Long-term Outcome in Patients With ACS and Dysglycaemia
Long-term Outcome in Patients With ACS and Dysglycaemia
The results of the present study show that a majority of patients with ACS had dysglycaemia, in other words, known diabetes or disturbed glucose metabolism discovered by OGTT.
Patients with known diabetes had significantly higher short- and long-term mortality as compared to both patients with NGT and those with dysglycaemia discovered by OGTT; however, the latter group showed a non-significant trend towards higher long-term mortality as compared to the patients with NGT.
The baseline characteristics between patients with NGT and abnormal OGTT were not significantly different, while patients with known diabetes had significantly higher co-morbidity as seen with, for example, previous myocardial infarction, higher serum creatinine and BMI, which, in addition to higher age, can at least partly explain the poor outcome in these patients. Furthermore, the prevalence of systolic left ventricular (LV) dysfunction measured by echocardiography was significantly higher in patients with known diabetes. Echocardiographic parameters such as ejection fraction and myocardial strain reflecting LV systolic function, are associated with clinical outcome in patients with myocardial infarction, and LV function is one the strongest predictors of outcome following PCI.
We found a high incidence of previously undiagnosed diabetes and/or IFG/IGT among patients with ACS. Notably, a substantial proportion of patients who died or had myocardial infarction during the follow-up were characterized as dysglycaemic, in other words, as having known diabetes at admission or disturbed glucose metabolism diagnosed by OGTT. Interestingly, the results indicate worsened prognosis, i.e. higher mortality and reinfarction for every stage that dysglycaemia progresses, that is, a trend towards higher mortality and reinfarction in patients with positive OGTT as compared to NGT, and significantly higher mortality and reinfarction in patients with known diabetes as compared to NGT. T2DM is preceded by disturbed glucose metabolism which at least at early stages may pass undiagnosed and untreated for several years. Disturbed glucose metabolism, also at early stages, seems to have a progressive adverse effect on the cardiovascular system reflected as poor clinical outcome, most significantly in patients with manifest diabetes. Early diagnosis and treatment of impaired glucose metabolism may slow down or even reverse the adverse effects on the cardiovascular system, while irreversible damages occur when impaired glucose metabolism progresses untreated to manifest diabetes.
Previous retrospective studies have investigated the prevalence of dysglycaemia and its influence on clinical outcome in patients with CAD. However, the accuracy of the results of some of these studies is worthy of discussion either due to the methods that were used to diagnose diabetes, which included fasting blood glucose and HbA1c levels, or inclusion of patients with different diagnosis of CAD, such as, for example, stable vs ACS, associated with different short- and long-term prognosis. In the present study, we performed OGTT to investigate the glycaemic status of all patients with previously unknown DM. The European Diabetes Society and European guidelines on cardiology recommend the performance of OGTT in patients with CVD, especially in those with ACS. In patients with ACS, an abnormal OGTT seems to be a better prognostic marker than fasting blood glucose or HbA1c alone.
Although the importance of hyperglycaemia as a predictor of survival in patients with ACS is well established, the association between dysglycaemia and mortality might differ across the spectrum of CAD. In the present study, we included only patients with ACS, in other words, those with unstable angina and myocardial infarction.
In our study a substantial number of patients with known diabetes were treated conservatively; that is, significantly fewer patients underwent coronary angiography and PCI. The reason why a less invasive approach was chosen in the treatment of patients with known diabetes in this study is unclear. One reason could be that patients with known diabetes had already undergone coronary angiography during previous admissions since more patients in this group had previous MI, and perhaps based on previous examinations and/or decisions, a more conservative approach was chosen when the patient was readmitted with a new event. Another possible explanation concerns the risks of kidney dysfunction caused by the contrast given during coronary angiography and PCI, in other words, contrast-induced nephropathy (CIN), since the renal function was already significantly deteriorated in these patients as compared to patients in the two other groups. Higher age and existence of significant co-morbidities may also have played a role in choosing a more conservative approach. A non-invasive treatment strategy may have influenced the long-term prognosis in patients with known diabetes, as it has been demonstrated that an invasive strategy in the management of patients with ACS reduces long-term cardiovascular mortality and morbidity.
Although kidney dysfunction influences the likelihood of choosing an invasive treatment strategy in patients with ACS, previous studies have shown that an early invasive therapy is associated with better clinical outcome in patients with mild to moderate kidney dysfunction. However, kidney function remains a significant prognostic marker of outcome following PCI. The interrelationship between kidney dysfunction and treatment strategy as, for example, with invasive vs non-invasive approaches, in patients with diabetes and ACS has not been fully investigated.
Of note, a majority of patients with known diabetes who underwent PCI were treated with bare metal stents (BMS), and less than 20 % of the patients with dysglycaemia detected by OGTT received drug-eluting stents (DES), since they were treated as non-diabetic patients at the time of PCI. As demonstrated in our study, a significant number of patients with positive OGTT before discharge from the hospital were actually treated as non-diabetic patients at the time of admission and, more importantly, during coronary angiography and PCI, which may have influenced the treatment strategies such as stent choice, thus possibly contributing to worse clinical outcome as seen in these patients. These findings highlight the necessity of investigating glycaemic status early in patients with ACS as, for example, before coronary angiography, since it has influence on therapeutic strategies such as PCI vs CABG, choice of stent, and more. However, since this study was performed, the use of DES has increased tremendously in our department as well as all over Sweden, and currently the majority of patients, with or without diabetes, receive DES.
Due to the lack of initial symptoms, the diabetes diagnosis may be delayed for several years, even after entering a diabetic state. The duration and severity of the disease are of great importance for cardiovascular risk as well as other diabetic complications. Both improved metabolic and blood pressure control has been shown to decrease morbidity and mortality in patients with CAD. Glycated haemoglobin (HbA1c) is commonly used as a measure of metabolic control. There is a strong relationship between HbA1c levels and mortality in patients with CAD, which is independent of other risk factors. In patients with ACS, high HbA1c levels are associated with worse short-term outcome, and elevated levels of HbA1c are associated with the progression and difficulty of CAD. However, improved glycaemic control was not associated with a decreased incidence of macrovascular complications or mortality. In the present study, there are no available data of HbA1c at the time of admission and/or during hospital stay, and no data regarding glycaemic and blood pressure control during follow-up.
Today there is no consensus among cardiologists how to treat patients with T2DM or IGT, and which glucose-lowering therapy is optimal after a coronary event. One large clinical trial found that treatment with insulin in patients with myocardial infarction was associated with an enhanced risk of recurrent nonfatal myocardial infarction or stroke, while treatment with metformin was more beneficial.
Another study found that insulin treatment with or without oral glucose-lowering therapy was associated with higher long-term mortality in patients with DM undergoing coronary angiography. T2DM patients are often treated with high insulin doses leading to weight gain and high blood pressure and, despite intensified insulin therapy, the treatment goals, which also include improved metabolic control and tight blood pressure control, are not reached.
A limitation of our study is when interpreting the results one should take into consideration that this is a retrospective single-center study analysing register data lacking information regarding long-term glycaemic control and incidence of CIN during the follow-up period which are important predictors of outcome in patients with ACS. Furthermore, the register data from SWEDEHEART and SCAAR does not provide information regarding changes of medical therapy including antidiabetic treatment during the follow-up period.
Discussion
The results of the present study show that a majority of patients with ACS had dysglycaemia, in other words, known diabetes or disturbed glucose metabolism discovered by OGTT.
Patients with known diabetes had significantly higher short- and long-term mortality as compared to both patients with NGT and those with dysglycaemia discovered by OGTT; however, the latter group showed a non-significant trend towards higher long-term mortality as compared to the patients with NGT.
The baseline characteristics between patients with NGT and abnormal OGTT were not significantly different, while patients with known diabetes had significantly higher co-morbidity as seen with, for example, previous myocardial infarction, higher serum creatinine and BMI, which, in addition to higher age, can at least partly explain the poor outcome in these patients. Furthermore, the prevalence of systolic left ventricular (LV) dysfunction measured by echocardiography was significantly higher in patients with known diabetes. Echocardiographic parameters such as ejection fraction and myocardial strain reflecting LV systolic function, are associated with clinical outcome in patients with myocardial infarction, and LV function is one the strongest predictors of outcome following PCI.
We found a high incidence of previously undiagnosed diabetes and/or IFG/IGT among patients with ACS. Notably, a substantial proportion of patients who died or had myocardial infarction during the follow-up were characterized as dysglycaemic, in other words, as having known diabetes at admission or disturbed glucose metabolism diagnosed by OGTT. Interestingly, the results indicate worsened prognosis, i.e. higher mortality and reinfarction for every stage that dysglycaemia progresses, that is, a trend towards higher mortality and reinfarction in patients with positive OGTT as compared to NGT, and significantly higher mortality and reinfarction in patients with known diabetes as compared to NGT. T2DM is preceded by disturbed glucose metabolism which at least at early stages may pass undiagnosed and untreated for several years. Disturbed glucose metabolism, also at early stages, seems to have a progressive adverse effect on the cardiovascular system reflected as poor clinical outcome, most significantly in patients with manifest diabetes. Early diagnosis and treatment of impaired glucose metabolism may slow down or even reverse the adverse effects on the cardiovascular system, while irreversible damages occur when impaired glucose metabolism progresses untreated to manifest diabetes.
Previous retrospective studies have investigated the prevalence of dysglycaemia and its influence on clinical outcome in patients with CAD. However, the accuracy of the results of some of these studies is worthy of discussion either due to the methods that were used to diagnose diabetes, which included fasting blood glucose and HbA1c levels, or inclusion of patients with different diagnosis of CAD, such as, for example, stable vs ACS, associated with different short- and long-term prognosis. In the present study, we performed OGTT to investigate the glycaemic status of all patients with previously unknown DM. The European Diabetes Society and European guidelines on cardiology recommend the performance of OGTT in patients with CVD, especially in those with ACS. In patients with ACS, an abnormal OGTT seems to be a better prognostic marker than fasting blood glucose or HbA1c alone.
Although the importance of hyperglycaemia as a predictor of survival in patients with ACS is well established, the association between dysglycaemia and mortality might differ across the spectrum of CAD. In the present study, we included only patients with ACS, in other words, those with unstable angina and myocardial infarction.
In our study a substantial number of patients with known diabetes were treated conservatively; that is, significantly fewer patients underwent coronary angiography and PCI. The reason why a less invasive approach was chosen in the treatment of patients with known diabetes in this study is unclear. One reason could be that patients with known diabetes had already undergone coronary angiography during previous admissions since more patients in this group had previous MI, and perhaps based on previous examinations and/or decisions, a more conservative approach was chosen when the patient was readmitted with a new event. Another possible explanation concerns the risks of kidney dysfunction caused by the contrast given during coronary angiography and PCI, in other words, contrast-induced nephropathy (CIN), since the renal function was already significantly deteriorated in these patients as compared to patients in the two other groups. Higher age and existence of significant co-morbidities may also have played a role in choosing a more conservative approach. A non-invasive treatment strategy may have influenced the long-term prognosis in patients with known diabetes, as it has been demonstrated that an invasive strategy in the management of patients with ACS reduces long-term cardiovascular mortality and morbidity.
Although kidney dysfunction influences the likelihood of choosing an invasive treatment strategy in patients with ACS, previous studies have shown that an early invasive therapy is associated with better clinical outcome in patients with mild to moderate kidney dysfunction. However, kidney function remains a significant prognostic marker of outcome following PCI. The interrelationship between kidney dysfunction and treatment strategy as, for example, with invasive vs non-invasive approaches, in patients with diabetes and ACS has not been fully investigated.
Of note, a majority of patients with known diabetes who underwent PCI were treated with bare metal stents (BMS), and less than 20 % of the patients with dysglycaemia detected by OGTT received drug-eluting stents (DES), since they were treated as non-diabetic patients at the time of PCI. As demonstrated in our study, a significant number of patients with positive OGTT before discharge from the hospital were actually treated as non-diabetic patients at the time of admission and, more importantly, during coronary angiography and PCI, which may have influenced the treatment strategies such as stent choice, thus possibly contributing to worse clinical outcome as seen in these patients. These findings highlight the necessity of investigating glycaemic status early in patients with ACS as, for example, before coronary angiography, since it has influence on therapeutic strategies such as PCI vs CABG, choice of stent, and more. However, since this study was performed, the use of DES has increased tremendously in our department as well as all over Sweden, and currently the majority of patients, with or without diabetes, receive DES.
Due to the lack of initial symptoms, the diabetes diagnosis may be delayed for several years, even after entering a diabetic state. The duration and severity of the disease are of great importance for cardiovascular risk as well as other diabetic complications. Both improved metabolic and blood pressure control has been shown to decrease morbidity and mortality in patients with CAD. Glycated haemoglobin (HbA1c) is commonly used as a measure of metabolic control. There is a strong relationship between HbA1c levels and mortality in patients with CAD, which is independent of other risk factors. In patients with ACS, high HbA1c levels are associated with worse short-term outcome, and elevated levels of HbA1c are associated with the progression and difficulty of CAD. However, improved glycaemic control was not associated with a decreased incidence of macrovascular complications or mortality. In the present study, there are no available data of HbA1c at the time of admission and/or during hospital stay, and no data regarding glycaemic and blood pressure control during follow-up.
Today there is no consensus among cardiologists how to treat patients with T2DM or IGT, and which glucose-lowering therapy is optimal after a coronary event. One large clinical trial found that treatment with insulin in patients with myocardial infarction was associated with an enhanced risk of recurrent nonfatal myocardial infarction or stroke, while treatment with metformin was more beneficial.
Another study found that insulin treatment with or without oral glucose-lowering therapy was associated with higher long-term mortality in patients with DM undergoing coronary angiography. T2DM patients are often treated with high insulin doses leading to weight gain and high blood pressure and, despite intensified insulin therapy, the treatment goals, which also include improved metabolic control and tight blood pressure control, are not reached.
A limitation of our study is when interpreting the results one should take into consideration that this is a retrospective single-center study analysing register data lacking information regarding long-term glycaemic control and incidence of CIN during the follow-up period which are important predictors of outcome in patients with ACS. Furthermore, the register data from SWEDEHEART and SCAAR does not provide information regarding changes of medical therapy including antidiabetic treatment during the follow-up period.
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