• „ Original article

Impact of diabetes mellitus on outcomes in patients with myocardial infarction according to varying degrees of left ventricular systolic dysfunction

11st Chair and Department of Cardiology, Medical University of Warsaw, Warszawa, Poland

2Department of Cardiology, University Hospital, Institute of Medical Sciences, University of Opole, Opole, Poland

33rd Department of Cardiology, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Silesian Center for Heart Diseases, Zabrze, Poland

41st Department of Obstetrics and Gynecology, Medical University of Warsaw, Warszawa, Poland

ABSTRACT Background: Diabetes mellitus (DM) is known to contribute to unfavorable short- and long-term outcomes in patients with myocardial infarction (MI). Particularly poor outcomes are associated with left ventricular systolic dysfunction after an MI. Our study aimed to compare the short- and long-term outcomes of MI in patients with DM and varying degrees of left ventricular systolic dysfunction with the corresponding outcomes in a non-diabetic control group. Methods: This analysis focused on patients with MI registered in the Polish National Registry of Acute Coronary Syndrome between 2009 and 2011. For this analysis, diabetic patients were additionally stratified into three subgroups depending on the degree of left ventricular systolic dysfunction, as assessed during their hospitalization for MI. Subsequently, the 30-day, 12-month, and 36-month outcomes in the diabetic study subgroups were compared with those in the corresponding non-diabetic subgroups. Results: This analysis encompassed a nationwide cohort of 58 123 patients. Twelve- and 36-months mortality was greater in diabetic patients than in non-diabetic patients. The highest 36-months mortality (46.64%) was in the group of patients with DM and reduced ejection fraction (EF) <40%. Multivariate analysis showed diabetes and low EF to be independent risk factors for 36-month mortality, increasing the risk of death by 35% for diabetes and by 30% for each 5-percentage point EF decrease. Higher mortality was observed in older patients, smokers, and patients with ischemic heart disease before the index hospitalization. Conclusions: Both diabetes and reduced EF proved to be independent risk factors for increased mortality over a long-term follow-up after MI. Key words: diabetes mellitus, ejection fraction, heart failure, myocardial infarction

Introduction

Non-cardiovascular comorbidities, depending on their severity, may render the prognosis for heart failure (HF) patients clinically challenging [1]. The correlation between diabetes mellitus (DM) and the risk of myocardial infarction (MI) has been thoroughly documented in the literature. DM increase the risk of hospitalisation for HF [2]. DM patients more commonly require extensive in-hospital treatment for MI compared to non-DM patients [3]. Diabetes worsens short- and long-term outcomes in patients with MI [4–6]. Left ventricular systolic dysfunction is an independent risk factor for mortality after MI [5]. Consequently, ejection fraction (EF) and HF symptoms included in the New York Heart Association (NYHA) functional classification are pivotal indicative criteria for cardioverter-defibrillator implantation as primary prevention of sudden cardiac death [6–8]. Our study aimed to compare the short- and long-term outcomes of MI in patients with diabetes mellitus with varying degrees of left ventricular systolic dysfunction (quantified in terms of EF values) with the corresponding outcomes in a non-diabetic control group.

Methods

Data of 58 123 consecutive patients who were hospitalized for MI (ST-segment elevation MI [STEMI] or non-ST-segment elevation MI [NSTEMI]) between January 2009 and December 2011 were obtained from the Polish National Registry of Acute Coronary Syndrome (PL-ACS). This Registry was initiated by the Silesian Centre for Heart Diseases in Zabrze and maintained in cooperation with the Ministry of Health and the National Health Fund as part of the National Program for the Prevention and Treatment of Cardiovascular Diseases. This vast nationwide Registry contains detailed data on over 640 000 patients hospitalized for the acute coronary syndrome (ACS) in Poland. It is not only the largest registry in Europe, but also it contains the most recent data relating to epidemiology, treatment, and outcomes in patients with ACS. Registry entry criteria were described elsewhere [9]. The investigation conformed to the principles outlined in the Declaration of Helsinki and was carried out in accordance with the local ethics department’s policy. The Ethics Committee of the Medical University of Warsaw was informed about the study (AKBE/81/2019).

The study population consisted of patients with diabetes (type 1, type 2, and new-onset, i.e. diagnosed during hospitalization) and patients without diabetes who constituted the control group. In line with the classification adopted within the Registry, patients with DM were defined as patients who received diabetes treatment (insulin, oral medications, or diet) before hospitalization, patients with new-onset diabetes were defined as those whose fasting blood glucose levels exceeded 7 mmol/l (≥126 mg/dl) in two measurements or blood glucose levels exceeded ≥11.1 mmol/l (≥200 mg/dl) following an oral glucose tolerance test conducted after the acute phase of MI [10].

The study population was stratified by EF values and assessed in terms of short- and long-term MI treatment outcomes. For this analysis, patients were further stratified into three subgroups based on the degree of left ventricular systolic dysfunction measured during their index hospitalization for MI. Left ventricular systolic dysfunction, expressed using EF, was determined by echocardiography. Based on the last measurement of the degree of left ventricular systolic dysfunction assessed during hospitalization, diabetic and non-diabetic patients were stratified into the following subgroups:

• • heart failure with reduced ejection fraction (HFrEF; <40%)
• • heart failure with mid-range ejection fraction (HFmrEF; 40%–49%)
• • heart failure with preserved ejection fraction (HfpEF; ≥50%).

Short-term (in-hospital and within 30 days post-discharge) and long-term (after 12 and 36 months) outcomes were assessed. Clinical endpoints are included in Supplementary material, Table S1.

Statistical methods

Continuous variables were presented as means and stan­dard deviations (SD). Categorical variables were presented as percentages and absolute values. The chi-square test for frequency data and Student’s t-test for continuous data were used to test the differences between the groups. The association between the groups and long-term mortality was analyzed using the Kaplan-Meier method for multiple group comparisons. Parameters from Table 1 and EF were included in the multivariable Cox proportional hazard model (the backward elimination method) to adjust the impact of diabetes on mortality at 36 months, and the results were expressed as hazard ratios (HRs) and 95% confidence interval (CI). Additional models were calculated to assess the impact of DM on 3-year mortality in different EF groups, and the impact of mildly reduced (40%–49%) and reduced (<40%) EF on 3-year mortality in dependence of diabetic status. Statistical significance was set at P <0.05. All reported P-values are two-sided. Analyses were performed with the use of Statistica version 13 (TIBCO Software Inc., Palo Alto, CA, USA) and NCSS 2020 Statistical Software, LLC (Kaysville, Utah, USA).

Results

DM patients (n = 11 689) comprised 20% of the study cohort, whereas non-diabetic patients (n = 46 434) comprised 80%. Ninety-seven percent of patients with DM were diagnosed with DM type 2. A total of 41.75% of diabetic patients and 52.07% of controls were diagnosed with STEMI (P <0.001). The EF ≥50%, EF 40%–49%, and EF <40% subgroups accounted for 53% (n = 30 780), 29% (n = 17 067), and 18% (n = 10 376) of the study cohort, respectively. The average EF values in the diabetic and control groups were 46% and 48%, respectively.

Table 1 presents the clinical characteristics of diabetic and non-diabetic patients. DM patients were usually older, were less likely to be male, and were more likely to suffer from chronic kidney disease in comparison with non-diabetic patients. In addition, DM patients were more likely to have a history of MI, stroke, HF, coronary artery disease, and peripheral vascular disease. Moreover, the diabetic group had a higher proportion of former smokers, whereas the non-diabetic group had a higher proportion of current smokers. Non-diabetic patients were more likely to have a history of hypertension and hypercholesterolemia.

In both groups, coronary angiography was performed in over 90% of cases involving MI. However, it was more frequently performed in the non-diabetic group than in the diabetic group (94.29% vs. 91.45%; P <0.001). Furthermore, non-diabetic patients underwent coronary angioplasty more often than patients with diabetes (79.64% vs. 74.62%; P <0.001). Likewise, patients with DM were more often qualified for coronary bypass surgery during hospitalization than non-diabetics (3.25% vs. 2.66%; P <0.001). Table 2 presents the number and percentage of diabetic and non-diabetic patients who underwent coronary angiography, coronary angioplasty, and coronary artery bypass surgery, as well as those who died in the hospital.

In multivariate analysis, diabetes (HR, 1.35; 95% CI, 1.30–1.42) and reduced EF (HR, 1.30; 95% CI, 1.29–1.31) proved to be independent risk factors for increased mortality within 36 months of the follow-up. Moreover, mortality was elevated in older patients (HR, 1.35; 95% CI, 1.33–1.36, for each 5-year age interval), smokers (former smokers: HR, 1.11; 95% CI, 1.07–1.17; current smokers: HR, 1.24; 95% CI 1.17–1.31), and patients with a history of ischemic heart disease (HR, 1.22; 95% CI, 1.16–1.28). Additionally, multivariate analysis showed hypercholesterolemia, hypertension, and higher body mass index (BMI) to be independent factors for lower mortality.

Diabetes increased the risk of death in all EF subgroups. The strongest effect was observed in the EF 40%–49% subgroup. On the other hand, low EF (<40%) doubled the risk of death in both diabetic and control groups in comparison with the risk of death in the preserved-EF subgroups (EF >50%). All multivariate analysis results are presented in Figure 1 and Tables 3 and 4.

All patients completed a 3-year follow-up. The total mortality rate over 36 months (including in-hospital mortality) is shown in Table 5.

Kaplan-Meier curves show the total risk of death during the 36-month follow-up in all evaluated groups (Figure 2).

Analysis of cardiovascular events after hospital discharge

Long-term (12- and 36-month) follow-up after hospital discharge demonstrated a higher risk of re-infarction and stroke in all three EF subgroups of diabetic patients than in non-diabetic patients. Diabetic patients from all three EF subgroups were also more likely to be hospitalized for HF than non-diabetic patients. This observation was true for both the short-term (30-day) and long-term (12- and 36-month) follow-ups. Diabetes was also associated with higher rates of end-stage renal disease and the resultant need for dialysis in all EF subgroups. The diabetic subgroup with the lowest EF of <40% showed that the rates of coronary angiography, coronary angioplasty, or coronary artery bypass grafting (CABG), within the 12- and 36-month follow-up periods, were no higher than those in the control group. Cardiovascular events over the 30-day, 12-month, and 36-month post-discharge follow-up have been presented in Table 6.

After hospital discharge, there was no difference in the 30-day mortality in the EF <40% and EF 40%–49% subgroups, regardless of diabetes status. However, in the EF ≥50% subgroup, the 30-day mortality was significantly higher in patients with diabetes (P = 0.03).

Similarly, in terms of left ventricular systolic dysfunction, 12- and 36-month post-discharge mortality was significantly higher in all diabetic subgroups compared with that in the control subgroups (P <0.001). For non-diabetic patients, the annual mortality rates after hospital discharge in the EF ≥50%, EF 49%–50%, and EF <40% subgroups were 3.62%, 6.05%, and 16.51%, respectively. The 12-month post-discharge mortality rates in the corresponding diabetic EF subgroups were considerably higher at 6.04%, 10.36%, and 21.18%, respectively. Ultimately, the highest 36-month mortality (38.65%) was found in patients with diabetes and an EF of <40%.

No significant differences were observed between patients with and without DM across all subgroups over the 30-day and 12-month follow-up periods in terms of the use of implantable cardiac defibrillators (ICD) or cardiac resynchronization therapy devices (CRT-D). This is in contrast with the 36-month follow-up data, in which non-diabetics from the EF <40% subgroup had higher rates of ICD implantation procedures compared with patients with DM from the EF <40% subgroup (P <0.05). There was no difference in the rates of CRT-D implantation between diabetic and non-diabetic patients.

Unexpectedly, patients with diabetes participated less often in cardiac rehabilitation than patients in the control group over the 1-year follow-up. Despite proven benefits of cardiac rehabilitation, the proportions of diabetic patients from EF ≥50%, 40%–49%, and <40% subgroups who underwent this type of treatment were lower, 23.65%, 19.99%, and 17.51%, respectively, than in the corresponding non-diabetic subgroups (25.66%, 27.56%, and 21.46%, respectively).

Discussion

The present study attempted to assess the long-term prognosis for diabetic patients who were treated for MI. The outcomes in diabetic patients with reduced left ventricular EF were particularly unfavorable, compared with those in non-diabetic patients with similar EF values.

Long-term outcomes of diabetic patients after MI in the era of thrombolytic treatment have been assessed pre­viously. The GUSTO-I study reported the annual mortality among diabetic patients with STEMI to be 14.5%, compared to 8.9% in non-diabetics [11]. Similar observations come from the OASIS and Valiant trials [12–13]. Also, the contemporary literature includes studies demonstrating a poor prognosis for diabetic patients undergoing treatment for MI [14]. Diabetic patients with MI are at a higher risk of adverse events than non-diabetic patients with MI (HR, 1.40; 95% CI, 1.20–1.64; P <0.001). Multivariate analysis results indicated that acute revascularization and medical therapy with aspirin and inhibitors of the renin-angiotensin system may improve patients’ prognoses [14]. DM patients with reduced EF are more commonly found to receive insulin or no anti-diabetic treatment compared to DM with normal range EF. Conversely, a tendency towards oral anti-diabetic medication is observed in normal EF range DM patients [3]. New classes of antidiabetic drugs, such as sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1-RAs), are nowadays recommended in diabetes mellitus type 2 (DM2) patients with cardiovascular disease to improve outcomes [15]. Empagliflozin decreased the death rate from cardiovascular causes, non-fatal MI, and stroke and death from any cause in patients with DM2 at high risk for cardiovascular events, as compared with placebo [16]. In the LEADER Trial, Liraglutide reduced the risk of death from cardiovascular causes, MI and stroke in patients with DM [17].

We analyzed the prognosis for MI patients based on the degree of left ventricular systolic dysfunction (expressed in terms of EF). Stolfo et al. concluded that the EF assessed at hospital discharge proved to be a better predictor than the EF recorded earlier during hospitalization [18]. Our study results were based on the last measurement of EF made during hospitalization. Solomon et al. [19] revealed that most of the observed functional improvement occurred by day 14 after MI. The improvement in left ventricular EF after MI begins within three days of coronary revascularization [19]. Stolfo et al. [18] evaluated EF at three different time points after STEMI (<24 hours after coronary angioplasty, at hospital discharge, and three months after MI) and reported that the independent predictors of decreased EF (<35%) 3 months after revascularization are creatinine levels on hospital admission, peak troponin I levels, and EF during hospitalization. In our analysis, patients with DM from all evaluated EF ranges fared worse than their non-diabetic counterparts in the long-term follow-up, as evidenced by increased risks of mortality, stroke, re-infarction, hospitalization for HF, and end-stage renal failure requiring dialysis. The mortality rate in patients with HF, or reduced EF after MI, was twice as high as in patients with preserved or mid-range EF and no symptoms of HF [20, 21].

Yet another important observation from our study concerns the prognosis for patients with mid-range ejection fraction. Our study revealed that patients with EF of 40%–49% have a much worse prognosis than those with preserved EF regardless of their diabetic status. Multivariate analysis results showed that patients with EF of 40%–49% from both the diabetic and control groups had an over 50% higher risk of death compared with the groups with an EF of ≥50%. There have been no data in the current literature that are consistent with our findings.

Our study proves beyond any doubt that patients with diabetes are more prone to cardiovascular events and hospitalization prompted by HF. Re-infarction was more common among diabetic patients in all three EF subgroups. Similarly, the EPHESUS study assessed the impact of diabetes on the prognosis for patients with MI with reduced EF. Diabetes was also identified as an independent risk factor for the onset of another MI, but not necessarily resulting in death. However, no correlation was found between diabetes and the incidence of fatal MI during 2.5 years of follow-up [22]. In our study, diabetes correlated with the rate of hospitalizations for HF across all three EF subgroups. In an observational registry, ACS exacerbated by HF was shown to result in significantly worse outcomes than ACS without HF over a 6-month follow-up. HF was associated with reduced hospitalization and 6-month survival rates across all ACS subsets. ACS patients who were diagnosed with HF on admission had an approximately threefold decrease in their 6-month post-discharge survival rate (mortality rates of 8.5% in those with an admission diagnosis of HF vs. 2.8% in those without HF, respectively; P <0.001) and were also more likely to be re-hospitalized (23.6% vs. 15.7%, respectively, P <0.001) [23]. Similarly, Hung et al. [24] showed that the incidence of death in patients with MI complicated by HF was greater than in patients without HF after a 1-year follow-up. Development of HF within 90 days of the index MI hospitalization yielded an adjusted HR of 2.7 for 1-year mortality in 90-day survivors.

Every 5% reduction in EF increases the risk of cardiac arrest or sudden cardiac death by 21% in the first 30 days after MI [5]. Similarly, our patients with reduced EF had a much higher 30-day mortality rate (15.09% in DM and 13.65% in non-DM patients) compared with patients with mid-range EF (4.04% in DM and 3.36% in non-DM patients). We concluded that a reduction in EF increased 36-month mortality by 30% for each 5% decrease in EF.

Future investigations after the implementation of new recommendations will be interesting. SGLT-2 inhibitors in addition to standard care found a new place for both diabetic and non-diabetic patients with cardiovascular disease. Dapagliflozin or empagliflozin are recommended for patients with symptomatic HF and EF≤40% despite optimal medical therapy to reduce the risk of hospitalization and death. This first-class recommendation of the ECS guidelines results from recently conducted studies [25, 26].

We identified the following three parameters as independent factors for lower mortality: BMI, hypercholesterolemia, and hypertension. Higher BMI and lower mortality in chronic coronary artery disease and ACS patients are considered a “BMI paradox”. Our observations are consistent with those resulting from analysis of other large registries [27, 28]. In the registry, which is a collection of data on 64 436 patients who underwent coronary angiography due to ACSs, the relation between BMI and mortality was U-shaped, the lower risk of mortality was noted in moderately overweight patients (BMI of 26.5–28 kg/m2) [27]. In-hospital mortality was also assessed in over 50 000 patients hospitalized for STEMI in the United States [28]. Using patients with BMI between 30 kg/m2 and 35 kg/m2 as a reference, risk-adjusted in-hospital mortality rates were significantly higher only for patients with BMI of ≥40 kg/m2 (HR, 1.64; CI, 95% 1.32–2.03).

Epidemiological data about the association between hypertension and prognosis in patients with ACS are inconclusive [29]. Some studies showed an unfavorable association between hypertension and in-hospital [30], 30-day [31], or long-term prognosis [32], whereas other studies demonstrated no association between hypertension and long-term mortality or even showed higher mortality in normotensive patients [33]. The possible explanation of lower mortality in patients with hypertension and hypercholesterolemia may be associated with the use of angiotensin-converting enzyme inhibitors, β-blockers, and statins in the period before hospitalization.

Our analysis of the 36-month data revealed that a greater proportion of non-diabetic patients in the EF <40% subgroup received an ICD compared with diabetic patients (P <0.05), despite the current guidelines. By way of explanation, diabetes may curtail the effectiveness of ICDs in patients with reduced EF [34]. In addition, in a recent meta-analysis [35] including a combined total of 3359 patients from MADIT I, MADIT II, DEFINITE, and SCD-HeFT studies, ICD implantation reduced overall mortality in non-diabetic patients but not in patients with DM. It is, therefore, imperative that prospective research studies be performed on whether to implant ICDs in patients with diabetes and reduced EF.

In-hospital and post-discharge care for AMI patients is related to a major adverse cardiovascular events rate reduction by 45% in 3 months [36]. Although cardiac rehabilitation after MI has been proven to reduce cardiovascular mortality by 20%, diabetic patients participated less frequently in cardiac rehabilitation within the first year after their MI (regardless of EF values) [37]. In addition, cardiac rehabilitation after MI improves exercise capacity, which is significantly lower in patients with diabetes compared to that in non-diabetics [38]. Consequently, greater emphasis should be placed on referring diabetic patients for cardiac rehabilitation.

Study strengths and limitations

The strength of this study derives from analyzing an extensive data set and the use of uniform diagnostic and treatment procedures. The percentage of missing values in the PL-ACS registry used in multivariate analyses was low (<0.5%) thus multivariate analyses were performed with the exclusion of patients with missing data. Since this was a non-randomized observational study, the possible interdependence of some variables, including the effects of the patients’ medications, is unknown. We were unable to measure the EF after the index hospitalization. Possibly, the inter-observer variability could be an issue in this study, but the huge number of patients we analyzed from the different centers strongly reduces the possibility of its negative impact.

Conclusion

We presented data, representing 36-month post-MI follow-up, obtained from a large national ACS Registry. In addition, we conducted outcome analyses as a function of the degree of left ventricular systolic dysfunction after MI. The worst outcome with a 36-month mortality rate of 46.64% was in patients with diabetes and EF below 40%. In our multivariate analysis, diabetes and decreased EF after MI were independent risk factors of mortality during the 36-month follow-up.

Finally, we would like to emphasize that the present study is only an attempt to highlight the common clinical problems posed by MI treatment in patients with comorbid diabetes. Certainly, further research on the group of patients with mid-range EF would be interesting.

Our study is intended to spur a discussion on multivariate aspects of in-hospital and, which is equally important, outpatient treatment to improve the unfavorable prognosis in DM patients with MI.

Supplementary material

Supplementary material is available at https://journals.viamedica.pl/kardiologia_polska.

Article information

Conflict of interest: None declared

Funding: The PL-ACS registry is a joint initiative of the Silesian Center for Heart Diseases in Zabrze and the Polish Ministry of Health. Logistic support is provided by the National Health Fund (NHF).

Open access: This article is available in open access under Creative Common Attribution-Non-Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0) license, allowing to download articles and share them with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially. For commercial use, please contact the journal office at kardiologiapolska@ptkardio.pl.

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