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1.  Prediction of Coronary Heart Disease Risk in a General, Pre-Diabetic, and Diabetic Population During 10 Years of Follow-up: Accuracy of the Framingham, SCORE, and UKPDS Risk Functions 
Diabetes Care  2009;32(11):2094-2098.
To test the validity of the Framingham, Systematic Coronary Risk Evaluation (SCORE), and UK Prospective Diabetes Study (UKPDS) risk function in the prediction of risk of coronary heart disease (CHD) in populations with normal glucose tolerance (NGT), intermediate hyperglycemia, and type 2 diabetes.
Calibration and discrimination of the three prediction models were tested using prospective data for 1,482 Caucasian men and women, 50–75 years of age, who participated in the Hoorn Study. All analyses were stratified by glucose status.
During 10 years of follow-up, a total of 197 CHD events, of which 43 were fatal, were observed in this population, with the highest percentage of first CHD events in the diabetic group. The Framingham and UKPDS prediction models overestimated the risk of first CHD event in all glucose tolerance groups. Overall, the prediction models had a low to moderate discriminatory capacity. The SCORE risk function was the best predictor of fatal CHD events in the group with NGT (area under the receiver operating characteristic curve 0.79 [95% CI 0.70–0.87]), whereas the UKPDS performed better in the intermediate hyperglycemia group (0.84 [0.74–0.94]) in the estimation of fatal CHD risk. After exclusion of known diabetic patients, all prediction models had a higher discriminatory ability in the group with diabetes.
The use of the Framingham function for prediction of the first CHD event is likely to overestimate an individual's absolute CHD risk. In CHD prevention, application of the SCORE and UKPDS functions might be useful in the absence of a more valid tool.
PMCID: PMC2768197  PMID: 19875606
2.  Comparison of four cardiovascular risk prediction functions among Chinese patients with diabetes mellitus in the primary care setting 
To assess the feasibility, convergent validity and sensitivity of four cardiovascular risk prediction functions in Chinese diabetic patients in the primary care setting.
Materials and Methods
A cross‐sectional study of 1,140 diabetic patients was carried out to compare four cardiovascular risk functions, which were respectively developed from the Framingham heart study, the USA–People's Republic of China Collaborative Study of Cardiovascular and Cardiopulmonary Epidemiology cohort (PRC), the United Kingdom Prospective Diabetes Study (UKPDS) and the Joint Asia Diabetes Evaluation program (JADE). Feasibility was assessed by the percentage of patients with complete data for risk prediction. Convergent validity was measured by Spearman's rank correlation, paired Wilcoxon signed‐rank sum test and Bland–Altman plots. Effect size differences between clinical risk groups were used to assess the sensitivity.
Risk prediction was feasible by the Framingham, UKPDS and PRC risk functions in more than 98% patients, whereas just 74% of patients had complete data for the JADE function. The annual total coronary heart disease (CHD) risk predicted by the JADE and the UKPDS functions showed excellent agreement with no significant difference, and a correlation of 0.8048. The Framingham and the PRC functions predicted significantly lower CHD risk than those by the UKPDS and the JADE functions. The UKPDS and the Framingham functions were more sensitive in differentiating clinical risk groups.
The UKPDS risk engine showed good feasibility, convergent validity and sensitivity in predicting CHD risk in Chinese diabetic patients. The JADE function showed excellent agreement with the UKPDS risk engine, but it was less feasible in the primary care setting.
PMCID: PMC4188120  PMID: 25411630
Cardiovascular diseases; Diabetes complications; Risk
3.  An independent external validation and evaluation of QRISK cardiovascular risk prediction: a prospective open cohort study 
Objective To independently evaluate the performance of the QRISK score for predicting 10 year risk of cardiovascular disease in an independent UK cohort of patients from general practice and compare the performance with Framingham equations.
Design Prospective open cohort study.
Setting 274 practices from England and Wales contributing to the THIN database.
Participants 1.07 million patients, registered between 1 January 1995 and 1 April 2006, aged 35-74 years (5.4 million person years) with 43 990 cardiovascular events.
Main outcome measures First diagnosis of cardiovascular disease (myocardial infarction, coronary heart disease, stroke, and transient ischaemic attack) recorded in general practice records.
Results This independent validation indicated that QRISK offers an improved performance in predicting the 10 year risk of cardiovascular disease in a large cohort of UK patients over the Anderson Framingham equation. Discrimination and calibration statistics were better with QRISK. QRISK explained 32% of the variation in men and 37% in women, compared with 27% and 31% respectively for Anderson Framingham. QRISK underpredicted risk by 13% for men and 10% for women, whereas Anderson Framingham overpredicted risk by 32% for men and 10% for women. In total, 85 010 (8%) of patients would be reclassified from high risk (≥20%) with Anderson Framingham to low risk with QRISK, with an observed 10 year cardiovascular disease risk of 17.5% (95% confidence interval 16.9% to 18.1%) for men and 16.8% (15.7% to 18.0%) for women. The incidence rate of cardiovascular disease events among men was 30.5 per 1000 person years (95% confidence interval 29.9 to 31.2) in high risk patients identified with QRISK and 23.7 per 1000 person years (23.2 to 24.1) in high risk patients identified with Anderson Framingham. Similarly, the incidence rate of cardiovascular disease events among women was 26.7 per 1000 person years (25.8 to 27.7) in high risk patients identified with QRISK compared with 22.2 per 1000 person years (21.4 to 23.0) in high risk patients identified with Anderson Framingham.
Conclusions The QRISK cardiovascular disease risk equation offers an improvement over the long established Anderson Framingham equation in terms of identifying a high risk population for cardiovascular disease in the United Kingdom. QRISK underestimates 10 year cardiovascular disease risk, but the magnitude of underprediction is smaller than the overprediction with Anderson Framingham.
PMCID: PMC2714681  PMID: 19584409
4.  Performance of the UK Prospective Diabetes Study Risk Engine and the Framingham Risk Equations in Estimating Cardiovascular Disease in the EPIC- Norfolk Cohort 
Diabetes Care  2008;32(4):708-713.
The purpose of this study was to examine the performance of the UK Prospective Diabetes Study (UKPDS) Risk Engine (version 3) and the Framingham risk equations (2008) in estimating cardiovascular disease (CVD) incidence in three populations: 1) individuals with known diabetes; 2) individuals with nondiabetic hyperglycemia, defined as A1C ≥6.0%; and 3) individuals with normoglycemia defined as A1C <6.0%.
This was a population-based prospective cohort (European Prospective Investigation of Cancer-Norfolk). Participants aged 40–79 years recruited from U.K. general practices attended a health examination (1993–1998) and were followed for CVD events/death until April 2007. CVD risk estimates were calculated for 10,137 individuals.
Over 10.1 years, there were 69 CVD events in the diabetes group (25.4%), 160 in the hyperglycemia group (17.7%), and 732 in the normoglycemia group (8.2%). Estimated CVD 10-year risk in the diabetes group was 33 and 37% using the UKPDS and Framingham equations, respectively. In the hyperglycemia group, estimated CVD risks were 31 and 22%, respectively, and for the normoglycemia group risks were 20 and 14%, respectively. There were no significant differences in the ability of the risk equations to discriminate between individuals at different risk of CVD events in each subgroup; both equations overestimated CVD risk. The Framingham equations performed better in the hyperglycemia and normoglycemia groups as they did not overestimate risk as much as the UKPDS Risk Engine, and they classified more participants correctly.
Both the UKPDS Risk Engine and Framingham risk equations were moderately effective at ranking individuals and are therefore suitable for resource prioritization. However, both overestimated true risk, which is important when one is using scores to communicate prognostic information to individuals.
PMCID: PMC2660447  PMID: 19114615
5.  Prediction of morbidity and mortality in patients with type 2 diabetes 
PeerJ  2013;1:e87.
Introduction. The objective of this study was to create a tool that accurately predicts the risk of morbidity and mortality in patients with type 2 diabetes according to an oral hypoglycemic agent.
Materials and Methods. The model was based on a cohort of 33,067 patients with type 2 diabetes who were prescribed a single oral hypoglycemic agent at the Cleveland Clinic between 1998 and 2006. Competing risk regression models were created for coronary heart disease (CHD), heart failure, and stroke, while a Cox regression model was created for mortality. Propensity scores were used to account for possible treatment bias. A prediction tool was created and internally validated using tenfold cross-validation. The results were compared to a Framingham model and a model based on the United Kingdom Prospective Diabetes Study (UKPDS) for CHD and stroke, respectively.
Results and Discussion. Median follow-up for the mortality outcome was 769 days. The numbers of patients experiencing events were as follows: CHD (3062), heart failure (1408), stroke (1451), and mortality (3661). The prediction tools demonstrated the following concordance indices (c-statistics) for the specific outcomes: CHD (0.730), heart failure (0.753), stroke (0.688), and mortality (0.719). The prediction tool was superior to the Framingham model at predicting CHD and was at least as accurate as the UKPDS model at predicting stroke.
Conclusions. We created an accurate tool for predicting the risk of stroke, coronary heart disease, heart failure, and death in patients with type 2 diabetes. The calculator is available online at under the heading “Type 2 Diabetes” and entitled, “Predicting 5-Year Morbidity and Mortality.” This may be a valuable tool to aid the clinician’s choice of an oral hypoglycemic, to better inform patients, and to motivate dialogue between physician and patient.
PMCID: PMC3685323  PMID: 23781409
Type 2 diabetes mellitus; Prediction; Propensity; Coronary heart disease; Heart failure; Stroke; Mortality; Electronic health record; Hypoglycemic agents
6.  External validation of the UK Prospective Diabetes Study (UKPDS) risk engine in patients with type 2 diabetes 
Diabetologia  2010;54(2):264-270.
Treatment guidelines recommend the UK Prospective Diabetes Study (UKPDS) risk engine for predicting cardiovascular risk in patients with type 2 diabetes, although validation studies showed moderate performance. The methods used in these validation studies were diverse, however, and sometimes insufficient. Hence, we assessed the discrimination and calibration of the UKPDS risk engine to predict 4, 5, 6 and 8 year cardiovascular risk in patients with type 2 diabetes.
The cohort included 1,622 patients with type 2 diabetes. During a mean follow-up of 8 years, patients were followed for incidence of CHD and cardiovascular disease (CVD). Discrimination and calibration were assessed for 4, 5, 6 and 8 year risk. Discrimination was examined using the c-statistic and calibration by visually inspecting calibration plots and calculating the Hosmer–Lemeshow χ2 statistic.
The UKPDS risk engine showed moderate to poor discrimination for both CHD and CVD (c-statistic of 0.66 for both 5 year CHD and CVD risks), and an overestimation of the risk (224% and 112%). The calibration of the UKPDS risk engine was slightly better for patients with type 2 diabetes who had been diagnosed with diabetes more than 10 years ago compared with patients diagnosed more recently, particularly for 4 and 5 year predicted CVD and CHD risks. Discrimination for these periods was still moderate to poor.
We observed that the UKPDS risk engine overestimates CHD and CVD risk. The discriminative ability of this model is moderate, irrespective of various subgroup analyses. To enhance the prediction of CVD in patients with type 2 diabetes, this model should be updated.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-010-1960-0) contains supplementary material, which is available to authorised users.
PMCID: PMC3017299  PMID: 21076956
Calibration; Cardiovascular disease; Coronary heart disease; Discrimination; Epidemiology; Multiple imputation; Prediction; Type 2 diabetes mellitus; Validation
7.  Risk Prediction of Coronary Heart Disease based on Retinal Vascular Caliber (From The Atherosclerosis Risk in Communities [ARIC] Study) 
Recent studies show that retinal vascular signs such as quantitative retinal vascular caliber are associated with an increased risk of incident coronary heart disease (CHD), but whether these retinal vascular signs add to the prediction of CHD over and above traditional CHD risk factors has not been addressed. We investigated whether these signs add to the prediction of CHD over and above the Framingham risk score amongst people (n=9,155) without diabetes selected from the Atherosclerosis Risk in Communities (ARIC) study. Incident CHD was ascertained using standardized methods and retinal vascular caliber and other retinal signs were measured from retinal photographs. After a mean of 8.8 years of follow up, there were 700 incident CHD events. Women with wider retinal venular caliber (hazard ratio 1.27 per 1 standard deviation increase [95% confidence interval, 1.08, 1.50]) and narrower retinal arteriolar caliber (1.31 per 1 standard deviation decrease [1.10, 1.56]) had a higher risk of incident CHD after adjusting for the Framingham risk score variables. The area under the receiver operator characteristic curve increased from 0.695 to 0.706 (1.7% increase) with the addition of retinal vascular caliber to the Framingham risk model. The risk prediction models with and without the retinal vascular caliber both fitted the data and were well calibrated for women. In men, retinal vascular caliber was not associated with CHD risk after adjustment. Other retinal vascular signs were not associated with 10-year incident CHD in men or women. In conclusion, although retinal vascular caliber independently predicts CHD risk in women, the incremental predictive ability over that of the Framingham model is modest, and unlikely to translate meaningfully into clinical practice.
PMCID: PMC2491714  PMID: 18572036
Coronary disease; retinal vascular disease; retinal imaging; risk prediction
8.  Predicting the 10 year risk of cardiovascular disease in the United Kingdom: independent and external validation of an updated version of QRISK2 
Objective To evaluate the performance of the QRISK2-2011 score for predicting the 10 year risk of cardiovascular disease in an independent UK cohort of patients from general practice and to compare it with earlier versions of the model and a National Institute for Health and Clinical Excellence version of the Framingham equation.
Design Prospective cohort study to validate a cardiovascular risk score with routinely collected data between June 1994 and June 2008.
Setting 364 practices from the United Kingdom contributing to The Health Improvement Network (THIN) database.
Participants Two million patients aged 30 to 84 years (11.8 million person years) with 93 564 cardiovascular events.
Main outcome measure First diagnosis of cardiovascular disease (myocardial infarction, angina, coronary heart disease, stroke, and transient ischaemic attack) recorded in general practice records.
Results Results from this independent and external validation of QRISK2-2011 indicate good performance data when compared with the NICE version of the Framingham equation. QRISK2-2011 had better ability to identify those at high risk of developing cardiovascular disease than did the NICE Framingham equation. QRISK2-2011 is well calibrated, with reasonable agreement between observed and predicted outcomes, whereas the NICE Framingham equation seems to consistently over-predict risk in men by about 5% and shows poor calibration in women.
Conclusions QRISK2-2011 seems to be a useful model, with good discriminative and calibration properties when compared with the NICE version of the Framingham equation. Furthermore, based on current high risk thresholds, concerns exist on the clinical usefulness of the NICE version of the Framingham equation for identifying women at high risk of developing cardiovascular disease. At current thresholds the NICE version of the Framingham equation has no clinical benefit in either men or women.
PMCID: PMC3380799  PMID: 22723603
9.  A coronary heart disease prediction model: the Korean Heart Study 
BMJ Open  2014;4(5):e005025.
The objectives of this study were to develop a coronary heart disease (CHD) risk model among the Korean Heart Study (KHS) population and compare it with the Framingham CHD risk score.
A prospective cohort study within a national insurance system.
18 health promotion centres nationwide between 1996 and 2001 in Korea.
268 315 Koreans between the ages of 30 and 74 years without CHD at baseline.
Outcome measure
Non-fatal or fatal CHD events between 1997 and 2011. During an 11.6-year median follow-up, 2596 CHD events (1903 non-fatal and 693 fatal) occurred in the cohort. The optimal CHD model was created by adding high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol and triglycerides to the basic CHD model, evaluating using the area under the receiver operating characteristic curve (ROC) and continuous net reclassification index (NRI).
The optimal CHD models for men and women included HDL-cholesterol (NRI=0.284) and triglycerides (NRI=0.207) from the basic CHD model, respectively. The discrimination using the CHD model in the Korean cohort was high: the areas under ROC were 0.764 (95% CI 0.752 to 0.774) for men and 0.815 (95% CI 0.795 to 0.835) for women. The Framingham risk function predicted 3–6 times as many CHD events than observed. Recalibration of the Framingham function using the mean values of risk factors and mean CHD incidence rates of the KHS cohort substantially improved the performance of the Framingham functions in the KHS cohort.
The present study provides the first evidence that the Framingham risk function overestimates the risk of CHD in the Korean population where CHD incidence is low. The Korean CHD risk model is well-calculated alternations which can be used to predict an individual's risk of CHD and provides a useful guide to identify the groups at high risk for CHD among Koreans.
PMCID: PMC4039825  PMID: 24848088
10.  Performance of the Framingham and SCORE cardiovascular risk prediction functions in a non-diabetic population of a Spanish health care centre: a validation study 
To analyse the 10-year performance of the original Framingham coronary risk function and of the SCORE cardiovascular death risk function in a non-diabetic population of 40–65 years of age served by a Spanish healthcare centre. Also, to estimate the percentage of patients who are candidates for antihypertensive and lipid-lowering therapy.
Longitudinal, observational study of a retrospective cohort followed up for 10 years.
Primary care health centre.
A total of 608 non-diabetic patients of 40–65 years of age (mean 52.8 years, 56.7% women), without evidence of cardiovascular disease were studied.
Main outcome measures
Coronary risk at 10 years from the time of their recruitment, using the tables based on the original Framingham function, and of their 10-year risk of fatal cardiovascular disease using the SCORE tables.
The actual incidence rates of coronary and fatal cardiovascular events were 7.9% and 1.5%, respectively. The original Framingham equation over-predicted risk by 64%, while SCORE function over-predicted risk by 40%, but the SCORE model performed better than the Framingham one for discrimination and calibration statistics. The original Framingham function classified 18.3% of the population as high risk and SCORE 9.2%. The proportions of patients who would be candidates for lipid-lowering therapy were 31.0% and 23.8% according to the original Framingham and SCORE functions, respectively, and 36.8% and 31.2% for antihypertensive therapy.
The SCORE function showed better values than the original Framingham function for each of the discrimination and calibration statistics. The original Framingham function selected a greater percentage of candidates for antihypertensive and lipid-lowering therapy.
PMCID: PMC3444797  PMID: 20873973
Antihypertensive treatment; cardiovascular risk functions; coronary risk; hypolipidemic treatment; SCORE risk chart
11.  Comparison of the Framingham Risk Score, UKPDS Risk Engine, and SCORE for Predicting Carotid Atherosclerosis and Peripheral Arterial Disease in Korean Type 2 Diabetic Patients 
Korean Journal of Family Medicine  2011;32(3):189-196.
To compare the predictability of the Framingham Risk Score (FRS), United Kingdom Prospective Diabetes Study (UKPDS) risk engine, and the Systematic Coronary Risk Evaluation (SCORE) for carotid atherosclerosis and peripheral arterial disease in Korean type 2 diabetic patients.
Among 1,275 registered type 2 diabetes patients in the health center, 621 subjects with type 2 diabetes participated in the study. Well-trained examiners measured the carotid intima-media thickness (IMT), carotid plaque, and ankle brachial index (ABI). The subject's 10-year risk of coronary heart disease was calculated according to the FRS, UKPDS, and SCORE risk scores. These three risk scores were compared to the areas under the curve (AUC).
The odds ratios (ORs) of all risk scores increased as the quartiles increased for plaque, IMT, and ABI. For plaque and IMT, the UKPDS risk score provided the highest OR (95% confidence interval) at 3.82 (2.36, 6.17) and at 6.21 (3.37, 11.45). For ABI, the SCORE risk estimation provided the highest OR at 7.41 (3.20, 17.18). However, no significant difference was detected for plaque, IMT, or ABI (P = 0.839, 0.313, and 0.113, respectively) when the AUCs of the three risk scores were compared. When we graphed the Kernel density distribution of these three risk scores, UKPDS had a higher distribution than FRS and SCORE.
No significant difference was observed when comparing the predictability of the FRS, UKPDS risk engine, and SCORE risk estimation for carotid atherosclerosis and peripheral arterial disease in Korean type 2 diabetic patients.
PMCID: PMC3383126  PMID: 22745854
Risk Assessment; Peripheral Arterial Disease; Carotid Artery Thrombosis; Diabetes Mellitus, Type 2
12.  Validation of the pooled cohort risk score in an Asian population – a retrospective cohort study 
The Pooled Cohort Risk Equation was introduced by the American College of Cardiology (ACC) and American Heart Association (AHA) 2013 in their Blood Cholesterol Guideline to estimate the 10-year atherosclerotic cardiovascular disease (ASCVD) risk. However, absence of Asian ethnicity in the contemporary cohorts and limited studies to examine the use of the risk score limit the applicability of the equation in an Asian population. This study examines the validity of the pooled cohort risk score in a primary care setting and compares the cardiovascular risk using both the pooled cohort risk score and the Framingham General Cardiovascular Disease (CVD) risk score.
This is a 10-year retrospective cohort study of randomly selected patients aged 40–79 years. Baseline demographic data, co-morbidities and cardiovascular (CV) risk parameters were captured from patient records in 1998. Pooled cohort risk score and Framingham General CVD risk score for each patient were computed. All ASCVD events (nonfatal myocardial infarction, coronary heart disease (CHD) death, fatal and nonfatal stroke) occurring from 1998–2007 were recorded.
A total of 922 patients were studied. In 1998, mean age was 57.5 ± 8.8 years with 66.7% female. There were 47% diabetic patients and 59.9% patients receiving anti-hypertensive treatment. More than 98% of patients with pooled cohort risk score ≥7.5% had FRS >10%. A total of 45 CVD events occurred, 22 (7.2%) in males and 23 (3.7%) in females. The median pooled cohort risk score for the population was 10.1 (IQR 4.7-20.6) while the actual ASCVD events that occurred was 4.9% (45/922). Our study showed moderate discrimination with AUC of 0.63. There was good calibration with Hosmer-Lemeshow test χ2 = 12.6, P = 0.12.
The pooled cohort risk score appears to overestimate CV risk but this apparent over-prediction could be a result of treatment. In the absence of a validated score in an untreated population, the pooled cohort risk score appears to be appropriate for use in a primary care setting.
PMCID: PMC4246627  PMID: 25410585
Pooled cohort risk score; Atherosclerotic cardiovascular disease; Validation; Asian population; Framingham risk score; Cardiovascular events; Primary care; Retrospective cohort; Malaysia
13.  Adding multiple risk factors improves Framingham coronary heart disease risk scores 
Since the introduction of the Framingham Risk Score (FRS), numerous versions of coronary heart disease (CHD) prediction models have claimed improvement over the FRS. Tzoulaki et al challenged the validity of these claims by illustrating methodology deficiencies among the studies. However, the question remains: Is it possible to create a new CHD model that is better than FRS while overcoming the noted deficiencies? To address this, a new CHD prediction model was developed by integrating additional risk factors, using a novel modeling process.
Using the National Health Nutritional Examination Survey III data set with CHD-specific mortality outcomes and the Atherosclerosis Risk in Communities data set with CHD incidence outcomes, two FRSs (FRSv1 from 1998 and FRSv2 from National Cholesterol Education Program Adult Treatment Panel III), along with an additional risk score in which the high density lipoprotein (HDL) component of FRSv1 was ignored (FRSHDL), were compared with a new CHD model (NEW-CHD). This new model contains seven elements: the original Framingham equation, FRSv1, and six additional risk factors. Discrimination, calibration, and reclassification improvements all were assessed among models.
Discrimination was improved for NEW-CHD in both cohorts when compared with FRSv1 and FRSv2 (P<0.05) and was similar in magnitude to the improvement of FRSv1 over FRSHDL. NEW-CHD had a similar calibration to FRSv2 and was improved over FRSv1. Net reclassification for NEW-CHD was substantially improved over both FRSv1 and FRSv2, for both cohorts, and was similar in magnitude to the improvement of FRSv1 over FRSHDL.
While overcoming several methodology deficiencies reported by earlier authors, the NEW-CHD model improved CHD risk assessment when compared with the FRSs, comparable to the improvement of adding HDL to the FRS.
PMCID: PMC4162681  PMID: 25228812
risk assessment; atherosclerotic risk in communities; NHANES; epidemiology
14.  Trends in the Risk for Coronary Heart Disease Among Adults With Diagnosed Diabetes in the U.S. 
Diabetes Care  2011;34(6):1337-1343.
Coronary heart disease (CHD) is a major cause of mortality among people with diabetes. The objective of this study was to examine the trend in an estimated 10-year risk for developing CHD among adults with diagnosed diabetes in the U.S.
Data from 1,977 adults, aged 30–79 years, with diagnosed diabetes who participated in the National Health and Nutrition Examination Survey from 1999–2000 to 2007–2008 were used. Estimated risk was calculated using risk prediction algorithms from the UK Prospective Diabetes Study (UKPDS), the Atherosclerosis Risk in Communities study, and the Framingham Heart Study.
Significant improvements in mean HbA1c concentrations, systolic blood pressure, and the ratio of total cholesterol to HDL cholesterol occurred. No significant linear trend for current smoking status was observed. The estimated UKPDS 10-year risk for CHD was 21.1% in 1999–2000 and 16.4% in 2007–2008 (Plinear trend < 0.001). The risk decreased significantly among men, women, whites, African Americans, and Mexican Americans.
The estimated 10-year risk for CHD among adults with diabetes has improved significantly from 1999–2000 to 2007–2008. Sustained efforts in improving risk factors should further benefit the cardiovascular health of people with diabetes.
PMCID: PMC3114334  PMID: 21505207
15.  Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study: baseline characteristics and short-term effects of fenofibrate [ISRCTN64783481] 
The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study is examining the effects of long-term fibrate therapy on coronary heart disease (CHD) event rates in patients with diabetes mellitus. This article describes the trial's run-in phase and patients' baseline characteristics.
Research design and methods
FIELD is a double-blind, placebo-controlled trial in 63 centres in 3 countries evaluating the effects of fenofibrate versus placebo on CHD morbidity and mortality in 9795 patients with type 2 diabetes mellitus. Patients were to have no indication for lipid-lowering therapy on randomization, but could start these or other drugs at any time after randomization. Follow-up in the study was to be for a median duration of not less than 5 years and until 500 major coronary events (fatal coronary heart disease plus nonfatal myocardial infarction) had occurred.
About 2100 patients (22%) had some manifestation of cardiovascular disease (CVD) at baseline and thus high risk status. Less than 25% of patients without CVD had a (UKPDS determined) calculated 5-year CHD risk of <5%, but nearly all had a 5-year stroke risk of <10%. Despite this, half of the cohort were obese (BMI > 30), most were men, two-thirds were aged over 60 years, and substantial proportions had NCEP ATP III features of the metabolic syndrome independent of their diabetes, including low HDL (60%), high blood pressure measurement or treatment for hypertension (84%), high waist measurement (68%), and raised triglycerides (52%).
After a 6-week run-in period before randomisation with all participants receiving 200 mg comicronized fenofibrate, there were declines in total and LDL cholesterol (10%) and triglycerides (26%) and an increase in HDL cholesterol (6.5%).
The study will show the effect of PPAR-alpha agonist action on CHD and other vascular outcomes in patients with type 2 diabetes including substantial numbers with low to moderate CVD risk but with the various components of the metabolic syndrome. The main results of the study will be reported in late 2005.
PMCID: PMC1266033  PMID: 16111499
16.  An independent and external validation of QRISK2 cardiovascular disease risk score: a prospective open cohort study 
Objective To evaluate the performance of the QRISK2 score for predicting 10-year cardiovascular disease in an independent UK cohort of patients from general practice records and to compare it with the NICE version of the Framingham equation and QRISK1.
Design Prospective cohort study to validate a cardiovascular risk score.
Setting 365 practices from United Kingdom contributing to The Health Improvement Network (THIN) database.
Participants 1.58 million patients registered with a general practice between 1 January 1993 and 20 June 2008, aged 35-74 years (9.4 million person years) with 71 465 cardiovascular events.
Main outcome measures First diagnosis of cardiovascular disease (myocardial infarction, angina, coronary heart disease, stroke, and transient ischaemic stroke) recorded in general practice records.
Results QRISK2 offered improved prediction of a patient’s 10-year risk of cardiovascular disease over the NICE version of the Framingham equation. Discrimination and calibration statistics were better with QRISK2. QRISK2 explained 33% of the variation in men and 40% for women, compared with 29% and 34% respectively for the NICE Framingham and 32% and 38% respectively for QRISK1. The incidence rate of cardiovascular events (per 1000 person years) among men in the high risk group was 27.8 (95% CI 27.4 to 28.2) with QRISK2, 21.9 (21.6 to 22.2) with NICE Framingham, and 24.8 (22.8 to 26.9) with QRISK1. Similarly, the incidence rate of cardiovascular events (per 1000 person years) among women in the high risk group was 24.3 (23.8 to 24.9) with QRISK2, 20.6 (20.1 to 21.0) with NICE Framingham, and 21.8 (18.9 to 24.6) with QRISK1.
Conclusions QRISK2 is more accurate in identifying a high risk population for cardiovascular disease in the United Kingdom than the NICE version of the Framingham equation. Differences in performance between QRISK2 and QRISK1 were marginal.
PMCID: PMC2869403  PMID: 20466793
17.  Cardiovascular disease risk assessment in older women: can we improve on Framingham? British Women's Heart and Health prospective cohort study 
Heart  2006;92(10):1396-1401.
To develop a cardiovascular risk assessment tool that is feasible and easy to use in primary care (general practice (GP) model).
Prospective cohort study.
23 towns in the United Kingdom.
3582 women aged 60 to 79 years who were free of coronary heart disease (CHD) at entry into the British Women's Heart and Health Study.
Main outcome measures
Predictive performance of a GP model compared with the standard Framingham model for both CHD and cardiovascular disease (CVD).
The Framingham tool predicted CHD events over 5 years accurately (predicted 5.7%, observed 5.5%) but overpredicted CVD events (predicted 10.5%, observed 6.8%). In higher‐risk groups, Framingham overpredicted both CHD and CVD events and was poorly calibrated for this cohort. Including C‐reactive protein and fibrinogen with standard Framingham risk factors did not improve discrimination of the model. The GP model, which used age, systolic blood pressure, smoking habit and self‐rated health (all of which can be easily obtained in one surgery visit) performed as well as the Framingham risk tool: area under the receiver operating curve discrimination statistic was 0.66 (95% confidence interval (CI) 0.62 to 0.70) for CHD and 0.67 (95% CI 0.64 to 0.71) for CVD compared with 0.65 (95% CI 0.61 to 0.68) and 0.66 (95% CI 0.62 to 0.69) for the corresponding Framingham models.
An alternative risk assessment based on only a simple routine examination and a small number of pertinent questions may be more useful in the primary care setting. This model appears to perform well but needs to be tested in different populations.
PMCID: PMC1861043  PMID: 16547204
18.  Cardiovascular risk prediction tools for populations in Asia 
Cardiovascular risk equations are traditionally derived from the Framingham Study. The accuracy of this approach in Asian populations, where resources for risk factor measurement may be limited, is unclear.
To compare “low‐information” equations (derived using only age, systolic blood pressure, total cholesterol and smoking status) derived from the Framingham Study with those derived from the Asian cohorts, on the accuracy of cardiovascular risk prediction.
Separate equations to predict the 8‐year risk of a cardiovascular event were derived from Asian and Framingham cohorts. The performance of these equations, and a subsequently “recalibrated” Framingham equation, were evaluated among participants from independent Chinese cohorts.
Six cohort studies from Japan, Korea and Singapore (Asian cohorts); six cohort studies from China; the Framingham Study from the US.
172 077 participants from the Asian cohorts; 25 682 participants from Chinese cohorts and 6053 participants from the Framingham Study.
Main results
In the Chinese cohorts, 542 cardiovascular events occurred during 8 years of follow‐up. Both the Asian cohorts and the Framingham equations discriminated cardiovascular risk well in the Chinese cohorts; the area under the receiver–operator characteristic curve was at least 0.75 for men and women. However, the Framingham risk equation systematically overestimated risk in the Chinese cohorts by an average of 276% among men and 102% among women. The corresponding average overestimation using the Asian cohorts equation was 11% and 10%, respectively. Recalibrating the Framingham risk equation using cardiovascular disease incidence from the non‐Chinese Asian cohorts led to an overestimation of risk by an average of 4% in women and underestimation of risk by an average of 2% in men.
A low‐information Framingham cardiovascular risk prediction tool, which, when recalibrated with contemporary data, is likely to estimate future cardiovascular risk with similar accuracy in Asian populations as tools developed from data on local cohorts.
PMCID: PMC2465638  PMID: 17234869
19.  Cardiometabolic Consequences of Therapy For Chronic Schizophrenia Using Second-Generation Antipsychotic Agents in a Medicaid Population 
Pharmacy and Therapeutics  2013;38(2):109-115.
A health economic model was constructed to predict the 5-year incidence of coronary heart disease and diabetes and associated costs after treatment in patients using second-generation antipsychotic agents.
We assessed the potential clinical and economic impact of coronary heart disease (CHD) and diabetes arising after the use of second-generation (“atypical”) antipsychotic agents for the treatment of chronic schizophrenia. We compared the use of these medications in patients with a higher risk of cardiometabolic adverse events (in a higher-risk scenario) and in patients with a lower risk (in a lower-risk scenario). Our U.S.-based analysis estimated the costs of CHD and diabetes arising from antipsychotic medication–related cardiometabolic effects.
We constructed a health economic model to predict the 5-year incidence of CHD and diabetes and associated costs after treatment. In this cost-consequence model, we used CHD risk functions derived from the Framingham Heart Study and diabetes risk functions derived from the Atherosclerosis Risk in Communities (ARIC) study. Patient characteristics and treatment effects on cardiometabolic risk factors were estimated from the Clinical Trials of Antipsychotic Treatment Effectiveness (CATIE) study.
We evaluated two cost-consequence scenarios: the incidence of CHD and diabetes predicted for 1,000 patients with chronic schizophrenia in a higher-risk scenario based on data from CATIE associated with olanzapine (Zyprexa) and in a lower-risk scenario with ziprasidone (Geodon). We evaluated rates of adverse outcomes for each scenario and the cost of treatment for CHD and diabetes. All costs were reported in 2011 U.S. dollars. Because Medicaid is often the payer for patients with chronic schizophrenia, all costs in this analysis were derived from the perspective of Medicaid.
Over a period of 5 years in 1,000 patients with chronic schizophrenia, the higher-risk scenario with olanzapine showed a 9% increased incidence of CHD and a 59% increased incidence of diabetes, compared with no change in treatment from baseline. By contrast, the lower-risk scenario with ziprasidone showed a 9% reduced incidence of CHD and a 10% reduced incidence of diabetes. The higher-risk scenario led to increased CHD-related costs of $83,206 and to increased diabetes-related costs of $456,399.
Our study underscores the importance of monitoring the established risk factors for CHD and diabetes in patients using second-generation antipsychotic drugs. Lower-risk agents from this class may lead to substantially decreased costs in the management of CHD and diabetes when compared with higher-risk agents.
PMCID: PMC3628175  PMID: 23599678
second-generation antipsychotic agents; Medicaid; schizophrenia; cardiometabolic
20.  Potential modification of the UKPDS risk engine and evaluation of macrovascular event rates in controlled clinical trials 
The aim of this study was to evaluate a modified UKPDS risk engine in order to establish a risk prediction benchmark for the general diabetes population.
Data sources were summary demographic and risk factor data from the major type 2 diabetes mellitus outcomes studies, including ACCORD, ADVANCE, VADT, RECORD, PROactive, ADOPT, and BARI 2D. Patients in these studies spanned a wide spectrum of disease, from drug-naïve to insulin-dependent. Cardiovascular events/major adverse coronary events (CVE/MACE) were primary or safety end points. Overall observed rates for cardiovascular events/MACE were summarized, and the observed annualized event rates were calculated using linear approximation. Simulation studies were then conducted using original (cardiovascular history excluded) and modified (cardiovascular history included) United Kingdom Prospective Diabetes Study (UKPDS) models; the predicted event rates were then compared with the observed event rates for all studies. The consistency of the predicted rates derived from each model was then evaluated using descriptive statistics and linear regression.
The original UKPDS model tended to overestimate event rates across studies. The ratio of predicted events versus observed MACE ranged from 0.9 to 2.0, with mean of 1.5 ± 0.4 and a coefficient of variation of 26% (R2 = 0.80). However, cardiovascular risk predictions were more precise using a modified UKPDS model; the ratio of predicted versus observed MACE events ranged from 1.8 to 2.4, with a mean of 2.1 ± 0.25 and a coefficient of variation of 13% (R2 = 0.94).
A modified UKPDS model which includes adjustments for prior cardiovascular history has the potential for use as a tool for benchmarking and may be useful for predicting cardiovascular rates in clinical studies. This modification could be further evaluated, recalibrated, and validated using patient-level information derived from prospective clinical studies to yield greater predictability.
PMCID: PMC3716447  PMID: 23885178
type 2 diabetes mellitus; macrovascular disease; outcomes; United Kingdom Prospective Diabetes Study; modeling
21.  Improved coronary risk assessment among intermediate risk patients using a clinical and biomarker based algorithm developed and validated in two population cohorts 
Current medical research and opinion  2012;28(11):1819-1830.
Many coronary heart disease (CHD) events occur in individuals classified as intermediate risk by commonly used assessment tools. Over half the individuals presenting with a severe cardiac event, such as Myocardial Infarction (MI), have at most one risk factor as included in the widely used Framingham risk assessment. Individuals classified as intermediate risk, who are actually at high risk, may not receive guideline recommended treatments. A clinically useful method for accurately predicting 5-year CHD risk among intermediate risk patients remains an unmet medical need.
This study sought to develop a CHD Risk Assessment (CHDRA) model that improves 5-year risk stratification among intermediate risk individuals.
Assay panels for biomarkers associated with atherosclerosis biology (inflammation, angiogenesis, apoptosis, chemotaxis, etc.) were optimized for measuring baseline serum samples from 1084 initially CHD-free Marshfield Clinic Personalized Medicine Research Project (PMRP) individuals. A multivariable Cox regression model was fit using the most powerful risk predictors within the clinical and protein variables identified by repeated cross-validation. The resulting CHDRA algorithm was validated in a Multiple-Ethnic Study of Atherosclerosis (MESA) case-cohort sample.
A CHDRA algorithm of age, sex, diabetes, and family history of MI, combined with serum levels of seven biomarkers (CTACK, Eotaxin, Fas Ligand, HGF, IL-16, MCP-3, and sFas) yielded a clinical net reclassification index of 42.7% (p<0.001) for MESA patients with a recalibrated Framingham 5-year intermediate risk level. Across all patients, the model predicted acute coronary events (hazard ratio=2.17, p<0.001), and remained an independent predictor after Framingham risk factor adjustments.
These include the slightly different event definition with the MESA samples and inability to include PMRP fatal CHD events.
A novel risk score of serum protein levels plus clinical risk factors, developed and validated in independent cohorts, demonstrated clinical utility for assessing the true risk of CHD events in intermediate risk patients. Improved accuracy in cardiovascular risk classification could lead to improved preventive care and fewer deaths.
PMCID: PMC3666558  PMID: 23092312
myocardial infarction; risk assessment; coronary heart disease; inflammation; clinical validation
22.  Primary prevention of coronary heart disease: integration of new data, evolving views, revised goals, and role of rosuvastatin in management. A comprehensive survey 
A recent explosion in the amount of cardiovascular risk and incipient, undetected subclinical cardiovascular pathology has swept across the globe. Nearly 70% of adult Americans are overweight or obese; the prevalence of visceral obesity stands at 53% and continues to rise. At any one time, 55% of the population is on a weight-loss diet, and almost all fail. Fewer than 15% of adults or children exercise sufficiently, and over 60% engage in no vigorous activity. Among adults, 11%–13% have diabetes, 34% have hypertension, 36% have prehypertension, 36% have prediabetes, 12% have both prediabetes and prehypertension, and 15% of the population with either diabetes, hypertension, or dyslipidemia are undiagnosed. About one-third of the adult population, and 80% of the obese, have fatty livers. With 34% of children overweight or obese, prevalence having doubled in just a few years, type 2 diabetes, hypertension, dyslipidemia, and fatty livers in children are at their highest levels ever. Half of adults have at least one cardiovascular risk factor. Not even 1% of the population attains ideal cardiovascular health. Despite falling coronary death rates for decades, coronary heart disease (CHD) death rates in US women 35 to 54 years of age may now be increasing because of the obesity epidemic. Up to 65% of patients do not have their conventional risk biomarkers under control. Only 30% of high risk patients with CHD achieve aggressive low density lipoprotein (LDL) targets. Of those patients with multiple risk factors, fewer than 10% have all of them adequately controlled. Even when patients are titrated to evidence-based targets, about 70% of cardiac events remain unaddressed. Undertreatment is also common. About two-thirds of high risk primary care patients are not taking needed medications for dyslipidemia. Poor patient adherence, typically below 50%, adds further difficulty. Hence, after all such fractional reductions are multiplied, only a modest portion of total cardiovascular risk burden is actually being eliminated, and the full potential of risk reduction remains unrealized. Worldwide the situation is similar, with the prevalence of metabolic syndrome approaching 50%. Primordial prevention, resulting from healthful lifestyle habits that do not permit the appearance of risk factors, is the preferred method to lower cardiovascular risk. Lowering the prevalence of obesity is the most urgent matter, and is pleiotropic since it affects blood pressure, lipid profiles, glucose metabolism, inflammation, and atherothrombotic disease progression. Physical activity also improves several risk factors, with the additional potential to lower heart rate. Given the current obstacles, success of primordial prevention remains uncertain. At the same time, the consequences of delay and inaction will inevitably be disastrous, and the sense of urgency mounts. Since most CHD events arise in a large subpopulation of low- to moderate-risk individuals, identifying a high proportion of those who will go on to develop events with accuracy remains unlikely. Without a refinement in risk prediction, the current model of targeting high-risk individuals for aggressive therapy may not succeed alone, especially given the rising burden of risk. Estimating cardiovascular risk over a period of 10 years, using scoring systems such as Framingham or SCORE, continues to enjoy widespread use and is recommended for all adults. Limitations in the former have been of concern, including the under- or over-estimation of risk in specific populations, a relatively short 10-year risk horizon, focus on myocardial infarction and CHD death, and exclusion of family history. Classification errors may occur in up to 37% of individuals, particularly women and the young. Several different scoring systems are discussed in this review. The use of lifetime risk is an important conceptual advance, since ≥90% of young adults with a low 10-year risk have a lifetime risk of ≥39%; over half of all American adults have a low 10-year risk but a high lifetime risk. At age 50 the absence of traditional risk factors is associated with extremely low lifetime risk and significantly greater longevity. Pathological and epidemiological data confirm that atherosclerosis begins in early childhood, and advances seamlessly and inexorably throughout life. Risk factors in childhood are similar to those in adults, and track between stages of life. When indicated, aggressive treatment should begin at the earliest indication, and be continued for years. For those patients at intermediate risk according to global risk scores, C-reactive protein (CRP), coronary artery calcium (CAC), and carotid intima-media thickness (CIMT) are available for further stratification. Using statins for primary prevention is recommended by guidelines, is prevalent, but remains underprescribed. Statin drugs are unrivaled, evidence-based, major weapons to lower cardiovascular risk. Even when low density lipoprotein cholesterol (LDL-C) targets are attained, over half of patients continue to have disease progression and clinical events. This residual risk is of great concern, and multiple sources of remaining risk exist. Though clinical evidence is incomplete, altering or raising the blood high density lipoprotein cholesterol (HDL-C) level continues to be pursued. Of all agents available, rosuvastatin produces the greatest reduction in LDL-C, LDL-P, and improvement in apoA-I/apoB, together with a favorable safety profile. Several recent proposals and methods to lower cardiovascular risk are reviewed. A combination of approaches, such as the addition of lifetime risk, refinement of risk prediction, guideline compliance, novel treatments, improvement in adherence, and primordial prevention, including environmental and social intervention, will be necessary to lower the present high risk burden.
PMCID: PMC3140289  PMID: 21792295
primary prevention; cardiovascular risk; coronary heart disease; primordial prevention; rosuvastatin; JUPITER study; statin drugs; C-reactive protein; inflammation; low-density lipoprotein; high-density lipoprotein; diabetes; metabolic syndrome; Framingham risk score; Reynolds risk score; SCORE; coronary artery calcification; carotid intima-media thickness; hypertension; obesity; non-HDL-cholesterol; LDL-P; dysfunctional HDL; lifetime risk; advanced lipid testing; Bogalusa Heart Study
23.  Framingham-based Tools to Calculate the Global Risk of Coronary Heart Disease 
Journal of General Internal Medicine  2003;18(12):1039-1052.
To examine the features of available Framingham-based risk calculation tools and review their accuracy and feasibility in clinical practice.
medline, 1966–April 2003, and the google search engine on the Internet.
We included risk calculation tools that used the Framingham risk equations to generate a global coronary heart disease (CHD) risk. To determine tool accuracy, we reviewed all articles that compared the performance of various Framingham-based risk tools to that of the continuous Framingham risk equations. To determine the feasibility of tool use in clinical practice, we reviewed articles on the availability of the risk factor information required for risk calculation, subjective preference for 1 risk calculator over another, or subjective ease of use.
Two reviewers independently reviewed the results of the literature search, all websites, and abstracted all articles for relevant information.
Multiple CHD risk calculation tools are available, including risk charts and computerized calculators for personal digital assistants, personal computers, and web-based use. Most are easy to use and available without cost. They require information on age, smoking status, blood pressure, total and HDL cholesterol, and the presence or absence of diabetes. Compared to the full Framingham equations, accuracy for identifying patients at increased risk was generally quite high. Data on the feasibility of tool use was limited.
Several easy-to-use tools are available for estimating patients' CHD risk. Use of such tools could facilitate better decision making about interventions for primary prevention of CHD, but further research about their actual effect on clinical practice and patient outcomes is required.
Drs. Sheridan and Pignone have participated in the development of Heart-to-Heart, one of the risk tools evaluated within. They have also received speaking and consulting fees from Bayer, Inc. Bayer, Inc. has licensed the Heart-to-Heart tool.
PMCID: PMC1494957  PMID: 14687264
risk assessment; coronary heart disease; Framingham Heart Study
24.  Predicting the short-term risk of diabetes in HIV-positive patients: the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study 
HIV-positive patients receiving combination antiretroviral therapy (cART) frequently experience metabolic complications such as dyslipidemia and insulin resistance, as well as lipodystrophy, increasing the risk of cardiovascular disease (CVD) and diabetes mellitus (DM). Rates of DM and other glucose-associated disorders among HIV-positive patients have been reported to range between 2 and 14%, and in an ageing HIV-positive population, the prevalence of DM is expected to continue to increase. This study aims to develop a model to predict the short-term (six-month) risk of DM in HIV-positive populations and to compare the existing models developed in the general population.
All patients recruited to the Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) study with follow-up data, without prior DM, myocardial infarction or other CVD events and with a complete DM risk factor profile were included. Conventional risk factors identified in the general population as well as key HIV-related factors were assessed using Poisson-regression methods. Expected probabilities of DM events were also determined based on the Framingham Offspring Study DM equation. The D:A:D and Framingham equations were then assessed using an internal-external validation process; area under the receiver operating characteristic (AUROC) curve and predicted DM events were determined.
Of 33,308 patients, 16,632 (50%) patients were included, with 376 cases of new onset DM during 89,469 person-years (PY). Factors predictive of DM included higher glucose, body mass index (BMI) and triglyceride levels, and older age. Among HIV-related factors, recent CD4 counts of<200 cells/µL and lipodystrophy were predictive of new onset DM. The mean performance of the D:A:D and Framingham equations yielded AUROC of 0.894 (95% CI: 0.849, 0.940) and 0.877 (95% CI: 0.823, 0.932), respectively. The Framingham equation over-predicted DM events compared to D:A:D for lower glucose and lower triglycerides, and for BMI levels below 25 kg/m2.
The D:A:D equation performed well in predicting the short-term onset of DM in the validation dataset and for specific subgroups provided better estimates of DM risk than the Framingham.
PMCID: PMC3494158  PMID: 23078769
HIV; combination antiretroviral treatment; diabetes mellitus; risk equation
25.  Critical appraisal of CRP measurement for the prediction of coronary heart disease events: new data and systematic review of 31 prospective cohorts 
Background Non-uniform reporting of relevant relationships and metrics hampers critical appraisal of the clinical utility of C-reactive protein (CRP) measurement for prediction of later coronary events.
Methods We evaluated the predictive performance of CRP in the Northwick Park Heart Study (NPHS-II) and the Edinburgh Artery Study (EAS) comparing discrimination by area under the ROC curve (AUC), calibration and reclassification. We set the findings in the context of a systematic review of published studies comparing different available and imputed measures of prediction. Risk estimates per-quantile of CRP were pooled using a random effects model to infer the shape of the CRP-coronary event relationship.
Results NPHS-II and EAS (3441 individuals, 309 coronary events): CRP alone provided modest discrimination for coronary heart disease (AUC 0.61 and 0.62 in NPHS-II and EAS, respectively) and only modest improvement in the discrimination of a Framingham-based risk score (FRS) (increment in AUC 0.04 and –0.01, respectively). Risk models based on FRS alone and FRS + CRP were both well calibrated and the net reclassification improvement (NRI) was 8.5% in NPHS-II and 8.8% in EAS with four risk categories, falling to 4.9% and 3.0% for 10-year coronary disease risk threshold of 15%. Systematic review (31 prospective studies 84 063 individuals, 11 252 coronary events): pooled inferred values for the AUC for CRP alone were 0.59 (0.57, 0.61), 0.59 (0.57, 0.61) and 0.57 (0.54, 0.61) for studies of <5, 5–10 and >10 years follow up, respectively. Evidence from 13 studies (7201 cases) indicated that CRP did not consistently improve performance of the Framingham risk score when assessed by discrimination, with AUC increments in the range 0–0.15. Evidence from six studies (2430 cases) showed that CRP provided statistically significant but quantitatively small improvement in calibration of models based on established risk factors in some but not all studies. The wide overlap of CRP values among people who later suffered events and those who did not appeared to be explained by the consistently log-normal distribution of CRP and a graded continuous increment in coronary risk across the whole range of values without a threshold, such that a large proportion of events occurred among the many individuals with near average levels of CRP.
Conclusions CRP does not perform better than the Framingham risk equation for discrimination. The improvement in risk stratification or reclassification from addition of CRP to models based on established risk factors is small and inconsistent. Guidance on the clinical use of CRP measurement in the prediction of coronary events may require updating in light of this large comparative analysis.
PMCID: PMC2639366  PMID: 18930961
C-reactive protein; prediction; coronary heart disease; primary prevention; risk stratification

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