Abstract
Background: In this study, we investigated whether different levels of hemoglobin A1c (HbA1c) are associated with different short-term and 1-year mortality rates among diabetic patients undergoing percutaneous coronary intervention. Patients & methods: Clinical events including in-hospital, 1-month and 1-year mortality were compared between three groups based on HbA1c levels of patients (I: ≤5.6%, II: 5.7–6.4%, III: ≥6.5%). Results: Among 165 diabetic individuals, patients with abnormal HbA1c levels (≥6.5%) experienced significantly higher hospitalization days (7.65 ± 1.64 days) compared with those with normal HbA1c (4.94 ± 0.97 days) (p < 0.0001). In-hospital mortality was significantly higher in group III (14.5%) and II (5.5%) compared with group I (0%) (p = 0.008). Conclusion: HbA1c levels may be a reliable predictor of short-term clinical events in diabetic patients.
Keywords: : diabetes mellitus, glycemic control, hemoglobin A1c, mortality, percutaneous coronary intervention
Plain language summary
Summary points.
Patients with higher hemoglobin A1c (HbA1c) levels had more coronary arteries involved detected during angiography.
Higher HbA1c was intimately linked with longer hospitalization and higher in-hospital mortality rates.
Less clear evidence was obtained regarding HbA1c level and 1-month and 1-year mortality rates.
Acute myocardial infarction (AMI) is the leading cause of death worldwide and occurs in more than 750,000 patients in the USA each year [1]. Percutaneous coronary intervention (PCI) has provided a therapeutic approach for decreased death and reinfarction rates within several months following ST-segment elevation myocardial infarction (STEMI) [2]. Emerging evidence has highlighted the reciprocal relationship between numerous risk factors including hyperlipidemia, smoking, lesion severity by luminal stenosis, and diabetes mellitus (DM) with adverse cardiovascular events after PCI in AMI patients [3–5]. It is corroborated that diabetes is obviously associated with a two- to four-times increase in cardiovascular disease compared with the nondiabetic population [6]. Diabetes can exert a substantial effect on worse coronary artery disease outcomes and plays a role in predicting outcomes in patients undergoing PCI [7]. It should be noted that the prognostic role of blood glucose levels at admission was regarded as a dichotomous variable because it could be affected by several confounding factors such as physiological stress response and the patient’s last meal [8,9].
Hemoglobin A1c (HbA1c) is a standard marker of plasma glucose level over the previous 2–3 months and has been introduced as a useful parameter in clinical practice [10]. It should be stressed that a raised HbA1c level is linked with an increased risk of cardiovascular disease [11,12]. Consistent with this notion, a 1% increase in HbA1c level has accounted for a 40% increase in ischemic heart disease mortality among subjects with underlying diabetes [13]. A previous meta-analysis reported a 17% decrease in adverse cardiovascular events following a 0.9% reduction in HbA1c levels among diabetic patients [14].
The potential association between HbA1c levels with short- and mid-term prognosis of diabetic patients with STEMI undergoing PCI has been investigated in the past. To contribute to this body of data, we conducted this study to evaluate whether the HbA1c level could predict adverse events following PCI in type 2 DM patients and whether the prognostic value of this marker could be helpful in the decision-making of STEMI patients.
Patients & methods
Design overview & patient selection
This was a single-center retrospective cohort study conducted between 2018 and 2020 and primarily comparing mortality rates of the patients with STEMI undergoing PCI based on their HbA1c level. Patients between 30 and 90 years of age with a first presentation of STEMI (defined as continuous chest pain of at least 30 min duration and ST-segment elevation ≥2 mm in two or more anatomically contiguous leads within 12 h of symptom onset) undergoing coronary angioplasty with an available glycosylated HbA1c level at the time of admission were considered potentially eligible. Data of participants admitted for PCI from 2019 to 2020 were collected retrospectively. Type 2 DM was defined as a previous diagnosis of type 2 DM made by a trained physician and a present history of insulin injection or taking oral glucose-lowering agents. Given that patients with type 2 diabetes have more metabolic dysfunctions and are the predominant population of patients with coronary artery disease, we decided to exclude type 1 patients. The main exclusion criteria included a history of previous acute myocardial infarction, loss of follow-up, unavailable medical records, patients younger than 30 or older than 90 years, and patients who did not undergo PCI for any reason. Patients were divided by their level of HbA1c into three groups (group I: ≤5.6%; group II: 5.7–6.4%; group III: ≥6.5%) to compare the impact of HbA1c on the clinical outcomes. The data regarding clinical events were collected by follow-up visits or by making phone calls. Written informed consent and verbal consent were obtained from all the included participants, and the local ethical committee approved the study design.
End points & follow-up
In this current study, we investigated the prognostic effects of HbA1c level at the time of admission on the occurrence of all-cause mortality rate at 1 month, 1 year, and during hospitalization as our primary objective. The secondary end points included a comparison of duration of hospital stay, baseline left ventricular ejection fraction (LVEF), and the number of coronary arteries involved during angiography (one-, two- or three-vessel disease) between the patient groups. Medical records of the eligible patients were retrieved and their data regarding gender, age, BMI, HbA1c, duration of hospital stay, LVEF, angiographic findings and mortality data were evaluated. Blood samples were also taken from all patients, and HbA1c levels on admission were measured by high-performance liquid chromatography. Patients were followed for 1 year after the occurrence of STEMI for clinical events.
Statistical analysis
We used SPSS Statistics for Windows, v.24.0 (IBM Corp., NY, USA) for statistical analysis. In the case of continuous variables, data were shown as mean and standard deviation, and for categorical variables, we presented them as numbers and associated percentages. Continuous data were compared between groups (HbA1c ≤5.6%, 5.7–6.4%, and ≥6.5%) using analysis of variance, while categorical data were compared using χ-square or Fisher’s exact test, as appropriate. For the post hoc analysis, we used Tukey’s honest significant difference test for comparison of the difference between pairs of group means. A two-tailed p-value of ≤ 0.05 was set as statistically significant.
Results
As shown in Table 1, a total of 165 patients were included during the study period and divided into three groups according to HbA1c level (group I: HbA1c ≤5.6%; group II: 5.7% ≤HbA1c ≤6.4%; group III: HbA1c ≥6.5%). The mean age was 53.97 years (range: 34–60) and the study population consisted of 17% females (n = 28). A significant difference was noted in BMI between groups (p = 0.0001). The post hoc test revealed that BMI was significantly lower in the patients with normal HbA1c (HbA1c ≤5.6%) than in the other two groups (p < 0.05). Mean LVEF was 52.09 ± 5.82% in group I and 36.36 ± 4.85% and 35.54 ± 3.28% in groups II and III, respectively (p = 0.0001).
Table 1.
Baseline characteristics of study groups.
| HbA1c ≤5.6% (n = 55) | 5.7% ≤HbA1c ≤6.4% (n = 55) | HbA1c ≥6.5% (n = 55) | p-value | |
|---|---|---|---|---|
| Age (years) | 53.78 ± 5.79 | 53.75 ± 6.31 | 54.40 ± 6.81 | 0.83 |
| Female gender | 14 (25.5) | 7 (12.7) | 7 (12.7) | 0.122 |
| BMI (kg/m2) | 32.14 ± 2.38 | 34.67 ± 2.85 | 34.68 ± 2.67 | < 0.0001 |
| LVEF (%) | 52.09 ± 5.82 | 36.36 ± 4.85 | 35.54 ± 3.28 | < 0.0001 |
Data are presented as mean ± standard deviation or number (percentage).
HbA1c: Hemoglobin A1c; LVEF: Left ventricular ejection fraction.
As shown in Table 2, the number of coronary arteries diagnosed with a culprit lesion in angiography differed significantly between groups (group I: 0.16 ± 0.37; group II: 1.04 ± 0.43; group III: 1.33 ± 0.58; p < 0.0001). None of the patients with normal HbA1c had an advanced three-vessel disease. However, patients with higher HbA1c levels had more coronary vessels involved with lesions during angiography compared with patients with normal HbA1c (three vessels: group III = 38.2%, group II = 10.9%, group I = 0%). Hospital stay length was significantly different among the studied groups: patients with abnormal HbA1c (group III) had a significantly longer hospital stay compared with those with normal HbA1c (group I) (7.65 ± 1.64 vs 4.94 ± 0.97 days; p < 0.0001). None of the patients with a normal HbA1c experienced in-hospital mortality, whereas the mortality rates were 5.5 and 14.5% among patients in groups II and III, respectively (p = 0.008). The studied groups were not statistically different regarding mortality rates after 1 month and 1 year (p = 0.35 and p = 0.08, respectively).
Table 2.
Clinical and angiographic outcomes in the study population.
| HbA1c ≤5.6% (n = 55) | 5.7% ≤HbA1c ≤6.4% (n = 55) | HbA1c ≥6.5% (n = 55) | p-value | ||
|---|---|---|---|---|---|
| Number of vessels involved | One | 48 (83.6) | 9 (16.4) | 5 (0.9) | < 0.0001 |
| Two | 4 (7.3) | 35 (63.6) | 9 (16.3) | ||
| Three | 3 (5.5) | 11 (20) | 41 (74.54) | ||
| Length of stay (days) | 4.94 ± 0.97 | 6.20 ± 1.06 | 7.65 ± 1.64 | < 0.0001 | |
| In-hospital mortality | 0 (0) | 3 (5.5) | 8 (14.5) | 0.008 | |
| 1-month mortality | 1 (1.8) | 4 (7.3) | 4 (7.3) | 0.347 | |
| 1-year mortality | 0 (0) | 3 (5.5) | 5 (9.1) | 0.082 | |
Data are presented as mean ± standard deviation or number (percentage).
HbA1c: Hemoglobin A1c.
The Kaplan–Meier curve displayed the hazard ratio for death based on various levels of HbA1c. The analysis showed that patients with 1-year mortality showed higher values of HbA1c compared with the surviving patients (non-survivors: 7.08 ± 0.38; survivors 6.46 ± 0.11) (Figure 1).
Figure 1.
Cumulative hazard ratios based on hemoglobin A1c levels among patients who did and did not survive.
Cum: Cumulative; HbA1c: Hemoglobin A1c.
Discussion
The findings of the present study showed that poor glycemic control, as measured by HbA1c, can serve as a prognostic factor. Herein, we showed that patients with abnormally high levels of HbA1c (≥6.5%) were more susceptible to adverse clinical outcomes including longer duration of hospitalization and in-hospital mortality. These patients were also diagnosed with more severe features of coronary artery disease during angiography: patients with higher levels of HbA1c were more frequently diagnosed with advanced three-vessel disease compared with those with normal levels of glycosylated hemoglobin. Our study also showed that patients with lower HbA1c levels had higher prevalence of normal coronary arteries shown during angiography, although the higher prevalence of diseased vessels in patients with abnormal HbA1c failed to have an impact on mid-term mortality. This may bring into question whether the HbA1c level in patients undergoing PCI is a causative factor or just a marker of patients with a more severe condition. It should be also mentioned that the small sample size and single-center design of the present study may have somewhat contributed to these results.
It has been demonstrated that a well-controlled blood glucose level in patients with diabetes is concomitant with better survival probability. In a study by Albugami et al., patients were stratified based on their HbA1c levels (>7 vs ≤7%). Patients with poor glycemic control experienced significantly higher rates of composite clinical events, although the rates of cardiovascular mortality and sudden death were not different among groups. The Kaplan–Meier curve analysis showed that patients with uncontrolled DM had a significantly lower survival probability. Also, patients with sufficient glycemic control throughout the study had similar survival rates compared with patients with uncontrolled DM who had regained control at the follow-up [15]. In another prospective cohort study, in accordance with our study, patients with DM and poor glycemic control (HbA1c ≥7%) showed similar rates of all-cause and cardiovascular-related death over a period of 7 years. Interestingly, in this cohort of 980 patients, patients with poor glycemic control had a significantly higher risk of major adverse cardiac and cerebrovascular events compared with the ones with well-controlled DM [16]. Findings from a retrospective analysis from a single-center registry demonstrated that 1-year major adverse cardiovascular events (MACEs) among patients undergoing PCI may show a U-shaped association with HbA1c levels, in that extreme levels of HbA1c (≤5.5 and >8%) may be associated with higher risk of a MACE [17]. More multicenter studies with large sample sizes should be conducted to confirm the findings of the above-mentioned studies.
A meta-analysis found that an abnormal HbA1c level is an independent risk factor for long-term adverse clinical events in nondiabetic patients diagnosed with coronary artery disease following PCI. Subgroup analysis suggested that HbA1c levels between 6 and 6.5% predicted a high long-term risk of MACEs, although values between 5.7 and 6.5% were not associated with higher risk of MACEs. This study also found that abnormal HbA1c level was associated with higher all-cause mortality in studies from the Netherlands, but not in those examining Asian and American populations [18]. Findings from another study showed that mortality rates are significantly higher in insulin users than in non-insulin users with DM undergoing PCI. An incremental mortality rate was observed in patients with higher baseline levels of HbA1c among non-insulin users, as patients with an HbA1c >10% had a significantly higher hazard ratio of death compared with the other groups. It should be noted that no association could be found between baseline HbA1c and long-term mortality among insulin users [19]. The proportion of females enrolled in our study was low (17% female vs 73% male); the lower incidence of AMI in women may be among the contributing factors to this proportion in our study [20].
There are some limitations to our study that should be noted. The results are from a single center with a limited sample size. This may introduce our results to some sort of bias. The participants were followed for 1 year after the performance of PCI, and long-term results of outcomes could not be yielded. Other clinical outcomes including target vessel revascularization, recurrence of myocardial infarction and stroke rates were not among the studied outcomes of interest.
Conclusion
In conclusion, our results showed that poor glycemic control in patients with DM (HbA1c ≥6.5%) may be associated with short-term outcomes that are worse than those in patients with well-controlled diabetes. Patients with high HbA1c levels had more coronary arteries involved during angiography. Also, our findings demonstrated that uncontrolled DM in patients undergoing PCI is associated with a longer duration of hospitalization and higher in-hospital mortality, although 1-month and 1-year mortality rates were not different among the studied groups. Future studies with a larger population should be undertaken to confirm or refute the findings of the present study.
Author contributions
P Izadpanah and T Dehghanzadeh contributed to the conceptualization. The primary draft was provided by N Rahimikashkooli, A Attar and A Hosseinpour. P Izadpanah, A Attar and A Hosseinpour reviewed the draft and edited the manuscript. All the listed authors contributed substantially to the manuscript and have agreed to the final submitted version.
Financial disclosure
The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Competing interests disclosure
The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Writing disclosure
No writing assistance was utilized in the production of this manuscript.
Ethical conduct of research
The authors state that they have obtained appropriate institutional review board approval (IR.SUMS.MED.REC.1398.635) and have followed the principles outlined in the Declaration of Helsinki for all human investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.
Data availability
The data supporting the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data supporting the findings of this study are available from the corresponding author upon reasonable request.