TY - JOUR T1 - Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JF - JAMA Y1 - 2009 A1 - Erqou, Sebhat A1 - Kaptoge, Stephen A1 - Perry, Philip L A1 - Di Angelantonio, Emanuele A1 - Thompson, Alexander A1 - White, Ian R A1 - Marcovina, Santica M A1 - Collins, Rory A1 - Thompson, Simon G A1 - Danesh, John KW - Cause of Death KW - Coronary Disease KW - Humans KW - Lipoprotein(a) KW - Risk Factors KW - Stroke AB -

CONTEXT: Circulating concentration of lipoprotein(a) (Lp[a]), a large glycoprotein attached to a low-density lipoprotein-like particle, may be associated with risk of coronary heart disease (CHD) and stroke.

OBJECTIVE: To assess the relationship of Lp(a) concentration with risk of major vascular and nonvascular outcomes.

STUDY SELECTION: Long-term prospective studies that recorded Lp(a) concentration and subsequent major vascular morbidity and/or cause-specific mortality published between January 1970 and March 2009 were identified through electronic searches of MEDLINE and other databases, manual searches of reference lists, and discussion with collaborators.

DATA EXTRACTION: Individual records were provided for each of 126,634 participants in 36 prospective studies. During 1.3 million person-years of follow-up, 22,076 first-ever fatal or nonfatal vascular disease outcomes or nonvascular deaths were recorded, including 9336 CHD outcomes, 1903 ischemic strokes, 338 hemorrhagic strokes, 751 unclassified strokes, 1091 other vascular deaths, 8114 nonvascular deaths, and 242 deaths of unknown cause. Within-study regression analyses were adjusted for within-person variation and combined using meta-analysis. Analyses excluded participants with known preexisting CHD or stroke at baseline.

DATA SYNTHESIS: Lipoprotein(a) concentration was weakly correlated with several conventional vascular risk factors and it was highly consistent within individuals over several years. Associations of Lp(a) with CHD risk were broadly continuous in shape. In the 24 cohort studies, the rates of CHD in the top and bottom thirds of baseline Lp(a) distributions, respectively, were 5.6 (95% confidence interval [CI], 5.4-5.9) per 1000 person-years and 4.4 (95% CI, 4.2-4.6) per 1000 person-years. The risk ratio for CHD, adjusted for age and sex only, was 1.16 (95% CI, 1.11-1.22) per 3.5-fold higher usual Lp(a) concentration (ie, per 1 SD), and it was 1.13 (95% CI, 1.09-1.18) following further adjustment for lipids and other conventional risk factors. The corresponding adjusted risk ratios were 1.10 (95% CI, 1.02-1.18) for ischemic stroke, 1.01 (95% CI, 0.98-1.05) for the aggregate of nonvascular mortality, 1.00 (95% CI, 0.97-1.04) for cancer deaths, and 1.00 (95% CI, 0.95-1.06) for nonvascular deaths other than cancer.

CONCLUSION: Under a wide range of circumstances, there are continuous, independent, and modest associations of Lp(a) concentration with risk of CHD and stroke that appear exclusive to vascular outcomes.

VL - 302 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19622820?dopt=Abstract ER - TY - JOUR T1 - C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. JF - Lancet Y1 - 2010 A1 - Kaptoge, Stephen A1 - Di Angelantonio, Emanuele A1 - Lowe, Gordon A1 - Pepys, Mark B A1 - Thompson, Simon G A1 - Collins, Rory A1 - Danesh, John KW - Alcohol Drinking KW - Biomarkers KW - Blood Pressure KW - Body Mass Index KW - C-Reactive Protein KW - Cholesterol KW - Coronary Disease KW - Databases, Factual KW - Diabetes Mellitus KW - Female KW - Fibrinogen KW - Humans KW - Interleukin-6 KW - Leukocyte Count KW - Lung Diseases KW - Male KW - Middle Aged KW - Motor Activity KW - Neoplasms KW - Regression Analysis KW - Risk Assessment KW - Risk Factors KW - Serum Albumin KW - Sex Factors KW - Smoking KW - Stroke KW - Triglycerides AB -

BACKGROUND: Associations of C-reactive protein (CRP) concentration with risk of major diseases can best be assessed by long-term prospective follow-up of large numbers of people. We assessed the associations of CRP concentration with risk of vascular and non-vascular outcomes under different circumstances.

METHODS: We meta-analysed individual records of 160 309 people without a history of vascular disease (ie, 1.31 million person-years at risk, 27 769 fatal or non-fatal disease outcomes) from 54 long-term prospective studies. Within-study regression analyses were adjusted for within-person variation in risk factor levels.

RESULTS: Log(e) CRP concentration was linearly associated with several conventional risk factors and inflammatory markers, and nearly log-linearly with the risk of ischaemic vascular disease and non-vascular mortality. Risk ratios (RRs) for coronary heart disease per 1-SD higher log(e) CRP concentration (three-fold higher) were 1.63 (95% CI 1.51-1.76) when initially adjusted for age and sex only, and 1.37 (1.27-1.48) when adjusted further for conventional risk factors; 1.44 (1.32-1.57) and 1.27 (1.15-1.40) for ischaemic stroke; 1.71 (1.53-1.91) and 1.55 (1.37-1.76) for vascular mortality; and 1.55 (1.41-1.69) and 1.54 (1.40-1.68) for non-vascular mortality. RRs were largely unchanged after exclusion of smokers or initial follow-up. After further adjustment for fibrinogen, the corresponding RRs were 1.23 (1.07-1.42) for coronary heart disease; 1.32 (1.18-1.49) for ischaemic stroke; 1.34 (1.18-1.52) for vascular mortality; and 1.34 (1.20-1.50) for non-vascular mortality.

INTERPRETATION: CRP concentration has continuous associations with the risk of coronary heart disease, ischaemic stroke, vascular mortality, and death from several cancers and lung disease that are each of broadly similar size. The relevance of CRP to such a range of disorders is unclear. Associations with ischaemic vascular disease depend considerably on conventional risk factors and other markers of inflammation.

FUNDING: British Heart Foundation, UK Medical Research Council, BUPA Foundation, and GlaxoSmithKline.

VL - 375 IS - 9709 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20031199?dopt=Abstract ER - TY - JOUR T1 - Lipoprotein-associated phospholipase A(2) and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies. JF - Lancet Y1 - 2010 A1 - Thompson, Alexander A1 - Gao, Pei A1 - Orfei, Lia A1 - Watson, Sarah A1 - Di Angelantonio, Emanuele A1 - Kaptoge, Stephen A1 - Ballantyne, Christie A1 - Cannon, Christopher P A1 - Criqui, Michael A1 - Cushman, Mary A1 - Hofman, Albert A1 - Packard, Chris A1 - Thompson, Simon G A1 - Collins, Rory A1 - Danesh, John KW - 1-Alkyl-2-acetylglycerophosphocholine Esterase KW - Blood Pressure KW - Coronary Disease KW - Female KW - Humans KW - Linear Models KW - Lipids KW - Male KW - Middle Aged KW - Prospective Studies KW - Risk Assessment KW - Risk Factors KW - Stroke KW - Systole AB -

BACKGROUND: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), an inflammatory enzyme expressed in atherosclerotic plaques, is a therapeutic target being assessed in trials of vascular disease prevention. We investigated associations of circulating Lp-PLA(2) mass and activity with risk of coronary heart disease, stroke, and mortality under different circumstances.

METHODS: With use of individual records from 79 036 participants in 32 prospective studies (yielding 17 722 incident fatal or non-fatal outcomes during 474 976 person-years at risk), we did a meta-analysis of within-study regressions to calculate risk ratios (RRs) per 1 SD higher value of Lp-PLA(2) or other risk factor. The primary outcome was coronary heart disease.

FINDINGS: Lp-PLA(2) activity and mass were associated with each other (r=0.51, 95% CI 0.47-0.56) and proatherogenic lipids. We noted roughly log-linear associations of Lp-PLA(2) activity and mass with risk of coronary heart disease and vascular death. RRs, adjusted for conventional risk factors, were: 1.10 (95% CI 1.05-1.16) with Lp-PLA(2) activity and 1.11 (1.07-1.16) with Lp-PLA(2) mass for coronary heart disease; 1.08 (0.97-1.20) and 1.14 (1.02-1.27) for ischaemic stroke; 1.16 (1.09-1.24) and 1.13 (1.05-1.22) for vascular mortality; and 1.10 (1.04-1.17) and 1.10 (1.03-1.18) for non-vascular mortality, respectively. RRs with Lp-PLA(2) did not differ significantly in people with and without initial stable vascular disease, apart from for vascular death with Lp-PLA(2) mass. Adjusted RRs for coronary heart disease were 1.10 (1.02-1.18) with non-HDL cholesterol and 1.10 (1.00-1.21) with systolic blood pressure.

INTERPRETATION: Lp-PLA(2) activity and mass each show continuous associations with risk of coronary heart disease, similar in magnitude to that with non-HDL cholesterol or systolic blood pressure in this population. Associations of Lp-PLA(2) mass and activity are not exclusive to vascular outcomes, and the vascular associations depend at least partly on lipids.

FUNDING: UK Medical Research Council, GlaxoSmithKline, and British Heart Foundation.

VL - 375 IS - 9725 U1 - https://www.ncbi.nlm.nih.gov/pubmed/20435228?dopt=Abstract ER - TY - JOUR T1 - Diabetes mellitus, fasting glucose, and risk of cause-specific death. JF - N Engl J Med Y1 - 2011 A1 - Rao Kondapally Seshasai, Sreenivasa A1 - Kaptoge, Stephen A1 - Thompson, Alexander A1 - Di Angelantonio, Emanuele A1 - Gao, Pei A1 - Sarwar, Nadeem A1 - Whincup, Peter H A1 - Mukamal, Kenneth J A1 - Gillum, Richard F A1 - Holme, Ingar A1 - Njølstad, Inger A1 - Fletcher, Astrid A1 - Nilsson, Peter A1 - Lewington, Sarah A1 - Collins, Rory A1 - Gudnason, Vilmundur A1 - Thompson, Simon G A1 - Sattar, Naveed A1 - Selvin, Elizabeth A1 - Hu, Frank B A1 - Danesh, John KW - Blood Glucose KW - Cause of Death KW - Diabetes Mellitus KW - Female KW - Humans KW - Hyperglycemia KW - Life Expectancy KW - Male KW - Middle Aged KW - Risk KW - Survival Analysis AB -

BACKGROUND: The extent to which diabetes mellitus or hyperglycemia is related to risk of death from cancer or other nonvascular conditions is uncertain.

METHODS: We calculated hazard ratios for cause-specific death, according to baseline diabetes status or fasting glucose level, from individual-participant data on 123,205 deaths among 820,900 people in 97 prospective studies.

RESULTS: After adjustment for age, sex, smoking status, and body-mass index, hazard ratios among persons with diabetes as compared with persons without diabetes were as follows: 1.80 (95% confidence interval [CI], 1.71 to 1.90) for death from any cause, 1.25 (95% CI, 1.19 to 1.31) for death from cancer, 2.32 (95% CI, 2.11 to 2.56) for death from vascular causes, and 1.73 (95% CI, 1.62 to 1.85) for death from other causes. Diabetes (vs. no diabetes) was moderately associated with death from cancers of the liver, pancreas, ovary, colorectum, lung, bladder, and breast. Aside from cancer and vascular disease, diabetes (vs. no diabetes) was also associated with death from renal disease, liver disease, pneumonia and other infectious diseases, mental disorders, nonhepatic digestive diseases, external causes, intentional self-harm, nervous-system disorders, and chronic obstructive pulmonary disease. Hazard ratios were appreciably reduced after further adjustment for glycemia measures, but not after adjustment for systolic blood pressure, lipid levels, inflammation or renal markers. Fasting glucose levels exceeding 100 mg per deciliter (5.6 mmol per liter), but not levels of 70 to 100 mg per deciliter (3.9 to 5.6 mmol per liter), were associated with death. A 50-year-old with diabetes died, on average, 6 years earlier than a counterpart without diabetes, with about 40% of the difference in survival attributable to excess nonvascular deaths.

CONCLUSIONS: In addition to vascular disease, diabetes is associated with substantial premature death from several cancers, infectious diseases, external causes, intentional self-harm, and degenerative disorders, independent of several major risk factors. (Funded by the British Heart Foundation and others.).

VL - 364 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21366474?dopt=Abstract ER - TY - JOUR T1 - Separate and combined associations of body-mass index and abdominal adiposity with cardiovascular disease: collaborative analysis of 58 prospective studies. JF - Lancet Y1 - 2011 A1 - Wormser, David A1 - Kaptoge, Stephen A1 - Di Angelantonio, Emanuele A1 - Wood, Angela M A1 - Pennells, Lisa A1 - Thompson, Alex A1 - Sarwar, Nadeem A1 - Kizer, Jorge R A1 - Lawlor, Debbie A A1 - Nordestgaard, Børge G A1 - Ridker, Paul A1 - Salomaa, Veikko A1 - Stevens, June A1 - Woodward, Mark A1 - Sattar, Naveed A1 - Collins, Rory A1 - Thompson, Simon G A1 - Whitlock, Gary A1 - Danesh, John KW - Age Factors KW - Blood Pressure KW - Body Mass Index KW - Cardiovascular Diseases KW - Cholesterol KW - Cholesterol, HDL KW - Diabetes Mellitus KW - Female KW - Humans KW - Male KW - Middle Aged KW - Obesity, Abdominal KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Assessment KW - Sex Factors KW - Smoking KW - Systole KW - Waist Circumference KW - Waist-Hip Ratio AB -

BACKGROUND: Guidelines differ about the value of assessment of adiposity measures for cardiovascular disease risk prediction when information is available for other risk factors. We studied the separate and combined associations of body-mass index (BMI), waist circumference, and waist-to-hip ratio with risk of first-onset cardiovascular disease.

METHODS: We used individual records from 58 cohorts to calculate hazard ratios (HRs) per 1 SD higher baseline values (4.56 kg/m(2) higher BMI, 12.6 cm higher waist circumference, and 0.083 higher waist-to-hip ratio) and measures of risk discrimination and reclassification. Serial adiposity assessments were used to calculate regression dilution ratios.

RESULTS: Individual records were available for 221,934 people in 17 countries (14,297 incident cardiovascular disease outcomes; 1.87 million person-years at risk). Serial adiposity assessments were made in up to 63,821 people (mean interval 5.7 years [SD 3.9]). In people with BMI of 20 kg/m(2) or higher, HRs for cardiovascular disease were 1.23 (95% CI 1.17-1.29) with BMI, 1.27 (1.20-1.33) with waist circumference, and 1.25 (1.19-1.31) with waist-to-hip ratio, after adjustment for age, sex, and smoking status. After further adjustment for baseline systolic blood pressure, history of diabetes, and total and HDL cholesterol, corresponding HRs were 1.07 (1.03-1.11) with BMI, 1.10 (1.05-1.14) with waist circumference, and 1.12 (1.08-1.15) with waist-to-hip ratio. Addition of information on BMI, waist circumference, or waist-to-hip ratio to a cardiovascular disease risk prediction model containing conventional risk factors did not importantly improve risk discrimination (C-index changes of -0.0001, -0.0001, and 0.0008, respectively), nor classification of participants to categories of predicted 10-year risk (net reclassification improvement -0.19%, -0.05%, and -0.05%, respectively). Findings were similar when adiposity measures were considered in combination. Reproducibility was greater for BMI (regression dilution ratio 0.95, 95% CI 0.93-0.97) than for waist circumference (0.86, 0.83-0.89) or waist-to-hip ratio (0.63, 0.57-0.70).

INTERPRETATION: BMI, waist circumference, and waist-to-hip ratio, whether assessed singly or in combination, do not importantly improve cardiovascular disease risk prediction in people in developed countries when additional information is available for systolic blood pressure, history of diabetes, and lipids.

FUNDING: British Heart Foundation and UK Medical Research Council.

VL - 377 IS - 9771 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21397319?dopt=Abstract ER - TY - JOUR T1 - Lipid-related markers and cardiovascular disease prediction. JF - JAMA Y1 - 2012 A1 - Di Angelantonio, Emanuele A1 - Gao, Pei A1 - Pennells, Lisa A1 - Kaptoge, Stephen A1 - Caslake, Muriel A1 - Thompson, Alexander A1 - Butterworth, Adam S A1 - Sarwar, Nadeem A1 - Wormser, David A1 - Saleheen, Danish A1 - Ballantyne, Christie M A1 - Psaty, Bruce M A1 - Sundström, Johan A1 - Ridker, Paul M A1 - Nagel, Dorothea A1 - Gillum, Richard F A1 - Ford, Ian A1 - Ducimetiere, Pierre A1 - Kiechl, Stefan A1 - Koenig, Wolfgang A1 - Dullaart, Robin P F A1 - Assmann, Gerd A1 - D'Agostino, Ralph B A1 - Dagenais, Gilles R A1 - Cooper, Jackie A A1 - Kromhout, Daan A1 - Onat, Altan A1 - Tipping, Robert W A1 - Gómez-de-la-Cámara, Agustín A1 - Rosengren, Annika A1 - Sutherland, Susan E A1 - Gallacher, John A1 - Fowkes, F Gerry R A1 - Casiglia, Edoardo A1 - Hofman, Albert A1 - Salomaa, Veikko A1 - Barrett-Connor, Elizabeth A1 - Clarke, Robert A1 - Brunner, Eric A1 - Jukema, J Wouter A1 - Simons, Leon A A1 - Sandhu, Manjinder A1 - Wareham, Nicholas J A1 - Khaw, Kay-Tee A1 - Kauhanen, Jussi A1 - Salonen, Jukka T A1 - Howard, William J A1 - Nordestgaard, Børge G A1 - Wood, Angela M A1 - Thompson, Simon G A1 - Boekholdt, S Matthijs A1 - Sattar, Naveed A1 - Packard, Chris A1 - Gudnason, Vilmundur A1 - Danesh, John KW - Aged KW - Biomarkers KW - Cardiovascular Diseases KW - Cholesterol, HDL KW - Cohort Studies KW - Female KW - Humans KW - Lipoproteins KW - Male KW - Middle Aged KW - Risk Assessment AB -

CONTEXT: The value of assessing various emerging lipid-related markers for prediction of first cardiovascular events is debated.

OBJECTIVE: To determine whether adding information on apolipoprotein B and apolipoprotein A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 to total cholesterol and high-density lipoprotein cholesterol (HDL-C) improves cardiovascular disease (CVD) risk prediction.

DESIGN, SETTING, AND PARTICIPANTS: Individual records were available for 165,544 participants without baseline CVD in 37 prospective cohorts (calendar years of recruitment: 1968-2007) with up to 15,126 incident fatal or nonfatal CVD outcomes (10,132 CHD and 4994 stroke outcomes) during a median follow-up of 10.4 years (interquartile range, 7.6-14 years).

MAIN OUTCOME MEASURES: Discrimination of CVD outcomes and reclassification of participants across predicted 10-year risk categories of low (<10%), intermediate (10%-<20%), and high (≥20%) risk.

RESULTS: The addition of information on various lipid-related markers to total cholesterol, HDL-C, and other conventional risk factors yielded improvement in the model's discrimination: C-index change, 0.0006 (95% CI, 0.0002-0.0009) for the combination of apolipoprotein B and A-I; 0.0016 (95% CI, 0.0009-0.0023) for lipoprotein(a); and 0.0018 (95% CI, 0.0010-0.0026) for lipoprotein-associated phospholipase A2 mass. Net reclassification improvements were less than 1% with the addition of each of these markers to risk scores containing conventional risk factors. We estimated that for 100,000 adults aged 40 years or older, 15,436 would be initially classified at intermediate risk using conventional risk factors alone. Additional testing with a combination of apolipoprotein B and A-I would reclassify 1.1%; lipoprotein(a), 4.1%; and lipoprotein-associated phospholipase A2 mass, 2.7% of people to a 20% or higher predicted CVD risk category and, therefore, in need of statin treatment under Adult Treatment Panel III guidelines.

CONCLUSION: In a study of individuals without known CVD, the addition of information on the combination of apolipoprotein B and A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 mass to risk scores containing total cholesterol and HDL-C led to slight improvement in CVD prediction.

VL - 307 IS - 23 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22797450?dopt=Abstract ER - TY - JOUR T1 - Glycated hemoglobin measurement and prediction of cardiovascular disease. JF - JAMA Y1 - 2014 A1 - Di Angelantonio, Emanuele A1 - Gao, Pei A1 - Khan, Hassan A1 - Butterworth, Adam S A1 - Wormser, David A1 - Kaptoge, Stephen A1 - Kondapally Seshasai, Sreenivasa Rao A1 - Thompson, Alex A1 - Sarwar, Nadeem A1 - Willeit, Peter A1 - Ridker, Paul M A1 - Barr, Elizabeth L M A1 - Khaw, Kay-Tee A1 - Psaty, Bruce M A1 - Brenner, Hermann A1 - Balkau, Beverley A1 - Dekker, Jacqueline M A1 - Lawlor, Debbie A A1 - Daimon, Makoto A1 - Willeit, Johann A1 - Njølstad, Inger A1 - Nissinen, Aulikki A1 - Brunner, Eric J A1 - Kuller, Lewis H A1 - Price, Jackie F A1 - Sundström, Johan A1 - Knuiman, Matthew W A1 - Feskens, Edith J M A1 - Verschuren, W M M A1 - Wald, Nicholas A1 - Bakker, Stephan J L A1 - Whincup, Peter H A1 - Ford, Ian A1 - Goldbourt, Uri A1 - Gómez-de-la-Cámara, Agustín A1 - Gallacher, John A1 - Simons, Leon A A1 - Rosengren, Annika A1 - Sutherland, Susan E A1 - Björkelund, Cecilia A1 - Blazer, Dan G A1 - Wassertheil-Smoller, Sylvia A1 - Onat, Altan A1 - Marín Ibañez, Alejandro A1 - Casiglia, Edoardo A1 - Jukema, J Wouter A1 - Simpson, Lara M A1 - Giampaoli, Simona A1 - Nordestgaard, Børge G A1 - Selmer, Randi A1 - Wennberg, Patrik A1 - Kauhanen, Jussi A1 - Salonen, Jukka T A1 - Dankner, Rachel A1 - Barrett-Connor, Elizabeth A1 - Kavousi, Maryam A1 - Gudnason, Vilmundur A1 - Evans, Denis A1 - Wallace, Robert B A1 - Cushman, Mary A1 - D'Agostino, Ralph B A1 - Umans, Jason G A1 - Kiyohara, Yutaka A1 - Nakagawa, Hidaeki A1 - Sato, Shinichi A1 - Gillum, Richard F A1 - Folsom, Aaron R A1 - van der Schouw, Yvonne T A1 - Moons, Karel G A1 - Griffin, Simon J A1 - Sattar, Naveed A1 - Wareham, Nicholas J A1 - Selvin, Elizabeth A1 - Thompson, Simon G A1 - Danesh, John KW - Aged KW - C-Reactive Protein KW - Cholesterol, HDL KW - Coronary Disease KW - Diabetes Mellitus KW - Female KW - Glycated Hemoglobin A KW - Humans KW - Male KW - Middle Aged KW - Predictive Value of Tests KW - Prospective Studies KW - Risk Assessment KW - Stroke AB -

IMPORTANCE: The value of measuring levels of glycated hemoglobin (HbA1c) for the prediction of first cardiovascular events is uncertain.

OBJECTIVE: To determine whether adding information on HbA1c values to conventional cardiovascular risk factors is associated with improvement in prediction of cardiovascular disease (CVD) risk.

DESIGN, SETTING, AND PARTICIPANTS: Analysis of individual-participant data available from 73 prospective studies involving 294,998 participants without a known history of diabetes mellitus or CVD at the baseline assessment.

MAIN OUTCOMES AND MEASURES: Measures of risk discrimination for CVD outcomes (eg, C-index) and reclassification (eg, net reclassification improvement) of participants across predicted 10-year risk categories of low (<5%), intermediate (5% to <7.5%), and high (≥ 7.5%) risk.

RESULTS: During a median follow-up of 9.9 (interquartile range, 7.6-13.2) years, 20,840 incident fatal and nonfatal CVD outcomes (13,237 coronary heart disease and 7603 stroke outcomes) were recorded. In analyses adjusted for several conventional cardiovascular risk factors, there was an approximately J-shaped association between HbA1c values and CVD risk. The association between HbA1c values and CVD risk changed only slightly after adjustment for total cholesterol and triglyceride concentrations or estimated glomerular filtration rate, but this association attenuated somewhat after adjustment for concentrations of high-density lipoprotein cholesterol and C-reactive protein. The C-index for a CVD risk prediction model containing conventional cardiovascular risk factors alone was 0.7434 (95% CI, 0.7350 to 0.7517). The addition of information on HbA1c was associated with a C-index change of 0.0018 (0.0003 to 0.0033) and a net reclassification improvement of 0.42 (-0.63 to 1.48) for the categories of predicted 10-year CVD risk. The improvement provided by HbA1c assessment in prediction of CVD risk was equal to or better than estimated improvements for measurement of fasting, random, or postload plasma glucose levels.

CONCLUSIONS AND RELEVANCE: In a study of individuals without known CVD or diabetes, additional assessment of HbA1c values in the context of CVD risk assessment provided little incremental benefit for prediction of CVD risk.

VL - 311 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24668104?dopt=Abstract ER - TY - JOUR T1 - Association of Cardiometabolic Multimorbidity With Mortality. JF - JAMA Y1 - 2015 A1 - Di Angelantonio, Emanuele A1 - Kaptoge, Stephen A1 - Wormser, David A1 - Willeit, Peter A1 - Butterworth, Adam S A1 - Bansal, Narinder A1 - O'Keeffe, Linda M A1 - Gao, Pei A1 - Wood, Angela M A1 - Burgess, Stephen A1 - Freitag, Daniel F A1 - Pennells, Lisa A1 - Peters, Sanne A A1 - Hart, Carole L A1 - Håheim, Lise Lund A1 - Gillum, Richard F A1 - Nordestgaard, Børge G A1 - Psaty, Bruce M A1 - Yeap, Bu B A1 - Knuiman, Matthew W A1 - Nietert, Paul J A1 - Kauhanen, Jussi A1 - Salonen, Jukka T A1 - Kuller, Lewis H A1 - Simons, Leon A A1 - van der Schouw, Yvonne T A1 - Barrett-Connor, Elizabeth A1 - Selmer, Randi A1 - Crespo, Carlos J A1 - Rodriguez, Beatriz A1 - Verschuren, W M Monique A1 - Salomaa, Veikko A1 - Svärdsudd, Kurt A1 - van der Harst, Pim A1 - Björkelund, Cecilia A1 - Wilhelmsen, Lars A1 - Wallace, Robert B A1 - Brenner, Hermann A1 - Amouyel, Philippe A1 - Barr, Elizabeth L M A1 - Iso, Hiroyasu A1 - Onat, Altan A1 - Trevisan, Maurizio A1 - D'Agostino, Ralph B A1 - Cooper, Cyrus A1 - Kavousi, Maryam A1 - Welin, Lennart A1 - Roussel, Ronan A1 - Hu, Frank B A1 - Sato, Shinichi A1 - Davidson, Karina W A1 - Howard, Barbara V A1 - Leening, Maarten J G A1 - Leening, Maarten A1 - Rosengren, Annika A1 - Dörr, Marcus A1 - Deeg, Dorly J H A1 - Kiechl, Stefan A1 - Stehouwer, Coen D A A1 - Nissinen, Aulikki A1 - Giampaoli, Simona A1 - Donfrancesco, Chiara A1 - Kromhout, Daan A1 - Price, Jackie F A1 - Peters, Annette A1 - Meade, Tom W A1 - Casiglia, Edoardo A1 - Lawlor, Debbie A A1 - Gallacher, John A1 - Nagel, Dorothea A1 - Franco, Oscar H A1 - Assmann, Gerd A1 - Dagenais, Gilles R A1 - Jukema, J Wouter A1 - Sundström, Johan A1 - Woodward, Mark A1 - Brunner, Eric J A1 - Khaw, Kay-Tee A1 - Wareham, Nicholas J A1 - Whitsel, Eric A A1 - Njølstad, Inger A1 - Hedblad, Bo A1 - Wassertheil-Smoller, Sylvia A1 - Engström, Gunnar A1 - Rosamond, Wayne D A1 - Selvin, Elizabeth A1 - Sattar, Naveed A1 - Thompson, Simon G A1 - Danesh, John KW - Adult KW - Aged KW - Comorbidity KW - Diabetes Mellitus KW - Female KW - Humans KW - Life Expectancy KW - Male KW - Middle Aged KW - Mortality KW - Myocardial Infarction KW - Risk Factors KW - Stroke AB -

IMPORTANCE: The prevalence of cardiometabolic multimorbidity is increasing.

OBJECTIVE: To estimate reductions in life expectancy associated with cardiometabolic multimorbidity.

DESIGN, SETTING, AND PARTICIPANTS: Age- and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689,300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128,843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499,808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates.

EXPOSURES: A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI).

MAIN OUTCOMES AND MEASURES: All-cause mortality and estimated reductions in life expectancy.

RESULTS: In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy.

CONCLUSIONS AND RELEVANCE: Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.

VL - 314 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26151266?dopt=Abstract ER - TY - JOUR T1 - Natriuretic peptides and integrated risk assessment for cardiovascular disease: an individual-participant-data meta-analysis. JF - Lancet Diabetes Endocrinol Y1 - 2016 A1 - Willeit, Peter A1 - Kaptoge, Stephen A1 - Welsh, Paul A1 - Butterworth, Adam A1 - Chowdhury, Rajiv A1 - Spackman, Sarah A1 - Pennells, Lisa A1 - Gao, Pei A1 - Burgess, Stephen A1 - Freitag, Daniel A1 - Sweeting, Michael A1 - Wood, Angela A1 - Cook, Nancy A1 - Judd, Suzanne A1 - Trompet, Stella A1 - Nambi, Vijay A1 - Olsen, Michael A1 - Everett, Brendan A1 - Kee, Frank A1 - Arnlöv, Johan A1 - Salomaa, Veikko A1 - Levy, Daniel A1 - Kauhanen, Jussi A1 - Laukkanen, Jari A1 - Kavousi, Maryam A1 - Ninomiya, Toshiharu A1 - Casas, Juan-Pablo A1 - Daniels, Lori A1 - Lind, Lars A1 - Kistorp, Caroline A1 - Rosenberg, Jens A1 - Mueller, Thomas A1 - Rubattu, Speranza A1 - Panagiotakos, Demosthenes A1 - Franco, Oscar A1 - de Lemos, James A1 - Luchner, Andreas A1 - Kizer, Jorge A1 - Kiechl, Stefan A1 - Salonen, Jukka A1 - Goya Wannamethee, S A1 - de Boer, Rudolf A1 - Nordestgaard, Børge A1 - Andersson, Jonas A1 - Jørgensen, Torben A1 - Melander, Olle A1 - Ballantyne, Christie A1 - DeFilippi, Christopher A1 - Ridker, Paul A1 - Cushman, Mary A1 - Rosamond, Wayne A1 - Thompson, Simon A1 - Gudnason, Vilmundur A1 - Sattar, Naveed A1 - Danesh, John A1 - Di Angelantonio, Emanuele KW - Aged KW - Biomarkers KW - Cardiovascular Diseases KW - Female KW - Humans KW - Male KW - Middle Aged KW - Natriuretic Peptide, Brain KW - Peptide Fragments KW - Prospective Studies KW - Risk Assessment AB -

BACKGROUND: Guidelines for primary prevention of cardiovascular diseases focus on prediction of coronary heart disease and stroke. We assessed whether or not measurement of N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration could enable a more integrated approach than at present by predicting heart failure and enhancing coronary heart disease and stroke risk assessment.

METHODS: In this individual-participant-data meta-analysis, we generated and harmonised individual-participant data from relevant prospective studies via both de-novo NT-proBNP concentration measurement of stored samples and collection of data from studies identified through a systematic search of the literature (PubMed, Scientific Citation Index Expanded, and Embase) for articles published up to Sept 4, 2014, using search terms related to natriuretic peptide family members and the primary outcomes, with no language restrictions. We calculated risk ratios and measures of risk discrimination and reclassification across predicted 10 year risk categories (ie, <5%, 5% to <7·5%, and ≥7·5%), adding assessment of NT-proBNP concentration to that of conventional risk factors (ie, age, sex, smoking status, systolic blood pressure, history of diabetes, and total and HDL cholesterol concentrations). Primary outcomes were the combination of coronary heart disease and stroke, and the combination of coronary heart disease, stroke, and heart failure.

FINDINGS: We recorded 5500 coronary heart disease, 4002 stroke, and 2212 heart failure outcomes among 95 617 participants without a history of cardiovascular disease in 40 prospective studies. Risk ratios (for a comparison of the top third vs bottom third of NT-proBNP concentrations, adjusted for conventional risk factors) were 1·76 (95% CI 1·56-1·98) for the combination of coronary heart disease and stroke and 2·00 (1·77-2·26) for the combination of coronary heart disease, stroke, and heart failure. Addition of information about NT-proBNP concentration to a model containing conventional risk factors was associated with a C-index increase of 0·012 (0·010-0·014) and a net reclassification improvement of 0·027 (0·019-0·036) for the combination of coronary heart disease and stroke and a C-index increase of 0·019 (0·016-0·022) and a net reclassification improvement of 0·028 (0·019-0·038) for the combination of coronary heart disease, stroke, and heart failure.

INTERPRETATION: In people without baseline cardiovascular disease, NT-proBNP concentration assessment strongly predicted first-onset heart failure and augmented coronary heart disease and stroke prediction, suggesting that NT-proBNP concentration assessment could be used to integrate heart failure into cardiovascular disease primary prevention.

FUNDING: British Heart Foundation, Austrian Science Fund, UK Medical Research Council, National Institute for Health Research, European Research Council, and European Commission Framework Programme 7.

VL - 4 IS - 10 ER - TY - JOUR T1 - Equalization of four cardiovascular risk algorithms after systematic recalibration: individual-participant meta-analysis of 86 prospective studies. JF - Eur Heart J Y1 - 2018 A1 - Pennells, Lisa A1 - Kaptoge, Stephen A1 - Wood, Angela A1 - Sweeting, Mike A1 - Zhao, Xiaohui A1 - White, Ian A1 - Burgess, Stephen A1 - Willeit, Peter A1 - Bolton, Thomas A1 - Moons, Karel G M A1 - van der Schouw, Yvonne T A1 - Selmer, Randi A1 - Khaw, Kay-Tee A1 - Gudnason, Vilmundur A1 - Assmann, Gerd A1 - Amouyel, Philippe A1 - Salomaa, Veikko A1 - Kivimaki, Mika A1 - Nordestgaard, Børge G A1 - Blaha, Michael J A1 - Kuller, Lewis H A1 - Brenner, Hermann A1 - Gillum, Richard F A1 - Meisinger, Christa A1 - Ford, Ian A1 - Knuiman, Matthew W A1 - Rosengren, Annika A1 - Lawlor, Debbie A A1 - Völzke, Henry A1 - Cooper, Cyrus A1 - Marín Ibañez, Alejandro A1 - Casiglia, Edoardo A1 - Kauhanen, Jussi A1 - Cooper, Jackie A A1 - Rodriguez, Beatriz A1 - Sundström, Johan A1 - Barrett-Connor, Elizabeth A1 - Dankner, Rachel A1 - Nietert, Paul J A1 - Davidson, Karina W A1 - Wallace, Robert B A1 - Blazer, Dan G A1 - Björkelund, Cecilia A1 - Donfrancesco, Chiara A1 - Krumholz, Harlan M A1 - Nissinen, Aulikki A1 - Davis, Barry R A1 - Coady, Sean A1 - Whincup, Peter H A1 - Jørgensen, Torben A1 - Ducimetiere, Pierre A1 - Trevisan, Maurizio A1 - Engström, Gunnar A1 - Crespo, Carlos J A1 - Meade, Tom W A1 - Visser, Marjolein A1 - Kromhout, Daan A1 - Kiechl, Stefan A1 - Daimon, Makoto A1 - Price, Jackie F A1 - Gómez de la Cámara, Agustin A1 - Wouter Jukema, J A1 - Lamarche, Benoît A1 - Onat, Altan A1 - Simons, Leon A A1 - Kavousi, Maryam A1 - Ben-Shlomo, Yoav A1 - Gallacher, John A1 - Dekker, Jacqueline M A1 - Arima, Hisatomi A1 - Shara, Nawar A1 - Tipping, Robert W A1 - Roussel, Ronan A1 - Brunner, Eric J A1 - Koenig, Wolfgang A1 - Sakurai, Masaru A1 - Pavlovic, Jelena A1 - Gansevoort, Ron T A1 - Nagel, Dorothea A1 - Goldbourt, Uri A1 - Barr, Elizabeth L M A1 - Palmieri, Luigi A1 - Njølstad, Inger A1 - Sato, Shinichi A1 - Monique Verschuren, W M A1 - Varghese, Cherian V A1 - Graham, Ian A1 - Onuma, Oyere A1 - Greenland, Philip A1 - Woodward, Mark A1 - Ezzati, Majid A1 - Psaty, Bruce M A1 - Sattar, Naveed A1 - Jackson, Rod A1 - Ridker, Paul M A1 - Cook, Nancy R A1 - D'Agostino, Ralph B A1 - Thompson, Simon G A1 - Danesh, John A1 - Di Angelantonio, Emanuele AB -

Aims: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after 'recalibration', a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied.

Methods and results: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at 'high' 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29-39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22-24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44-51 such individuals using original algorithms, in contrast to 37-39 individuals with recalibrated algorithms.

Conclusion: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need.

ER - TY - JOUR T1 - Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies. JF - Lancet Y1 - 2018 A1 - Wood, Angela M A1 - Kaptoge, Stephen A1 - Butterworth, Adam S A1 - Willeit, Peter A1 - Warnakula, Samantha A1 - Bolton, Thomas A1 - Paige, Ellie A1 - Paul, Dirk S A1 - Sweeting, Michael A1 - Burgess, Stephen A1 - Bell, Steven A1 - Astle, William A1 - Stevens, David A1 - Koulman, Albert A1 - Selmer, Randi M A1 - Verschuren, W M Monique A1 - Sato, Shinichi A1 - Njølstad, Inger A1 - Woodward, Mark A1 - Salomaa, Veikko A1 - Nordestgaard, Børge G A1 - Yeap, Bu B A1 - Fletcher, Astrid A1 - Melander, Olle A1 - Kuller, Lewis H A1 - Balkau, Beverley A1 - Marmot, Michael A1 - Koenig, Wolfgang A1 - Casiglia, Edoardo A1 - Cooper, Cyrus A1 - Arndt, Volker A1 - Franco, Oscar H A1 - Wennberg, Patrik A1 - Gallacher, John A1 - de la Cámara, Agustin Gómez A1 - Völzke, Henry A1 - Dahm, Christina C A1 - Dale, Caroline E A1 - Bergmann, Manuela M A1 - Crespo, Carlos J A1 - van der Schouw, Yvonne T A1 - Kaaks, Rudolf A1 - Simons, Leon A A1 - Lagiou, Pagona A1 - Schoufour, Josje D A1 - Boer, Jolanda M A A1 - Key, Timothy J A1 - Rodriguez, Beatriz A1 - Moreno-Iribas, Conchi A1 - Davidson, Karina W A1 - Taylor, James O A1 - Sacerdote, Carlotta A1 - Wallace, Robert B A1 - Quiros, J Ramon A1 - Tumino, Rosario A1 - Blazer, Dan G A1 - Linneberg, Allan A1 - Daimon, Makoto A1 - Panico, Salvatore A1 - Howard, Barbara A1 - Skeie, Guri A1 - Strandberg, Timo A1 - Weiderpass, Elisabete A1 - Nietert, Paul J A1 - Psaty, Bruce M A1 - Kromhout, Daan A1 - Salamanca-Fernandez, Elena A1 - Kiechl, Stefan A1 - Krumholz, Harlan M A1 - Grioni, Sara A1 - Palli, Domenico A1 - Huerta, José M A1 - Price, Jackie A1 - Sundström, Johan A1 - Arriola, Larraitz A1 - Arima, Hisatomi A1 - Travis, Ruth C A1 - Panagiotakos, Demosthenes B A1 - Karakatsani, Anna A1 - Trichopoulou, Antonia A1 - Kühn, Tilman A1 - Grobbee, Diederick E A1 - Barrett-Connor, Elizabeth A1 - van Schoor, Natasja A1 - Boeing, Heiner A1 - Overvad, Kim A1 - Kauhanen, Jussi A1 - Wareham, Nick A1 - Langenberg, Claudia A1 - Forouhi, Nita A1 - Wennberg, Maria A1 - Després, Jean-Pierre A1 - Cushman, Mary A1 - Cooper, Jackie A A1 - Rodriguez, Carlos J A1 - Sakurai, Masaru A1 - Shaw, Jonathan E A1 - Knuiman, Matthew A1 - Voortman, Trudy A1 - Meisinger, Christa A1 - Tjønneland, Anne A1 - Brenner, Hermann A1 - Palmieri, Luigi A1 - Dallongeville, Jean A1 - Brunner, Eric J A1 - Assmann, Gerd A1 - Trevisan, Maurizio A1 - Gillum, Richard F A1 - Ford, Ian A1 - Sattar, Naveed A1 - Lazo, Mariana A1 - Thompson, Simon G A1 - Ferrari, Pietro A1 - Leon, David A A1 - Smith, George Davey A1 - Peto, Richard A1 - Jackson, Rod A1 - Banks, Emily A1 - Di Angelantonio, Emanuele A1 - Danesh, John AB -

BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease.

METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose-response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th-95th percentile 1·04-13·5]) from 71 011 participants from 37 studies.

FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10-1·17), coronary disease excluding myocardial infarction (1·06, 1·00-1·11), heart failure (1·09, 1·03-1·15), fatal hypertensive disease (1·24, 1·15-1·33); and fatal aortic aneurysm (1·15, 1·03-1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91-0·97). In comparison to those who reported drinking >0-≤100 g per week, those who reported drinking >100-≤200 g per week, >200-≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1-2 years, or 4-5 years, respectively.

INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines.

FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

VL - 391 IS - 10129 ER -