Author + information
- Received January 15, 2015
- Revision received May 11, 2015
- Accepted May 19, 2015
- Published online August 4, 2015.
- Thomas Nyström, MD, PhD∗,†,
- Martin J. Holzmann, MD, PhD‡,§,
- Björn Eliasson, MD, PhD‖,
- Jeanette Kuhl, MD, PhD¶,# and
- Ulrik Sartipy, MD, PhD∗∗,††∗ ()
- ∗Department of Clinical Science and Research, Karolinska Institutet, Stockholm, Sweden
- †Division of Internal Medicine, Södersjukhuset, Stockholm, Sweden
- ‡Department of Emergency Medicine, Karolinska University Hospital, Stockholm, Sweden
- §Department of Internal Medicine, Karolinska Institutet, Stockholm, Sweden
- ‖Institute of Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
- ¶Department of Cardiovascular Medicine, Danderyds Hospital, Stockholm, Sweden
- #Department of Clinical Sciences, Karolinska Institutet, Stockholm, Sweden
- ∗∗Department of Cardiothoracic Surgery and Anesthesiology, Karolinska University Hospital, Stockholm, Sweden
- ††Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- ↵∗Reprint requests and correspondence:
Dr. Ulrik Sartipy, Department of Cardiothoracic Surgery and Anesthesiology, Karolinska University Hospital, SE-171 76, Stockholm, Sweden.
Background Patients with type 1 diabetes mellitus (T1DM) have a high risk of cardiovascular events.
Objectives The aim of this study was to investigate whether preoperative hemoglobin A1c (HbA1c) levels could predict cardiovascular events or death after coronary artery bypass grafting (CABG).
Methods This was a nationwide population-based observational cohort study that included all patients with T1DM who underwent primary isolated nonemergency CABG in Sweden between 1997 and 2012, according to the Swedish National Diabetes Register and the SWEDEHEART (Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies) register. We calculated the crude incidence rates and 95% confidence intervals (CIs) and used Cox regression and multivariable hazard ratios (HRs) to estimate the risk of both all-cause mortality and major adverse cardiovascular events (MACE), defined as myocardial infarction, stroke, heart failure, or repeat revascularization, in relation to HbA1c levels.
Results In total, 764 patients with T1DM were included. During a median follow-up of 4.7 years, 334 (44%) patients died or had MACE (incidence rate: 82 events/1,000 person-years). After multivariable adjustment, the HR (95% CI) for death or MACE in patients with HbA1c levels of 7.1% to 8.0%, 8.1% to 9.0%, 9.1% to 10.0%, and >10.0% were 1.34 (0.82 to 2.21), 1.59 (1.00 to 2.54), 1.73 (1.03 to 2.90), and 2.25 (1.29 to 3.94), respectively, compared with the reference category. When HbA1c was used as a continuous variable, the HR for a 1% increase in HbA1c level was 1.18, and the 95% CI was 1.06 to 1.32.
Conclusions In patients with T1DM, poor glycemic control before CABG was associated with increased long-term risk of death or MACE. (HeAlth-data Register sTudies of Risk and Outcomes in Cardiac Surgery [HARTROCS]; NCT02276950)
Advances in treatment for type 1 diabetes mellitus (T1DM) have improved life expectancy and decreased mortality rates over time (1). Despite declining rates of diabetes-associated complications in the past 2 decades (2), the disease persists in large numbers, and the prevalence of cardiovascular disease (CVD), the most common complication among patients with diabetes, remains very high (3). Abnormal vascular findings associated with atherosclerosis are much more common in patients with T1DM compared with nondiabetic patients (4). The risk of CVD events is high and occurs earlier in patients with T1DM; incidence rates of deaths, even in patients with T1DM who have good glycemic control, are reached at a much younger age compared with the general population (5,6).
Revascularization surgery for patients with multivessel coronary heart disease (CHD) is a common procedure; approximately 25% of these patients have diabetes. Patients with diabetes and established CHD often have more complicated atherosclerosis and are at higher risk of developing major adverse CVD events and death than are patients without diabetes (7–10). Revascularization studies have evaluated patients on the basis of various categorizations, including the presence or absence of diabetes (8,9) and the presence of insulin-dependent or not insulin-dependent diabetes (7). In patients with T1DM and CHD, the association between glycemic control and cardiovascular outcomes after revascularization remains unclear (11). Because patients with T1DM have a high risk of CVD events and death (5), we wanted to investigate whether different levels of glycemic control could predict CVD events after coronary artery bypass graft (CABG) procedures in these patients.
The aim of this study was to analyze the association between preoperative hemoglobin A1c (HbA1c) levels and combined all-cause mortality and myocardial infarction, heart failure, stroke, or repeat revascularization in patients with T1DM who were undergoing primary isolated nonemergency CABG.
This was an observational nationwide population-based cohort study. The study was approved by the regional Human Research Ethics Committee, Stockholm, Sweden.
The study population was obtained by cross-referencing patient-level data from the SWEDEHEART (Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies) register (12) and the National Diabetes Register (13). All patients with T1DM (according to the Swedish National Diabetes Register) who underwent primary isolated nonemergency CABG in Sweden between 1997 and 2012 were included. Further information regarding baseline characteristics was extracted from the National Patient Register. Cross-referencing was possible through the unique personal identity number assigned to every Swedish citizen (14). The epidemiological definition of T1DM in the Swedish National Diabetes Register is onset of diabetes before the age of 30 years and treatment with insulin only (13).
Analyses of HbA1c were carried out at local laboratories with the high-performance liquid chromatography Mono-S method and were quality assured nationwide by regular calibration. We converted all HbA1c values to standard values according to the National Glycohemoglobin Standardization Program (15). We calculated the mean of all available HbA1c values before the date of CABG for each patient (16). On the basis of their preoperative mean HbA1c values, patients were assigned to 1 of the following HbA1c categories: ≤7.0%, 7.1% to 8.0%, 8.1% to 9.0%, 9.1% to 10.0%, and >10.0%.
The primary outcome measure was a combination of all-cause mortality and major adverse cardiovascular event (MACE), defined as rehospitalization for a primary diagnosis of myocardial infarction (International Classification of Diseases-Tenth Revision [ICD-10] codes: I21 to I21.9), heart failure (ICD-10 codes: I50 to I50.9), stroke (ICD-10 codes: I60 to I69.9), or repeat revascularization (ICD-10 codes: FNG, FNA, FNC). The date and cause of death were obtained from the national Cause of Death Register; the date and cause of rehospitalization were obtained from the National Patient Register. The validity of the diagnoses of myocardial infarction, heart failure, and stroke has been evaluated in the National Patient Register and found to be 95% for a primary diagnosis of heart failure; the positive predictive value is 98% to 100% for myocardial infarction and 98.6% for stroke (17,18). We also assessed death from cardiovascular and noncardiovascular causes separately. Finally, the following ICD-10 codes were used to analyze hospitalizations for hypoglycemia: E10.0, E10.6, and E16 to E16.2.
We excluded patients with missing information regarding preoperative HbA1c. For the following variables that were used as covariates in the multivariable analyses, some data were missing: renal function (7.5%), number of bypass grafts (11%), and left ventricular ejection fraction (34%). We used multiple imputation by chained equations to handle missing data (19). The imputation models included 26 variables, including the event indicator and the Nelson-Aalen estimator of the cumulative baseline hazard (20), under the assumption that the missing values were missing at random. Twenty-five datasets were imputed, and estimates from these datasets were combined according to Rubin’s rules.
Patients’ characteristics were described using frequencies and percentages for categorical variables and using means and standard deviations for continuous variables. The primary outcome measure was death from any cause or hospitalization for a MACE (myocardial infarction, heart failure, stroke, or repeat revascularization). Patients contributed person-time in days from the date of the surgical procedure until the date of death from any cause, the date of a MACE, or at the end of the follow-up period (December 31, 2012), whichever occurred first. We calculated the crude incidence rates and 95% confidence intervals (CIs). We used Cox regression to estimate the risk of the combined endpoint all-cause mortality or myocardial infarction, heart failure, stroke, or repeat revascularization according to the following preoperative HbA1c categories: 7.1% to 8.0%, 8.1% to 9.0%, 9.1% to 10.0%, and >10.0%, by using HbA1c ≤7.0% as the reference level. We calculated crude age- and sex-adjusted and multivariable adjusted hazard ratios (HRs) and 95% CIs. All variables listed in Table 1 were included as covariates in the final multivariable model. We investigated the potential nonlinear relationship between HbA1c and outcome in a Cox model, where HbA1c was modeled by restricted cubic splines, and adjusted HRs and 95% CIs were plotted against HbA1c levels. We investigated differences in each cause of mortality (cardiovascular death or noncardiovascular causes) by competing risk regression on the basis of the Fine-Gray proportional subhazards model (21), and we calculated subdistribution HRs and 95% CIs. Data management and statistical analyses were performed using Stata version 13.1 (Stata Corp., College Station, Texas) and R version 3.1.2 (R Foundation for Statistical Computing, Vienna, Austria).
Baseline patient characteristics are presented in Table 1. The study population included 764 patients, and during a median follow-up time of 4.7 years (interquartile range [IQR]: 1.8 to 8.8 years), 334 (44%) patients died or had a MACE, for an incidence rate of 82 events per 1,000 person-years (95% CI: 73 to 91). The mean age was highest in the lowest HbA1c category, and the mean age decreased with increasing preoperative HbA1c level. The proportion of women was highest among those with very poor glycemic control (HbA1c >10.0%). Early mortality (death within 30 days of the surgical procedure) was 4 of 67 (5.6%), 2 of 190 (1.1%), 5 of 296 (1.7%), 2 of 146 (1.4%), and 1 of 65 (1.5%), in the low to high HbA1c categories, respectively.
The age-adjusted freedom from death or MACE is shown in Figure 1. The crude incidence of death or MACE in patients with preoperative HbA1c levels ≤7.0%, 7.1% to 8.0%, 8.1% to 9.0%, 9.1% to 10.0%, and >10.0% was 81 (95% CI: 56 to 116), 76 (95% CI: 61 to 96), 77 (95% CI: 64 to 92), 80 (95% CI: 63 to 103), and 121 (95% CI: 90 to 163) per 1,000 person-years, respectively (Table 2).
No significant association was observed between preoperative HbA1c level and death or MACE in the unadjusted analyses (Table 2). After adjustment for age and sex, patients with high HbA1c levels (i.e., poor glycemic control) had a significantly higher risk of death or MACE compared with patients with low HbA1c levels (≤7.0%).
After multivariable adjustment, the HR (95% CI) for death or MACE was 1.34 (0.82 to 2.21) in patients with HbA1c from 7.1% to 8.0%, 1.59 (1.00 to 2.54) in patients with HbA1c from 8.1% to 9.0%, 1.73 (1.03 to 2.90) in patients with HbA1c from 9.1% to 10.0%, and 2.25 (1.29 to 3.94) in patients with HbA1c >10.0% compared with patients with low HbA1c levels (≤7.0%), as shown in Table 2 and the Central Illustration.
The numbers of patients who were hospitalized at least once for hypoglycemia after CABG were 7 of 67 (10%), 15 of 190 (7.9%), 24 of 296 (8.1%), 19 of 146 (13%), and 11 of 65 (17%) in the low to high HbA1c categories, respectively.
Death from cardiovascular and noncardiovascular causes
We also investigated the relationship between preoperative HbA1c levels and death from cardiovascular versus noncardiovascular causes. In a competing risk regression analysis, we found that the subdistribution HRs for death from cardiovascular and noncardiovascular causes increased with increasing preoperative HbA1c levels. However, because of the relatively low number of events, these risk estimates were not significant (Figure 2).
Nonlinear relationship between HbA1c and prognosis
We analyzed the potential nonlinear relationship between HbA1c level and risk of death or MACE by entering HbA1c modeled with restricted cubic splines in an age- and sex-adjusted Cox regression model. As shown in the Central Illustration, a very small risk increase was found in the HbA1c range from 6.0% to 8.5%. However, a steep increase in the risk of death or MACE was noted for each 1% increase in HbA1c level >8.5%. When HbA1c was used as a continuous variable in a Cox model adjusted for all variables shown in Table 1, the HR for an absolute 1% increase in HbA1c level was 1.18 (95% CI: 1.06 to 1.32; p = 0.002).
The main finding in this long-term (median, 4.7 years) follow-up study was that high preoperative HbA1c levels were significantly associated with an increased risk of death or MACE in patients with T1DM who were undergoing primary isolated nonemergency CABG in Sweden between 1997 and 2012. The association between higher pre-operative HbA1c levels and worse cardiovascular prognosis was independent of a number of clinical characteristics and previously identified risk factors. In patients with very poor glycemic control, the risk of death or MACE was more than twice that of patients with lower preoperative HbA1c levels (<7.0%).
Chronic hyperglycemia affects several target organs, including the heart, brain, and kidney, and it contributes to organ damage. Although the development of atherosclerosis is multifactorial, evidence indicates that chronic hyperglycemia is a culprit in macrovascular complications (22). Coronary atheroma is more common among diabetic patients, and HbA1c level is associated with progression of atherosclerosis and CHD (23). In the follow-up of patients with T1DM in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Control, intensive glycemic control reduced the risk of CVD events (24). Recent epidemiological data also support a relationship between hyperglycemia and CVD mortality in patients with T1DM (5,25–28). CVD events occur as much as 10 to 15 years earlier in patients with T1DM compared with nondiabetic patients (6). In our study, there was a robust association between preoperative HbA1c levels and all-cause mortality or MACE that confirmed hyperglycemia as a major risk factor in T1DM. Chronic hyperglycemia is generally thought to be the most important modifiable risk factor for long-term complications in T1DM (29). As HbA1c rises, other risk factors for CVD events also tend to increase. Blood pressure, hyperlipidemia, body mass index, and renal failure can all modify the risk of CVD events. Age, sex, and diabetes duration are additional risk factors for CVD events. After adjustment for age and sex, patients with poor glycemic control and high HbA1c levels had a significantly higher risk of death or MACE. Multivariable adjustment for a number of other risk factors did not attenuate the HRs for death or MACE. In fact, the relationship between HbA1c level and death or MACE was already significant at HbA1c levels of 7.1% to 8.0%, and it increased further by 18% for every 1% absolute increase in HbA1c levels.
In a recent large study from the Swedish National Diabetes Register, patients with T1DM, even those with very good glycemic control (HbA1c <6.9%), had more than double the risk of death compared with the general population. This risk increased further for every 1% absolute increase in HbA1c level, with a more than 5-fold increased risk of death from cardiovascular causes in patients with the highest HbA1c levels (5). Patients in our study all had manifest severe CHD, they were old, and they had diabetes of long duration. These patients were therefore at high risk for death or MACE, as confirmed by the high incidence of these outcomes, an incidence higher than that reported in another recently published study (30). However, in that study, no distinction was made between the types of diabetes. Patients with earlier CHD have an increased incidence of new CVD events. Patients with type 2 diabetes mellitus (T2DM) have the same increased risk of myocardial infarction as nondiabetic patients who have had an earlier myocardial infarction (31). Findings of this 1998 index study resulted in the recommendation that patients with T2DM should be regarded as CHD equivalent (31). Intensified intervention against multiple risk factors in patients with T2DM strongly reduces the risk of CVD events (32). Whether this reduced risk is seen in patients with T1DM is not fully understood (4). Standard CHD risk factors (e.g., lipids, blood pressure, and obesity) are clearly operational in T1DM. However, management approaches to CHD reduction have been extrapolated from T2DM studies and are therefore not easily applied to patients with T1DM. In the present study, HRs did not change after adjustments for well-known CVD risk factors, including chronic kidney disease, a finding suggesting glycemic control as the most important risk factor for death or MACE.
A recent study examined whether preoperative HbA1c levels can help predict mortality and morbidity after CABG (11). Some studies (33–35), but not all (36–38), have demonstrated an association between HbA1c levels and CVD outcome in patients after CABG. Earlier studies that examined the impact of preoperative HbA1c as a risk factor for long-term mortality after CABG (39,40) found that patients with HbA1c higher than 7% had lower 5-year survival compared with patients with HbA1c lower than 7%. After adjustment, higher HbA1c was associated with reduced long-term survival (39). Recently, it was also demonstrated that HbA1c levels predict insulin sensitivity during cardiac surgical procedures and possibly outcome in diabetic patients (41). However, none of these studies (39–41) distinguished between T1DM and T2DM. Studies investigating the prognostic impact of diabetes in patients after CABG are even more ambiguous (7–10). Results from these studies have been conflicting, demonstrating either an association with adverse outcome (9) or no association with outcome (8). Importantly, categorization into T1DM and T2DM in these studies is lacking (8,9). To the best of our knowledge, only one study categorized CABG-treated patients into T1DM and T2DM. In that study, the investigators found an increased risk of death or myocardial infarction for both T1DM and T2DM (42). However, that study was conducted more than 3 decades ago, and considering that the risks of death and CVD events associated with diabetes have been reduced by more than one-half during the last 2 decades (2), those results should be interpreted with caution in a contemporary population. Our findings are in line with those of a recent study of diabetic patients who underwent percutaneous coronary intervention procedures and were categorized according to HbA1c levels. Patients with poor glycemic control had higher long-term mortality than did patients with good glycemic control (HbA1c <7.0%) (28). In that study, there was no attempt to distinguish between types of diabetes; therefore, the results cannot be translated to patients with T1DM (28).
This study investigated the incidence of death and MACE in T1DM patients after CABG. The information used to categorize patients as T1DM has been shown to have a high validity (43). Other strengths of this study were its nationwide population-based design, the long follow-up period, and the accurate determination of mortality and MACE because of the high-quality national Swedish health data registers.
We lacked information regarding CVD medications and insulin doses. Within the scope of this study, we cannot rule out the role of underlying microvascular complications. However, we considered estimated glomerular filtration rate as a proxy for microvascular disease, which could be controlled for in the multivariable models. As in any observational study, we cannot rule out that residual confounding factors affected our findings.
Our study found that patients with T1DM who were undergoing CABG were at high risk for death or MACE during a median follow-up period of 4.7 years, and we also found that elevated preoperative HbA1c levels were significantly associated with an increased risk for all-cause mortality or MACE. In patients with T1DM with very poor glycemic control before CABG, the long-term risk of death or MACE was more than double that in patients with T1DM who had adequate glycemic control.
COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: Although CABG surgical intervention is the preferred method of revascularization for patients with diabetes and multivessel coronary artery disease, patients with T1DM who had poor glycemic control before CABG faced risks of death or MACE over the ensuing 5 years that were more than twice as high as risks in patients with T1DM who had adequate glycemic control.
TRANSLATIONAL OUTLOOK: Interventions to achieve better control of blood glucose concentrations and other cardiovascular risk factors in patients with T1DM should be evaluated in prospective trials.
The authors are grateful to the steering committee of SWEDEHEART and the National Diabetes Register for providing data for this study.
This study was supported by grants from the Swedish Society of Medicine to Drs. Holzmann, Kuhl, and Sartipy; Karolinska Institutet Foundations and Funds to Dr. Sartipy; the Mats Kleberg Foundation to Dr. Sartipy, and the Swedish Heart and Lung Foundation to Dr. Nyström. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- coronary artery bypass grafting
- coronary heart disease
- cardiovascular disease
- hemoglobin A1c
- major adverse cardiovascular event(s)
- type 1 diabetes mellitus
- Received January 15, 2015.
- Revision received May 11, 2015.
- Accepted May 19, 2015.
- American College of Cardiology Foundation
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