Delaying and reversing frailty: a systematic review of primary care interventions.

BACKGROUND: Recommendations for routine frailty screening in general practice are increasing as frailty prevalence grows. In England, frailty identification became a contractual requirement in 2017. However, there is little guidance on the most effective and practical interventions once frailty has been identified. AIM: To assess the comparative effectiveness and ease of implementation of frailty interventions in primary care. DESIGN AND SETTING: A systematic review of frailty interventions in primary care. METHOD: Scientific databases were searched from inception to May 2017 for randomised controlled trials or cohort studies with control groups on primary care frailty interventions. Screening methods, interventions, and outcomes were analysed in included studies. Effectiveness was scored in terms of change of frailty status or frailty indicators and ease of implementation in terms of human resources, marginal costs, and time requirements. RESULTS: A total of 925 studies satisfied search criteria and 46 were included. There were 15 690 participants (median study size was 160 participants). Studies reflected a broad heterogeneity. There were 17 different frailty screening methods. Of the frailty interventions, 23 involved physical activity and other interventions involved health education, nutrition supplementation, home visits, hormone supplementation, and counselling. A significant improvement of frailty status was demonstrated in 71% (n = 10) of studies and of frailty indicators in 69% (n=22) of studies where measured. Interventions with both muscle strength training and protein supplementation were consistently placed highest for effectiveness and ease of implementation. CONCLUSION: A combination of muscle strength training and protein supplementation was the most effective intervention to delay or reverse frailty and the easiest to implement in primary care. A map of interventions was created that can be used to inform choices for managing frailty.

Simplifying the audit of risk factor recording and control: A report from an international study in 11 countries.

BACKGROUND: To simplify the assessment of the recording and control of coronary heart disease risk factors in different countries and regions. DESIGN: The SUrvey of Risk Factors (SURF) is an international clinical audit. METHODS: Data on consecutive patients with established coronary heart disease from countries in Europe, Asia and the Middle East were collected on a one-page collection sheet or electronically during routine clinic visits. Information on demographics, diagnostic category, risk factors, physical and laboratory measurements, and medications were included and key variables summarized in a Cardiovascular Health Index Score. RESULTS: Coronary heart disease patients (N = 10,186; 29% women) were enrolled from 79 centres in 11 countries. Recording of risk factors varied considerably: smoking was recorded in over 98% of subjects, while about 20% lacked data on laboratory measurements relevant to cardiovascular disease risk. Sixteen per cent of participants reported smoking, 29% were obese, and 46% had abdominal obesity. Sixty per cent of participants had blood pressure <140/90 mmHg (140/80 mmHg for diabetics), 48% had HbA1c<7%, 30% had low-density lipoprotein <1.8 mmol/l and 17% had a good cardiovascular health index score. There were substantial regional variations. Less than 3% of patients attended cardiac rehabilitation in Asia or the Middle East, compared with 45% in Europe. In Asia, 15% of patients had low-density lipoprotein cholesterol <1.8 mmol/l compared with 33% in Europe and 36% in the Middle East. Variations in medications were noted, with lower use of statins in Asia. CONCLUSIONS: SURF proved to be practical in daily practice. Results indicated poor control of risk factors with substantial variation between countries, calling for development and implementation of clinical standards of secondary prevention of coronary heart disease.

Cardiovascular risk estimation in older persons: SCORE O.P.

AIMS: Estimation of cardiovascular disease risk, using SCORE (Systematic COronary Risk Evaluation) is recommended by European guidelines on cardiovascular disease prevention. Risk estimation is inaccurate in older people. We hypothesized that this may be due to the assumption, inherent in current risk estimation systems, that risk factors function similarly in all age groups. We aimed to derive and validate a risk estimation function, SCORE O.P., solely from data from individuals aged 65 years and older. METHODS AND RESULTS: 20,704 men and 20,121 women, aged 65 and over and without pre-existing coronary disease, from four representative, prospective studies of the general population were included. These were Italian, Belgian and Danish studies (from original SCORE dataset) and the CONOR (Cohort of Norway) study. The variables which remained statistically significant in Cox proportional hazards model and were included in the SCORE O.P. model were: age, total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, smoking status and diabetes. SCORE O.P. showed good discrimination; area under receiver operator characteristic curve (AUROC) 0.74 (95% confidence interval: 0.73 to 0.75). Calibration was also reasonable, Hosmer-Lemeshow goodness of fit test: 17.16 (men), 22.70 (women). Compared with the original SCORE function extrapolated to the ≥65 years age group discrimination improved, p = 0.05 (men), p < 0.001 (women). Simple risk charts were constructed. On simulated external validation, performed using 10-fold cross validation, AUROC was 0.74 and predicted/observed ratio was 1.02. CONCLUSION: SCORE O.P. provides improved accuracy in risk estimation in older people and may reduce excessive use of medication in this vulnerable population.

Determinants of risk factor control in subjects with coronary heart disease: a report from the EUROASPIRE III investigators.

The EUROASPIRE audits of risk factor control have indicated that, even in those with established coronary heart disease, risk factor control remains poor. We therefore analysed the EUROASPRE III data set to establish the factors associated with success or failure in risk factor control in order to inform future risk factor management strategies. University education, attendance at a specialist cardiology clinic, and participation in a cardiac rehabilitation programme were associated with improved risk factor control. Risk factor control was poorer in women, those with diabetes, and those undergoing coronary artery bypass surgery as opposed to medical therapy or percutaneous coronary intervention. Increasing age, depression, and anxiety were not associated with poorer risk factor control.

Residual risk of cardiovascular mortality in patients with coronary heart disease: the EUROASPIRE risk categories.

BACKGROUND: The EUROASPIRE I, II and III surveys revealed high prevalences of modifiable risk factors in the high priority group of coronary patients all over Europe. The potential to further reduce coronary heart disease (CHD) morbidity and mortality rates is still considerable. We report here on the relative risk of cardiovascular disease (CVD) death associated with common modifiable risk factor levels based on the mortality follow-up of patients participating in the first two EUROASPIRE surveys. We also present a novel simple risk classification system (ERC) that can be used in the management of patients with existing CHD. METHODS: The study cohort consisted of a consecutive sample of CHD patients aged ≤ 70 years from 12 European countries. Baseline data gathered in 1995-2000 through standardized methods, were linked to cardiovascular mortality in 5216 patients according to an accelerated failure time model. RESULTS: During 28,143 person-years of follow-up, 332 patients died from cardiovascular disease denoting a CVD mortality risk of 12.3 per 1000 person-years in men and 10.2 per 1000 person-years in women. In multivariate analysis, fasting glucose, total cholesterol and smoking emerged as the strongest independent modifiable predictors of cardiovascular mortality. CONCLUSIONS: The results of the mortality follow-up of the EUROASPIRE I and II CHD patients emphasize the continuing risk from elevated glucose and total cholesterol levels and underline the importance of smoking cessation in secondary prevention. The ERC risk tool that we developed may prove helpful to obtain these goals in the setting of secondary prevention.

Dyslipidemias in the prevention of cardiovascular disease: risks and causality.

Atherosclerotic cardiovascular disease is now the major global cause of death, despite reductions in CVD deaths in developed societies. Dyslipidemias are a major contributor, but the mass occurrence of CVD relates to the combined effects of hyperlipidemia, hypertension, and smoking. Total blood cholesterol and LDL-cholesterol relate to CVD risk in an independent and graded manner and fulfill the criteria for causality. Therapeutic reduction of these lipid fractions is associated with improved outcomes. There is good evidence that HDL-cholesterol, triglycerides, and Lp(a) relate to CVD although the evidence for a causal relationship is weaker. The HDL association with CVD is largely independent of other risk factors whereas triglycerides may be more important as signaling a need to look intensively for other measures of risk such as central obesity, hypertension, low HDL-cholesterol, and glucose intolerance. Lp(a) is an inherited risk marker. The benefit of lowering it is uncertain, but it may be that its impact on risk is attenuated if LDL-cholesterol is low.

Do novel biomarkers add to existing scores of total cardiovascular risk?

While cardiovascular disease and certain other conditions are considered to confer a high or very high risk of cardiovascular events, the asymptomatic population can be subdivided in different categories of total CV risk using risk models; this allows the clinician to adapt the intensity of preventive strategies accordingly. Risk models, such as that based on the US Framingham Study and the SCORE model, based on European cohorts, estimate risk according to the presence of risk factors, including age, gender, smoking habits, systolic blood pressure, and cholesterol levels. However, estimation of an individual's cardiovascular risk remains approximate, and whether new biomarkers of risk will improve risk assessment is a key question. Several novel cardiovascular risk markers have been suggested, including lipid, inflammatory, thrombotic, and genetic biomarkers. Demonstrating that a novel biomarker is predictive of cardiovascular disease is, by itself, insufficient proof that it adds incremental value to existing risk estimation models. The Net Reclassification Improvement index provides an indication of the ability of a novel marker to improve risk estimation by classifying individuals to a more correct category. In addition, new risk models may be calibrated by measuring how closely predicted outcomes agree with actual outcomes. Traditional cardiovascular risk factors explain most of an individual's risk. Consequently, the addition of new risk factors to existing models has provided disappointingly small effects overall. However, there addition to conventional risk estimation may be useful in correctly reclassifying individuals at intermediate risk as above or below a chosen intervention threshold.

Relationships between body mass index, cardiovascular mortality, and risk factors: a report from the SCORE investigators.

BACKGROUND: Although cardiovascular disease (CVD) is the biggest global cause of death, CVD mortality is falling in developed countries. There is concern that this trend may be offset by increasing levels of obesity. DESIGN: We used the Systematic Coronary Risk Evaluation (SCORE) data set to examine relationships between body mass index (BMI), conventional risk factors and CVD mortality. METHODS: The SCORE data set comprises data from 12 European cohort studies. The relationship between BMI and CVD mortality was examined in each BMI category using univariable and multivariable (Cox) analyses. The SCORE population was also divided into gender and age strata: under 40, 40-49, 50-59, and over 60. The rate of CVD mortality in each BMI category was calculated within each gender and age stratum. Relationships between BMI and other CVD risk factors were also examined. RESULTS: There was a strong, graded but J-shaped univariable relationship between BMI and CVD mortality in both genders. Each 5-unit increase in BMI was associated with an increase in CVD mortality of 34% in men and 29% in women. The hazard ratios remained significant when adjusted for age, self-reported smoking status, total cholesterol, and systolic blood pressure (SBP). On additional adjustment for diabetes and high-density lipoprotein cholesterol (HDL), the association between BMI and CVD mortality did not persist. In all age groups except those over 60 there were significant relationships between increased BMI and CVD mortality. In the over-60 age group the only significant relationships with mortality were in underweight and severely overweight women and mildly obese men. After adjustment for age, each 1-unit increase in BMI was associated with a 1.14 mmHg increase in SBP, 0.055 mmol/l increase in total cholesterol, and a 0.024 mmol/l decrease in HDL in men. Figures were slightly lower in women. CONCLUSIONS: Overall, overweight and obesity relate to CVD mortality in a strong and graded manner. The effects are greater in women and markedly so in younger persons. It is likely that a substantial part of the BMI-associated risk of CVD mortality is mediated through other known CVD risk factors. This increases the public health importance of BMI as both a simple indicator and mediator of CVD risk.

Integrin α(IIb)ß3 exists in an activated state in subjects with elevated plasma homocysteine levels.

Elevated levels of plasma homocysteine (Hcy) are an independent risk factor for cardiovascular disease and thrombosis. The molecular basis for this phenomenon is not known but may relate to modification of cell surface thiols. The platelet specific integrin α(IIb)ß3 is a cysteine-rich cell adhesion molecule that plays a critical role in platelet aggregation and adhesion in haemostasis and thrombosis. In this study, we looked for evidence of a homocysteine-induced modification of α(IIb)ß3 using a fluorescently labeled PAC-1 antibody that recognizes the activated conformation of the integrin on the platelet surface. We show that exogenous Hcy (10-100 µM) and homocysteine thiolactone (HcyTL) (10-100 µM) increased PAC-1 binding to platelets in a concentration dependent manner in vitro. In parallel, we show subjects with clinical hyperhomocysteinemia exhibit a greater degree of activation of α(IIb)ß3 compared to age-matched controls. These findings demonstrate that circulating Hcy can modulate the activation state of the platelet integrin α(IIb)ß3, a key player in platelet aggregation and thrombosis.

Assessment of cardiovascular risk.

Atherosclerotic cardiovascular disease (CVD) is the most common cause of death worldwide. Usually atherosclerosis is caused by the combined effects of multiple risk factors. For this reason, most guidelines on the prevention of CVD stress the assessment of total CVD risk. The most intensive risk factor modification can then be directed towards the individuals who will derive the greatest benefit. To assist the clinician in calculating the effects of these multiple interacting risk factors, a number of risk estimation systems have been developed. This review address several issues regarding total CVD risk assessment: Why should total CVD risk be assessed? What risk estimation systems are available? How well do these systems estimate risk? What are the advantages and disadvantages of the current systems? What are the current limitations of risk estimation systems and how can they be resolved? What new developments have occurred in CVD risk estimation?

Simplifying cardiovascular risk estimation using resting heart rate.

AIMS: Elevated resting heart rate (RHR) is a known, independent cardiovascular (CV) risk factor, but is not included in risk estimation systems, including Systematic COronary Risk Evaluation (SCORE). We aimed to derive risk estimation systems including RHR as an extra variable and assess the value of this addition. METHODS AND RESULTS: The National FINRISK study (including 14,997 men and 15,861 women) was used to derive two formulas for estimation of 10 year risk of CV disease (CVD) mortality. The first formula contained current SCORE variables-total cholesterol, systolic blood pressure, smoking, age and gender. Inclusion of RHR resulted in only minor improvements in discrimination, based on both area under receiver operating characteristic curve (AUROC, men: 0.840 from 0.838, P = 0.5038; women: 0.87 from 0.865, P = 0.0522) and net reclassification index (NRI). The second, simplified formula contained only, age, smoking, gender, and body mass index. Addition of RHR to this simplified formula resulted in a statistically significant and meaningful improvement in AUROC (men: 0.819 from 0.812, P = 0.037; women: 0.862 from 0.827, P = 0.023) and NRI (0.05). Calibration also improved. A simple chart for estimating 10 year risk of fatal CVD including RHR is presented. CONCLUSION: Addition of RHR to formulas already containing lipid and blood pressure measures does not appreciably improve risk estimation. However, inclusion of RHR in simple systems, which can potentially enhance cost-effectiveness and accessibility of risk estimation, is useful.

Italian cardiovascular mortality charts of the CUORE project: are they comparable with the SCORE charts?

BACKGROUND: The aim of this study was to build risk charts for the assessment of cardiovascular mortality of the CUORE project, an Italian longitudinal study, and to compare them with the systematic coronary risk evaluation (SCORE) project charts for low risk European countries. DESIGN: Random population samples enrolled in the 1980s and 1990s in Italy were included in the analysis: 7,520 men and 13,127 women aged 35-69 years without previous cardiovascular events and with a mean follow-up period of 10 years for cardiovascular disease. ICD-9 codes of death certificates similar to those of the SCORE project were considered when they appear as first cause of death. METHODS: Sex-stratified Cox proportional hazard model including age, systolic blood pressure, ratio between total and HDL cholesterol, and smoking habit as risk factors was used to assess cardiovascular mortality. RESULTS: Analysis showed that all risk factors included in the model were statistically significant. The corresponding area under the receiver operating characteristic curve was 0.825 (95% confidence interval: 0.803-0.846) for men and 0.850 (0.823-0.877) for women. The CUORE project charts yielded similar results to the corresponding charts of the SCORE project: Lin's coefficient was 0.929 for men and 0.935 for women. CONCLUSION: The comparison between CUORE and SCORE mortality risk charts shows that SCORE charts reflect quite well the Italian cardiovascular mortality and, correspondingly, Italian cohorts of the CUORE project are quite representative of European countries at low risk for cardiovascular mortality.

Re-evaluating the Rose approach: comparative benefits of the population and high-risk preventive strategies.

BACKGROUND: Options for the prevention of cardiovascular disease, the greatest global cause of death, include population preventive measures (the Rose approach), or specifically seeking out and managing high-risk cases. However, the likely benefit of a population approach has been recently questioned. OBJECTIVE: To compare the estimated effects of population strategies at varying levels of population-wide risk factor reduction and high-risk strategies at varying rates of screening uptake on cardiovascular disease mortality. METHODS: Data (of 109 954 participants) were pooled from six European general population cohort studies [the high-risk cohorts from the SCORE (Systematic COronary Risk Evaluation) dataset]. The effects of various population and high-risk strategies for the reduction of risk factors were estimated by calculating the change in 10-year risk of cardiovascular disease mortality (SCORE risk) before and after the particular intervention. Risk factors studied were: total cholesterol, blood pressure and smoking. RESULTS: At population level, if a 10-year reduction of blood cholesterol level of 10%, a BP reduction of 10% and a 10% reduction in the prevalence of smoking is considered possible, then 9125 lives per million of the population would be saved over 10 years. In contrast, an approach that treats all high-risk individuals with a polypill containing statin, three half-dose antihypertensives and aspirin, with a 20-80% uptake, would save 1861-7452 lives per million. However, the high-risk estimates are very optimistic, as their achievement would require complete compliance. CONCLUSION: High-risk and population strategies are complementary. These estimates of the benefits of each may be useful to health planners, when combined with their local knowledge. Recently, benefits of population strategies have been underestimated.

Value and limitations of existing scores for the assessment of cardiovascular risk: a review for clinicians.

Atherosclerotic cardiovascular diseases (CVDs) are the biggest causes of death worldwide. In most people, CVD is the product of a number of causal risk factors. Several seemingly modest risk factors may, in combination, result in a much higher risk than an impressively raised single factor. For this reason, risk estimation systems have been developed to assist clinicians to assess the effects of risk factor combinations in planning management strategies. In this article, the performances of the major risk estimation systems are reviewed. Most perform usably well in populations that are similar to the one used to derive the system, and in other populations if calibrated to allow for different CVD mortality rates and different risk factor distributions. The effect of adding "new" risk factors to age, sex, smoking, lipid status, and blood pressure is usually small, but may help to appropriately reclassify some of those patients who are close to a treatment threshold to a more correct "treat/do not treat" category. Risk estimation in the young and old needs more research. Quantification of the hoped-for benefits of the multiple risk estimation approach in terms of improved outcomes is still needed. But, it is likely that the widespread use of such an approach will help to address the issues of both undertreatment and overtreatment.

How much does HDL cholesterol add to risk estimation? A report from the SCORE Investigators.

BACKGROUND: Systematic COronary Risk Evaluation (SCORE), the risk estimation system recommended by the European guidelines on cardiovascular disease prevention, estimates 10-year risk of cardiovascular disease mortality based on age, sex, country of origin, systolic blood pressure, smoking status and either total cholesterol (TC) or TC/high-density lipoprotein cholesterol (HDL-C) ratio. As, counterintuitively, these two systems perform very similarly, we have investigated whether incorporating HDL-C and TC as separate variables improves risk estimation. METHODS: The study consisted of 57,302 men and 47,659 women. Cox proportional hazards method was used to derive the function including HDL-C and an identical function without HDL-C for comparison. Risk charts were developed to illustrate the results. RESULTS: Inclusion of HDL-C resulted in a modest but statistically significant improvement in risk estimation, based on the area under receiver operating characteristic curve (AUROC); 0.814 versus 0.808, P value less than 0.0001, for the functions with and without HDL-C, respectively. Addition of HDL-C also resulted in a significant and important improvement in risk estimation as measured by net reclassification index, which is highly clinically relevant. Improvement in risk estimation was greatest in women from high-risk countries, in terms of both AUROC and net reclassification index. CONCLUSION: For the general population, the inclusion of HDL-C in risk estimation results in only a modest improvement in overall risk estimation based on AUROC. However, when using the more clinically that examines reclassification of individuals, clinically useful improvements occur. Inclusion of HDL may be particularly useful in women from high-risk countries and individuals with unusually high or low HDL-C levels. Addition of HDL-C is particularly applicable to electronic, interactive risk estimation systems such as HeartScore.

Homocysteine increases the risk associated with hyperlipidaemia.

BACKGROUND: The European Concerted Action Project 'Homocysteine and Vascular Disease' showed that an elevated homocysteine is associated with a substantially increased risk of cardiovascular disease, and particularly when combined with other factors such as smoking, hypertension and hypercholesterolaemia. The purpose of this study was to examine the potential interactions between homocysteine and individual lipid subfractions. In addition, it was hypothesized that HDL cholesterol may protect against hyperhomocysteinaemia because HDL cholesterol is associated with the enzyme paroxonase, which reduces oxidization of homocysteine to the harmful metabolite, homocysteine thiolactonase. METHODS: Data from a multicentre European case-control study (750 cases and 800 controls) were used for analysis. The risks of vascular disease associated with homocysteine, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, apoprotein A1 and apoprotein B were established. The effect of elevated homocysteine on the cardiovascular risk associated with each lipid subfraction was then examined. RESULTS: As expected, homocysteine, total cholesterol, LDL cholesterol, triglycerides and apolipoprotein B were associated with cardiovascular risk. HDL cholesterol was inversely related to risk. Homocysteine increased the risk associated with all lipid measures. In contrast, a low plasma cholesterol does not seem to confer protection against the risk associated with a raised plasma homocysteine. Hyperhomocysteinaemia is associated with an increased risk at all levels of HDL cholesterol, conversely, in those with elevated homocysteine HDL cholesterol levels result in reduced risk. CONCLUSION: In general, the increased cardiovascular risk associated with elevated homocysteine is evident across the spectrum cholesterol subfraction levels.