Diabetologia (2013) 56:275–283 DOI 10.1007/s00125-012-2772-1
ARTICLE
Prediction and classification of cardiovascular disease risk in older adults with diabetes K. J. Mukamal & J. R. Kizer & L. Djoussé & J. H. Ix & S. Zieman & D. S. Siscovick & C. T. Sibley & R. P. Tracy & A. M. Arnold
Received: 28 June 2012 / Accepted: 2 October 2012 / Published online: 10 November 2012 # Springer-Verlag (outside the USA) 2012
Abstract Aims/hypothesis We sought to derive and validate a cardiovascular disease (CVD) prediction algorithm for older adults with diabetes, and evaluate the incremental benefit of adding novel circulating biomarkers and measures of subclinical atherosclerosis. Methods As part of the Cardiovascular Health Study (CHS), a population-based cohort of adults aged ≥65 years, we examined the 10 year risk of myocardial infarction, stroke and cardiovascular death in 782 older adults with diabetes, in whom 265 events occurred. We validated predictive models in 843 adults with diabetes, who were followed for 7 years in a second cohort, the Multi-Ethnic Study of Atherosclerosis (MESA); here 71 events occurred. Results The best fitting standard model included age, smoking, systolic blood pressure, total and HDL-cholesterol,
creatinine and the use of glucose-lowering agents; however, this model had a C statistic of 0.64 and poorly classified risk in men. Novel biomarkers did not improve discrimination or classification. The addition of ankle–brachial index, electrocardiographic left ventricular hypertrophy and internal carotid intima–media thickness modestly improved discrimination (C statistic 0.68; p00.002) and classification (net reclassification improvement [NRI] 0.12; p00.01), mainly in those remaining free of CVD. Results were qualitatively similar in the MESA, with a change in C statistic from 0.65 to 0.68 and an NRI of 0.09 upon inclusion of subclinical disease measures. Conclusions/interpretation Standard clinical risk factors and novel biomarkers poorly discriminate and classify CVD risk in older adults with diabetes. The inclusion of subclinical atherosclerotic measures modestly improves these features, but to develop more robust risk prediction, a better
Electronic supplementary material The online version of this article (doi:10.1007/s00125-012-2772-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users. K. J. Mukamal (*) Division of General Medicine and Primary Care, Beth Israel Deaconess Medical Center, 1309 Beacon Street, 2nd Floor, Brookline, MA 02446, USA e-mail:
[email protected] J. R. Kizer New York Presbyterian Hospital and Weill Cornell Medical College, New York, NY, USA
S. Zieman National Institute of Aging, National Institutes of Health, Bethesda, MD, USA D. S. Siscovick : A. M. Arnold Departments of Medicine, Epidemiology and Biostatistics, University of Washington, Seattle, WA, USA
L. Djoussé Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
C. T. Sibley Clinical Center, National Institutes of Health, Bethesda, MD, USA
J. H. Ix Veterans Affairs San Diego Healthcare System and University of California San Diego School of Medicine, San Diego, CA, USA
R. P. Tracy Department of Pathology, University of Vermont, Burlington, VT, USA
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understanding of the pathophysiology and determinants of CVD in this patient group is needed. Keywords Biological markers . Cardiovascular diagnostic techniques . Cardiovascular disease . Cohort . Diabetes . Regression analysis . Risk factors Abbreviations ABI Ankle–brachial index CHS Cardiovascular Health Study CVD Cardiovascular disease IMT Intima–media thickness MESA Multi-Ethnic Study of Atherosclerosis NRI Net reclassification improvement nt-BNP N-terminal pro-B-type natriuretic peptide
Introduction Diabetes (specifically type 2 diabetes) is a problem of enormous importance in older adults. The incidence and prevalence of diabetes continue to rise throughout older age until late life, resulting in an enormous burden of diabetes in older adults [1]. Diabetes is particularly strongly associated with macrovascular complications in older adults, especially in individuals with subclinical vascular disease [2]. Despite the prevalence and magnitude of cardiovascular disease (CVD) risk associated with diabetes in older adults, the determinants of CVD in this population, as well as the degree to which they can successfully identify persons at greater or lesser risk, have not been well clarified. Indeed, it is clear that in middle-aged adults with diabetes, risk varies substantially as a function of other risk factors [3, 4]. While a number of risk prediction models are available, some of the most commonly used, such as the Framingham Risk Score [5] and the Reynolds Risk Score [6], were specifically tested in adults without diabetes and, like many others, systematically excluded older adults in their derivation. An important area of controversy in screening for CVD is the role of specialised modalities, such as electrocardiographic stress testing or computed tomography estimates of coronary calcium. Some experts have recommended electrocardiographic stress testing in at least some subgroups of patients with diabetes [7, 8], although a recent randomised trial of adenosine-stress perfusion imaging suggested this was unlikely to improve long-term outcomes [9]. However, given the high risk of CVD that diabetes confers upon older adults in the presence of subclinical atherosclerosis, older adults with diabetes may be an appropriate target for selective screening [2]. The discriminatory power of non-invasive testing has not been formally tested in older adults with diabetes, but the risk associated with subclinical disease could be high enough to improve CVD discrimination and prediction.
Diabetologia (2013) 56:275–283
To address these questions, we examined the risk of CVD in older adults with diabetes who were enrolled in the Cardiovascular Health Study (CHS) [10]. The CHS is a population-based longitudinal study of CVD and its risk factors in 5,888 community-dwelling older adults from four regions throughout the USA. After deriving a risk score and examining the incremental benefit of adding novel biomarkers and subclinical disease measures, we validated the model in the Multi-Ethnic Study of Atherosclerosis (MESA) [11], a population-based cohort of adults free of CVD.
Methods Study population and design The CHS is a prospective study of men and women aged 65 years or older, who were recruited from Medicare-eligibility lists in Pittsburgh, PA, Sacramento, CA, Hagerstown, MD, and Forsyth County, NC, all in the USA. Participants were not institutionalised or wheelchair-dependent, did not require a proxy for consent, were not under treatment for cancer at the time of enrolment and were expected to remain in their respective regions for at least 3 years. Between 1989 and 1990, 5,201 participants were recruited and examined (the original cohort); from 1992 to 1993 an additional 687 AfricanAmerican participants were recruited and examined. The CHS study design and objectives have been published previously [10]. The baseline examination included standardised medical history questionnaires, physical examination, resting ECG and laboratory examination; these procedures were generally repeated in the original cohort between 1992 and 1993 when the African-American cohort was added. Follow-up contact occurred every 6 months, alternating between telephone calls and clinic visits through to 1999; contact was by phone calls thereafter. The MESA is a population-based sample of 6,814 men and women, who were free of clinical CVD, aged 45 to 84 years and were recruited from Forsyth County, NC, Northern Manhattan and the Bronx, NY, Baltimore County, MD, St Paul, MN, Chicago, IL, and Los Angeles County, CA, all in the USA. Approximately 38% of the recruited participants are white, 28% African-American, 22% Hispanic and 12% Asian, predominantly of Chinese descent. As previously described [11], MESA participants underwent an extensive baseline examination between 2000 and 2002, which included questionnaires, physical examination, laboratory examination and several measures of subclinical vascular disease. Subclinical measures overlapping with CHS measures include: carotid ultrasonography, ECG and measurement of the ankle–brachial index (ABI). Participants are contacted every 9 to 12 months throughout the study to assess CVD events. Neither study performed formal categorisation of type of diabetes, and data on duration of diabetes was not available
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for every participant, but it is likely that participants with diabetes in both cohorts had type 2 diabetes. In both the CHS and the MESA, participants gave written informed consent upon enrolment. The institutional review boards at each field centre and the central data coordinating centre approved the respective studies. Determination of diabetes In the CHS, fasting glucose was measured between 1989 and 1990, and 1992 and 1993 in all participants who attended the clinic examination. Medication use for diabetes was ascertained yearly with a validated medication inventory [12–14]. Prevalent diabetes was defined at both examinations as fasting blood glucose ≥7.0 mmol/l, non-fasting blood glucose ≥11.1 mmol/l (if participants had failed to fast; n06) or the use of glucoselowering agents; at baseline in the CHS, only first- and second-generation sulfonylureas and insulin were in use. An identical approach was used in the MESA to identify diabetic participants, who reported their medication use and underwent fasting blood glucose measurement at the baseline examination. Determination of incident CVD All cases of myocardial infarction, stroke and death in the CHS are adjudicated by central committees. Details of the protocols for adjudication and confirmation of these events, including the algorithms used for classification, have been published [15, 16]. In brief, participants reported incident CVD events at annual clinic visits and interim telephone interviews when questioned about hospitalisations and other acute events. Discharge summaries and diagnoses were obtained for all hospitalisations. For all potential incident events, additional information, such as cardiac enzyme levels, serial ECGs and cranial imaging studies was collected. To be categorised as a stroke, a new neurological deficit had to have persisted for 24 h; for deficits persisting for less than 24 h, a lesion appropriate to the clinical deficit had to have been detected on brain imaging studies. In these analyses, we used a primary composite outcome that included incident myocardial infarction, stroke, and death from coronary or cerebrovascular causes. In sensitivity analyses, we also included adjudicated incident congestive heart failure as an endpoint. The MESA uses similar procedures, with events adjudicated by a central Morbidity and Mortality Committee. In the MESA, we used a composite endpoint of incident myocardial infarction, stroke and death from CVD in order to achieve comparability with the CHS. Potential covariates To develop a risk score in the CHS, we used covariates assessed at the time of diabetes ascertainment, whether 1989 to 1990 or 1992 to 1993. Seated systolic and diastolic blood pressure, weight, waist circumference and standing height were measured by trained field centre staff.
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Smoking was reported in three categories (current, former, never). Laboratory values measured at the University of Vermont Central Laboratory included total, HDL- and LDLcholesterol, triacylglycerol, glucose, creatinine, C-reactive protein, fibrinogen, albumin, factor VII coagulant activity, leucocyte count, cystatin C, lipoprotein a, potassium and uric acid [17]. N-terminal pro-B-type natriuretic peptide (nt-BNP) and HbA1c were also available in subsets of participants at baseline [18, 19]. Family histories of stroke and heart disease were reported at baseline. We categorised the duration of diabetes in original cohort participants identified in 1992 and 1993 and in all African-American cohort participants as: newly diagnosed, >0 to 3 years, and >3 years. Subclinical vascular disease measures included electrocardiography, which underwent standardised coding for major and minor electrocardiographic abnormalities as previously described [20, 21]. Carotid ultrasonography was conducted to evaluate intima–media thickness (IMT) and maximum stenosis for the internal and common carotid arteries [22]. The ABI was assessed bilaterally with a standardised protocol [23], using the ratio of the average of two blood pressure measurements in the right arm and the lower of two leg measurements, one in the right and one in the left leg. To validate the models in the MESA, we adopted a similar approach, using those covariates from the baseline MESA examination that were selected for model inclusion in the CHS derivation cohort. Statistical analysis In Stata 11 (Stata, College Station, TX, USA), we conducted multivariable Cox proportional hazards analyses to examine the associations between potential covariates and the composite CVD outcome variable in the CHS; we also evaluated a second outcome that added congestive heart failure. Follow-up was ended at 10 years to reduce misclassification in predictor variables and to concord most closely with previous risk stratification models. Because sex did not conform to the proportional hazards assumption, we stratified baseline hazards by sex and tested other predictors for interaction with age, sex and race. We evaluated potential predictors of CVD with three successive models, retaining significant predictors (at p110.5 μmol/l Oral hypoglycaemic agent or insulin use CRP per 10 nmol/l up to 190 nmol/l ABI
