Sanne A.E. Peters

Common Carotid Intima-Media Thickness Measurements in Cardiovascular Risk Prediction: A Meta-analysis

CONTEXT The evidence that measurement of the common carotid intima-media thickness (CIMT) improves the risk scores in prediction of the absolute risk of cardiovascular events is inconsistent. OBJECTIVE To determine whether common CIMT has added value in 10-year risk prediction of first-time myocardial infarctions or strokes, above that of the Framingham Risk Score. DATA SOURCES Relevant studies were identified through literature searches of databases (PubMed from 1950 to June 2012 and EMBASE from 1980 to June 2012) and expert opinion. STUDY SELECTION Studies were included if participants were drawn from the general population, common CIMT was measured at baseline, and individuals were followed up for first-time myocardial infarction or stroke. DATA EXTRACTION Individual data were combined into 1 data set and an individual participant data meta-analysis was performed on individuals without existing cardiovascular disease. RESULTS We included 14 population-based cohorts contributing data for 45,828 individuals. During a median follow-up of 11 years, 4007 first-time myocardial infarctions or strokes occurred. We first refitted the risk factors of the Framingham Risk Score and then extended the model with common CIMT measurements to estimate the absolute 10-year risks to develop a first-time myocardial infarction or stroke in both models. The C statistic of both models was similar (0.757; 95% CI, 0.749-0.764; and 0.759; 95% CI, 0.752-0.766). The net reclassification improvement with the addition of common CIMT was small (0.8%; 95% CI, 0.1%-1.6%). In those at intermediate risk, the net reclassification improvement was 3.6% in all individuals (95% CI, 2.7%-4.6%) and no differences between men and women. CONCLUSION The addition of common CIMT measurements to the Framingham Risk Score was associated with small improvement in 10-year risk prediction of first-time myocardial infarction or stroke, but this improvement is unlikely to be of clinical importance.

Improvements in risk stratification for the occurrence of cardiovascular disease by imaging subclinical atherosclerosis: a systematic review

Context Imaging for subclinical atherosclerosis on top of conventional risk factor assessment may improve risk prediction for the occurrence of cardiovascular disease events in asymptomatic individuals. Objective To systematically review the available evidence on this issue. Data Sources PubMed MEDLINE was systematically searched on 7 September 2011. Study selection Studies were included that evaluated the added value of flow mediated dilation (FMD), carotid intima-media thickness (CIMT), carotid plaques and/or coronary artery calcification (CAC) scoring in the prediction of risk for developing fatal or non-fatal cardiovascular events. Data extraction Data on general study characteristics and the added predictive performance of imaging markers in terms of discrimination, calibration and (re)classification were extracted. Results 25 studies were selected that provided information on added predictive value of FMD (n=2), CIMT (n=12), carotid plaques (n=6) and/or CAC (n=9). Heterogeneity existed across studies in the conventional risk models that were used and in the measurements of the imaging marker. The added predictive value, quantified by the difference in c-index, of FMD, CIMT, carotid plaques or CAC ranged from 0.00 to 0.01 for FMD, from 0.00 to 0.03 for CIMT, from 0.01 to 0.05 for carotid plaque and from 0.05 to 0.13 for CAC. The reported net reclassification improvement (NRI) by the imaging markers ranged from −1.4% to 12% for CIMT, 8% to 11% for carotid plaques, 14% to 25% for CAC and 29% for FMD). Although the definition of intermediate cardiovascular risk varied across studies, the NRI was the highest in those at intermediate cardiovascular risk. Conclusions Published evidence on the added value of atherosclerosis imaging varies across the different markers, with limited evidence for FMD and considerable evidence for CIMT, carotid plaque and CAC. The added predictive value of additional screening may be primarily found in asymptomatic individuals at intermediate cardiovascular risk. Additional research in asymptomatic individuals is needed to quantify the cost effectiveness and impact of imaging for subclinical atherosclerosis on cardiovascular risk factor management and patient outcomes.

Association of Cardiometabolic Multimorbidity With Mortality.

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.

Sex differences in cardiovascular risk factors and disease prevention

Cardiovascular disease (CVD) has been seen as a mens disease for decades, however it is more common in women than in men. It is generally assumed in medicine that the effects of the major risk factors (RF) on CVD outcomes are the same in women as in men. Recent evidence has emerged that recognizes new, potentially independent, CVD RF exclusive to women. In particular, common disorders of pregnancy, such as gestational hypertension and diabetes, as well as frequently occurring endocrine disorders in women of reproductive age (e.g. polycystic ovary syndrome (PCOS) and early menopause) are associated with accelerated development of CVD and impaired CVD-free survival. With the recent availability of prospective studies comprising men and women, the equivalency of major RF prevalence and effects on CVD between men and women can be examined. Furthermore, female-specific RFs might be identified enabling early detection of apparently healthy women with a high lifetime risk of CVD. Therefore, we examined the available literature regarding the prevalence and effects of the traditional major RFs for CVD in men and women. This included large prospective cohort studies, cross-sectional studies and registries, as randomised trials are lacking. Furthermore, a literature search was performed to examine the impact of female-specific RFs on the traditional RFs and the occurrence of CVD. We found that the effects of elevated blood pressure, overweight and obesity, and elevated cholesterol on CVD outcomes are largely similar between women and men, however prolonged smoking is significantly more hazardous for women than for men. With respect to female-specific RF only associations (and no absolute risk data) could be found between preeclampsia, gestational diabetes and menopause onset with the occurrence of CVD. This review shows that CVD is the main cause of death in men and women, however the prevalence is higher in women. Determination of the CV risk profile should take into account that there are differences in impact of major CV RF leading to a worse outcome in women. Lifestyle interventions and awareness in women needs more consideration. Furthermore, there is accumulating evidence that female-specific RF are of influence on the impact of major RF and on the onset of CVD. Attention for female specific RF may enable early detection and intervention in apparently healthy women. Studies are needed on how to implement the added RFs in current risk assessment and management strategies to maximize benefit and cost-effectiveness specific in women.

Risk of all-cause mortality and vascular events in women versus men with type 1 diabetes: a systematic review and meta-analysis

BACKGROUND Studies have suggested sex differences in the mortality rate associated with type 1 diabetes. We did a meta-analysis to provide reliable estimates of any sex differences in the effect of type 1 diabetes on risk of all-cause mortality and cause-specific outcomes. METHODS We systematically searched PubMed for studies published between Jan 1, 1966, and Nov 26, 2014. Selected studies reported sex-specific estimates of the standardised mortality ratio (SMR) or hazard ratios associated with type 1 diabetes, either for all-cause mortality or cause-specific outcomes. We used random effects meta-analyses with inverse variance weighting to obtain sex-specific SMRs and their pooled ratio (women to men) for all-cause mortality, for mortality from cardiovascular disease, renal disease, cancer, the combined outcome of accident and suicide, and from incident coronary heart disease and stroke associated with type 1 diabetes. FINDINGS Data from 26 studies including 214 114 individuals and 15 273 events were included. The pooled women-to-men ratio of the SMR for all-cause mortality was 1·37 (95% CI 1·21-1·56), for incident stroke 1·37 (1·03-1·81), for fatal renal disease 1·44 (1·02-2·05), and for fatal cardiovascular diseases 1·86 (1·62-2·15). For incident coronary heart disease the sex difference was more extreme; the pooled women-to-men ratio of the SMR was 2·54 (95% CI 1·80-3·60). No evidence suggested a sex difference for mortality associated with type 1 diabetes from cancer, or accident and suicide. INTERPRETATION Women with type 1 diabetes have a roughly 40% greater excess risk of all-cause mortality, and twice the excess risk of fatal and nonfatal vascular events, compared with men with type 1 diabetes. FUNDING None.

Smoking as a Risk Factor for Stroke in Women Compared With Men: A Systematic Review and Meta-analysis of 81 Cohorts, Including 3 980 359 Individuals and 42 401 Strokes

Background and Purpose— It is currently unknown whether the excess risk of stroke by smoking is the same for women and men. We performed a systematic review and meta-analysis to estimate the effect of smoking on stroke in women compared with men. Methods— PubMed MEDLINE was systematically searched for prospective population-based cohort studies published between January 1, 1966, and January 26, 2013. Studies that presented sex-specific estimates of the relative risk of stroke comparing current smoking with nonsmoking and its associated variability were selected. The sex-specific relative risks and their ratio (RRR), comparing women with men, were pooled using random-effects meta-analysis with inverse variance weighting. Similarly, the RRR for former versus never smoking was pooled. Results— Data from 81 prospective cohort studies that included 3 980 359 individuals and 42 401 strokes were available. Smoking was an independent risk factor for stroke in both sexes. Overall, the pooled multiple-adjusted RRR indicated a similar risk of stroke associated with smoking in women compared with men (RRR, 1.06 [95% confidence interval, 0.99–1.13]). In a regional analysis, there was evidence of a more harmful effect of smoking in women than in men in Western (RRR, 1.10 [1.02–1.18)] but not in Asian (RRR, 0.97 [0.87–1.09]) populations. Compared with never-smokers, the beneficial effects of quitting smoking among former smokers on stroke risk were similar between the sexes (RRR, 1.10 [0.99–1.22]). Conclusions— Compared with nonsmokers, the excess risk of stroke is at least as great among women who smoke compared with men who smoke.

Type 2 Diabetes as a Risk Factor for Dementia in Women Compared With Men: A Pooled Analysis of 2.3 Million People Comprising More Than 100,000 Cases of Dementia

OBJECTIVE Type 2 diabetes confers a greater excess risk of cardiovascular disease in women than in men. Diabetes is also a risk factor for dementia, but whether the association is similar in women and men remains unknown. We performed a meta-analysis of unpublished data to estimate the sex-specific relationship between women and men with diabetes with incident dementia. RESEARCH DESIGN AND METHODS A systematic search identified studies published prior to November 2014 that had reported on the prospective association between diabetes and dementia. Study authors contributed unpublished sex-specific relative risks (RRs) and 95% CIs on the association between diabetes and all dementia and its subtypes. Sex-specific RRs and the women-to-men ratio of RRs (RRRs) were pooled using random-effects meta-analyses. RESULTS Study-level data from 14 studies, 2,310,330 individuals, and 102,174 dementia case patients were included. In multiple-adjusted analyses, diabetes was associated with a 60% increased risk of any dementia in both sexes (women: pooled RR 1.62 [95% CI 1.45–1.80]; men: pooled RR 1.58 [95% CI 1.38–1.81]). The diabetes-associated RRs for vascular dementia were 2.34 (95% CI 1.86–2.94) in women and 1.73 (95% CI 1.61–1.85) in men, and for nonvascular dementia, the RRs were 1.53 (95% CI 1.35–1.73) in women and 1.49 (95% CI 1.31–1.69) in men. Overall, women with diabetes had a 19% greater risk for the development of vascular dementia than men (multiple-adjusted RRR 1.19 [95% CI 1.08–1.30]; P < 0.001). CONCLUSIONS Individuals with type 2 diabetes are at ∼60% greater risk for the development of dementia compared with those without diabetes. For vascular dementia, but not for nonvascular dementia, the additional risk is greater in women.

Atrial fibrillation as risk factor for cardiovascular disease and death in women compared with men: systematic review and meta-analysis of cohort studies

Objective To determine whether atrial fibrillation is a stronger risk factor for cardiovascular disease and death in women compared with men. Design Meta-analysis of cohort studies. Data sources Studies published between January 1966 and March 2015, identified through a systematic search of Medline and Embase and review of references. Eligibility for selecting studies Cohort studies with a minimum of 50 participants with and 50 without atrial fibrillation that reported sex specific associations between atrial fibrillation and all cause mortality, cardiovascular mortality, stroke, cardiac events (cardiac death and non-fatal myocardial infarction), and heart failure. Data extraction Two independent reviewers extracted study characteristics and maximally adjusted sex specific relative risks. Inverse variance weighted random effects meta-analysis was used to pool sex specific relative risks and their ratio. Results 30 studies with 4 371 714 participants were identified. Atrial fibrillation was associated with a higher risk of all cause mortality in women (ratio of relative risks for women compared with men 1.12, 95% confidence interval 1.07 to 1.17) and a significantly stronger risk of stroke (1.99, 1.46 to 2.71), cardiovascular mortality (1.93, 1.44 to 2.60), cardiac events (1.55, 1.15 to 2.08), and heart failure (1.16, 1.07 to 1.27). Results were broadly consistent in sensitivity analyses. Conclusion Atrial fibrillation is a stronger risk factor for cardiovascular disease and death in women compared with men, though further research would be needed to determine any causality.

Carotid intima–media thickness: a suitable alternative for cardiovascular risk as outcome?

Background: Surrogate markers for cardiovascular disease might be of great value in observational research, clinical trials, and clinical practice. Carotid intima–media thickness (CIMT) is probably the most commonly used marker for atherosclerotic disease as an alternative for cardiovascular morbidity and mortality. A suitable marker for atherosclerosis, however, should meet several criteria before it can be validly used. Methods and results: We reviewed the literature following a set of criteria for a surrogate marker. These include a comparison with a ‘gold standard’; adequate reproducibility; cross-sectional relations with established risk factors and prevalent disease; relations with severity of atherosclerosis elsewhere in the arterial system; relations with the occurrence with future events; ability for a biomarker to change over time; ability to be affected by interventions over time; and relations between change over time in biomarker level and change in risk. A large number of studies from a variety of populations provide evidence for the validity of CIMT as a suitable measure of atherosclerotic disease. Data on the relation between change in CIMT and change in risk, however, is much sparser. Conclusion: CIMT progression meets the criteria of a surrogate for cardiovascular disease endpoints and may be considered as a valid alternative for cardiovascular events as outcome. Further studies should examine the association between changes in CIMT and changes in risk for future events.

Multiple imputation of missing repeated outcome measurements did not add to linear mixed-effects models

OBJECTIVE To assess the added value of multiple imputation (MI) of missing repeated outcomes measures in longitudinal data sets analyzed with linear mixed-effects (LME) models. STUDY DESIGN AND SETTING Data were used from a trial on the effects of Rosuvastatin on rate of change in carotid intima-media thickness (CIMT). The reference treatment effect was derived from a complete data set. Scenarios and proportions of missing values in CIMT measurements were applied and LME analyses were used before and after MI. The added value of MI, in terms of bias and precision, was assessed using the mean-squared error (MSE) of the treatment effects and coverage of the 95% confidence interval. RESULTS The reference treatment effect was -0.0177 mm/y. The MSEs for LME analysis without and with MI were similar in scenarios with up to 40% missing values. Coverage was large in all scenarios and was similar for LME with and without MI. CONCLUSION Our study empirically shows that MI of missing end point data before LME analyses does not increase precision in the estimated rate of change in the end point. Hence, MI had no added value in this setting and standard LME modeling remains the method of choice.