1.32)	<0.0001
Supraventricular arrhythmias	25 (0.81)	3 (0.44)
Ventricular arrhythmias (except for sudden cardiac death)	19 (0.61)	2 (0.32)
Conduction disorders	35 (1.13)	11 (1.76)
Sudden cardiac arrest	18 (0.59)	68 (11.02)
Pulmonary embolism	14 (0.45)	5 (0.88)
Valvular heart disease	110 (3.56)	16 (2.64)
Heart failure	1130 (36.64)	239 (38.77)
Myocardial infarction	230 (7.46)	60 (9.69)
Unstable angina	366 (11.87)	19 (3.08)
Stable coronary artery disease	897 (29.09)	73 (11.89)
Other	165 (5.36)	112 (18.19)
Procedures performed during follow-up, n (%)
Coronary angiography	2026 (11.64)	11 (0.81)	<0.001
PCI	1004 (5.77)	2 (0.15)	<0.0001
CABG	132 (0.76)	0 (0)	0.27
Cardiac ablation	38 (0.22)	0 (0)	0.55

Abbreviations — see Table 1

Discussion

In the present study patients with MI and reduced LVEF were analyzed. This group included 14.5% of all patients with MI, who had survived the in-hospital period. This percentage was slightly lower than described in other studies, i.e. 21.4% in the study by Zaman et al. [11]. The above-mentioned discrepancies might stem from the fact that in the present analysis, patients treated conservatively and patients with implanted ICD or CRT-D were excluded. Nevertheless, it is worth emphasizing, that every seventh patient with MI had LVEF <40% at hospital discharge. The ESC guidelines suggest a subsequent reassessment of LVEF 40 days after MI in these patients. After this period further therapeutic decisions should be made. Considering the results of our study, it seems that this recommendation should be re-examined. In our study, we showed, that approximately 38% of deaths in the first year after MI occur within the first 40 days. It means that one-third of patients die within the first year of MI before LVEF reassessment and starting adequate treatment, which could affect the survival of this group of patients. Thus, it seems reasonable to re-evaluate whether there is a subgroup of patients who should undergo ICD or CRT-D implantation in primary prevention before hospital discharge or shortly after MI.

To the best of our knowledge, there is no clear solution to the problem in the available literature. Randomized clinical trials assessing ICD effectiveness for primary prevention of sudden cardiac death within the first 40 days after MI have shown unambiguously no significant survival benefit from ICD implantation over optimal medical therapy. The way of randomization and timing of the procedure in these studies is worth analyzing. Patients recruited to the IRIS trial had acute MI 5–31 days before randomization. Approximately 7% of patients did not undergo ICD implantation despite allocation to the ICD group. Moreover, 9% of patients were discharged from the hospital before the planned procedure, and 1% of patients died before ICD implantation [4]. The inclusion criteria for the DINAMIT trial were acute MI 6–40 days before enrollment (18 days on average) and the possibility of ICD implantation within 7 days of randomization. Approximately 6% of patients allocated to the ICD group did not undergo device implantation. The mean time between randomization and the procedure was 6.3 ± 7.3 days [5]. It should be noted that in both studies, survival analysis was conducted from the moment of randomization and not from the MI [4, 5]. The Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II, based on which the ESC recommends ICD implantation at least 40 days after MI, showed a significant reduction of overall mortality compared to optimal medical therapy only after approximately 9 months of ICD therapy. It is noteworthy that 88% of patients who underwent ICD implantation were included in the study >6 months after MI [1]. It appears from the above data that patients included in the trials, on which ESC guidelines were based, did not reflect the “real-world” population. Some patients may have died before recruitment or between randomization and ICD implantation. Nowadays, in the era of interventional treatment of MI, patients are discharged from the hospital early (usually on the 4th or 5th day), and the early start post-hospital period is characterized by a high risk of death in some patients. In our study, the eligibility criteria analogous to those for randomized clinical trials regarding ICD implantation after MI were not applied. Elimination of these limitations should enable researchers to establish the role of primary prevention ICD implantation in reducing early sudden cardiac deaths after MI.

In our study, we showed that 40-day mortality after MI is still very high (during this period occurs approximately one-third of all deaths within the first year). Our results are consistent with previous reports. In the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial, the highest risk of death was within the first week after MI. During the first month of MI, the risk of cardiovascular death or nonfatal cardiac arrest was 1.4%, but between months 6 and 12, the risk declined to 0.27% per month [6]. We found independent predictors of 40-day mortality, which enabled us to identify patients with a greater risk of death early after MI.

The highest risk of death in patients with reduced LVEF occurs within 40 days after MI. These deaths constitute one-third of all deaths that occur during the first year. The development of an optimal treatment strategy and possible ICD implantation during this period, in a certain group of patients, can be another step toward reducing mortality.

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