Association of Impaired Fasting Glucose & Diabetes With PAD
Association of Impaired Fasting Glucose & Diabetes With PAD
An expanded methods section is provided in the Additional file 1 http://www.cardiab.com/content/13/1/147/additional.
This study was part of on-going prospective cohort investigation of peripheral vascular disease patients aimed at assessing risk predictors of peripheral vascular disease presence and outcome. Monte-Carlo simulations suggest that a multivariate regression model is adequately powered when using 10 outcome events per degree of freedom of the predictor variable. We estimated that mortality at one year would be ~10% and planned to adjust for up to 15 variables in our regression model. This suggested that ~1600 patients would provide sufficient power to examine the association of diabetes with mortality.
Patients were recruited from in and out-patient vascular services at The Townsville Hospital, The Mater Hospital Townsville and The Royal Brisbane and Women's Hospital, Australia. Patients with all types of peripheral vascular disease were considered for inclusion as previously described. Inclusion criteria for the current study included a diagnosis of PAD, assessment of fasting blood glucose and at least one follow-up assessment as an in or out-patient. This study was conducted in accordance with the Declaration of Helsinki. Ethical approval for the study was granted by the local Institutional Ethics Committees at The Townsville Hospital, The Mater Hospital Townsville, The Royal Brisbane and Women's Hospital and James Cook University (61/05, MHS2006-01, H2196, 2007/004, 12/QTHS/202, MHS20140114-01, H5206, 13/QTHS/125). Participants provided written informed consent for inclusion.
The current study included patients with occlusive or aneurysmal disease of their peripheral arteries. Presenting complaints included asymptomatic carotid stenosis, mild lower limb or upper limb peripheral athero-thrombosis, aneurysm of the aorta or peripheral arteries, symptomatic carotid artery stenosis and critical lower limb ischaemia, as previously described.
Patients were asked if they were receiving medications for the treatment of diabetes, specifically oral hypoglycaemics or insulin. Patients provided blood samples after an overnight fast for automated assessment of serum glucose as part of their clinical care. Utilising clinical information and blood glucose measurements, patients were grouped as follows:
Hypertension was defined by a history of high blood pressure or receiving treatment to reduce blood pressure. Smoking status was classified as ever and never smokers. Coronary heart disease (CHD) was defined by a history of myocardial infarction, angina or treatment for coronary artery disease. Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease-Epidemiology Collaboration group (CKD-EPI) formula since we have previously found this to be most accurately associated with complications in PVD patients.
In addition to anti-diabetic drugs, each patient's medications were recorded including whether the participants were prescribed a statin, aspirin, another anti-platelet agent, a beta-blocker, a calcium channel blocker (CCB), an angiotensin converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB) and frusemide.
Patients were followed up through attendance at out-patient clinics and/or as an in-patient as part of their normal medical care as previously described.
The primary outcome was mortality. The secondary outcome was requirement for a peripheral artery intervention. Outcome data was recorded during clinical reviews on prospectively defined report forms. Charts and hospital electronic records of all patients were reviewed by a vascular specialist or clinical researcher. For peripheral artery intervention assessments, patients were censored at the time of the first intervention or at the date of last in/out patient review or death if no intervention was required.
Nominal data are presented as numbers and percentages. The association of diabetes categories with the clinical presentation and risk factors of the patients was assessed using Kruskal Wallis and chi-squared tests. The associations of diabetes categories with death and requirement for peripheral artery intervention were assessed using Kaplan Meier estimates, log rank test and Cox proportional hazard analyses. Cox proportional hazard analyses were adjusted for varying combinations of risk factors (age, sex, hypertension, ever smoking, CHD, presenting complaint, statin prescription, aspirin prescription, other anti-platelet prescription, beta blocker prescription, CCB prescription, ACE inhibitor prescription, ARB prescription, frusemide prescription and eGFR) across four different models. These covariates were included as they are recognised determinants of outcome for patients with cardiovascular disease.
For Cox proportional hazards analyses, diabetes categories were defined as indicators in the following order: No diabetes; impaired fasting glucose; non-medicated diabetes; diabetes prescribed oral hypoglycaemics only; and diabetes prescribed insulin. Presenting peripheral artery disease complaint was defined as indicators in the following order: asymptomatic carotid stenosis; mild lower limb or upper limb peripheral athero-thrombosis; aneurysm of the aorta or peripheral arteries; symptomatic carotid artery stenosis; and critical lower limb ischemia. Age and eGFR were included in regression models as continuous numbers. Binary variables were defined as present or absent.
Methods
An expanded methods section is provided in the Additional file 1 http://www.cardiab.com/content/13/1/147/additional.
Study Design and Sample Size
This study was part of on-going prospective cohort investigation of peripheral vascular disease patients aimed at assessing risk predictors of peripheral vascular disease presence and outcome. Monte-Carlo simulations suggest that a multivariate regression model is adequately powered when using 10 outcome events per degree of freedom of the predictor variable. We estimated that mortality at one year would be ~10% and planned to adjust for up to 15 variables in our regression model. This suggested that ~1600 patients would provide sufficient power to examine the association of diabetes with mortality.
Patients
Patients were recruited from in and out-patient vascular services at The Townsville Hospital, The Mater Hospital Townsville and The Royal Brisbane and Women's Hospital, Australia. Patients with all types of peripheral vascular disease were considered for inclusion as previously described. Inclusion criteria for the current study included a diagnosis of PAD, assessment of fasting blood glucose and at least one follow-up assessment as an in or out-patient. This study was conducted in accordance with the Declaration of Helsinki. Ethical approval for the study was granted by the local Institutional Ethics Committees at The Townsville Hospital, The Mater Hospital Townsville, The Royal Brisbane and Women's Hospital and James Cook University (61/05, MHS2006-01, H2196, 2007/004, 12/QTHS/202, MHS20140114-01, H5206, 13/QTHS/125). Participants provided written informed consent for inclusion.
Definitions and Diagnosis of PAD
The current study included patients with occlusive or aneurysmal disease of their peripheral arteries. Presenting complaints included asymptomatic carotid stenosis, mild lower limb or upper limb peripheral athero-thrombosis, aneurysm of the aorta or peripheral arteries, symptomatic carotid artery stenosis and critical lower limb ischaemia, as previously described.
Assessment of Fasting Blood Glucose and Diabetes
Patients were asked if they were receiving medications for the treatment of diabetes, specifically oral hypoglycaemics or insulin. Patients provided blood samples after an overnight fast for automated assessment of serum glucose as part of their clinical care. Utilising clinical information and blood glucose measurements, patients were grouped as follows:
No diabetes: Receiving no medications for diabetes and fasting blood glucose <5.6 mM;
Impaired fasting glucose: Receiving no medications for diabetes and fasting blood glucose 5.6–6.9 mM;
Non-medicated diabetes: Receiving no medications for diabetes and fasting blood glucose ≥7.0 mM;
Diabetes prescribed oral hypoglycaemics only: Currently prescribed one or more oral hypoglycaemic agents but not insulin for previously diagnosed diabetes;
Diabetes prescribed insulin: Currently prescribed insulin for previously diagnosed diabetes.
Definitions of Other Risk Factors
Hypertension was defined by a history of high blood pressure or receiving treatment to reduce blood pressure. Smoking status was classified as ever and never smokers. Coronary heart disease (CHD) was defined by a history of myocardial infarction, angina or treatment for coronary artery disease. Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease-Epidemiology Collaboration group (CKD-EPI) formula since we have previously found this to be most accurately associated with complications in PVD patients.
Medications
In addition to anti-diabetic drugs, each patient's medications were recorded including whether the participants were prescribed a statin, aspirin, another anti-platelet agent, a beta-blocker, a calcium channel blocker (CCB), an angiotensin converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB) and frusemide.
Follow-up
Patients were followed up through attendance at out-patient clinics and/or as an in-patient as part of their normal medical care as previously described.
Recording of Outcome Data
The primary outcome was mortality. The secondary outcome was requirement for a peripheral artery intervention. Outcome data was recorded during clinical reviews on prospectively defined report forms. Charts and hospital electronic records of all patients were reviewed by a vascular specialist or clinical researcher. For peripheral artery intervention assessments, patients were censored at the time of the first intervention or at the date of last in/out patient review or death if no intervention was required.
Statistical Analyses
Nominal data are presented as numbers and percentages. The association of diabetes categories with the clinical presentation and risk factors of the patients was assessed using Kruskal Wallis and chi-squared tests. The associations of diabetes categories with death and requirement for peripheral artery intervention were assessed using Kaplan Meier estimates, log rank test and Cox proportional hazard analyses. Cox proportional hazard analyses were adjusted for varying combinations of risk factors (age, sex, hypertension, ever smoking, CHD, presenting complaint, statin prescription, aspirin prescription, other anti-platelet prescription, beta blocker prescription, CCB prescription, ACE inhibitor prescription, ARB prescription, frusemide prescription and eGFR) across four different models. These covariates were included as they are recognised determinants of outcome for patients with cardiovascular disease.
For Cox proportional hazards analyses, diabetes categories were defined as indicators in the following order: No diabetes; impaired fasting glucose; non-medicated diabetes; diabetes prescribed oral hypoglycaemics only; and diabetes prescribed insulin. Presenting peripheral artery disease complaint was defined as indicators in the following order: asymptomatic carotid stenosis; mild lower limb or upper limb peripheral athero-thrombosis; aneurysm of the aorta or peripheral arteries; symptomatic carotid artery stenosis; and critical lower limb ischemia. Age and eGFR were included in regression models as continuous numbers. Binary variables were defined as present or absent.
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