Jacqueline F. Price

Ankle brachial index combined with Framingham risk score to predict cardiovascular events and mortality - A meta-analysis

CONTEXT Prediction models to identify healthy individuals at high risk of cardiovascular disease have limited accuracy. A low ankle brachial index (ABI) is an indicator of atherosclerosis and has the potential to improve prediction. OBJECTIVE To determine if the ABI provides information on the risk of cardiovascular events and mortality independently of the Framingham risk score (FRS) and can improve risk prediction. DATA SOURCES Relevant studies were identified. A search of MEDLINE (1950 to February 2008) and EMBASE (1980 to February 2008) was conducted using common text words for the term ankle brachial index combined with text words and Medical Subject Headings to capture prospective cohort designs. Review of reference lists and conference proceedings, and correspondence with experts was conducted to identify additional published and unpublished studies. STUDY SELECTION Studies were included if participants were derived from a general population, ABI was measured at baseline, and individuals were followed up to detect total and cardiovascular mortality. DATA EXTRACTION Prespecified data on individuals in each selected study were extracted into a combined data set and an individual participant data meta-analysis was conducted on individuals who had no previous history of coronary heart disease. RESULTS Sixteen population cohort studies fulfilling the inclusion criteria were included. During 480,325 person-years of follow-up of 24,955 men and 23,339 women, the risk of death by ABI had a reverse J-shaped distribution with a normal (low risk) ABI of 1.11 to 1.40. The 10-year cardiovascular mortality in men with a low ABI (< or = 0.90) was 18.7% (95% confidence interval [CI], 13.3%-24.1%) and with normal ABI (1.11-1.40) was 4.4% (95% CI, 3.2%-5.7%) (hazard ratio [HR], 4.2; 95% CI, 3.3-5.4). Corresponding mortalities in women were 12.6% (95% CI, 6.2%-19.0%) and 4.1% (95% CI, 2.2%-6.1%) (HR, 3.5; 95% CI, 2.4-5.1). The HRs remained elevated after adjusting for FRS (2.9 [95% CI, 2.3-3.7] for men vs 3.0 [95% CI, 2.0-4.4] for women). A low ABI (< or = 0.90) was associated with approximately twice the 10-year total mortality, cardiovascular mortality, and major coronary event rate compared with the overall rate in each FRS category. Inclusion of the ABI in cardiovascular risk stratification using the FRS would result in reclassification of the risk category and modification of treatment recommendations in approximately 19% of men and 36% of women. CONCLUSION Measurement of the ABI may improve the accuracy of cardiovascular risk prediction beyond the FRS.

Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials

BACKGROUND Daily aspirin reduces the long-term incidence of some adenocarcinomas, but effects on mortality due to some cancers appear after only a few years, suggesting that it might also reduce growth or metastasis. We established the frequency of distant metastasis in patients who developed cancer during trials of daily aspirin versus control. METHODS Our analysis included all five large randomised trials of daily aspirin (≥75 mg daily) versus control for the prevention of vascular events in the UK. Electronic and paper records were reviewed for all patients with incident cancer. The effect of aspirin on risk of metastases at presentation or on subsequent follow-up (including post-trial follow-up of in-trial cancers) was stratified by tumour histology (adenocarcinoma vs other) and clinical characteristics. FINDINGS Of 17,285 trial participants, 987 had a new solid cancer diagnosed during mean in-trial follow-up of 6·5 years (SD 2·0). Allocation to aspirin reduced risk of cancer with distant metastasis (all cancers, hazard ratio [HR] 0·64, 95% CI 0·48-0·84, p=0·001; adenocarcinoma, HR 0·54, 95% CI 0·38-0·77, p=0·0007; other solid cancers, HR 0·82, 95% CI 0·53-1·28, p=0·39), due mainly to a reduction in proportion of adenocarcinomas that had metastatic versus local disease (odds ratio 0·52, 95% CI 0·35-0·75, p=0·0006). Aspirin reduced risk of adenocarcinoma with metastasis at initial diagnosis (HR 0·69, 95% CI 0·50-0·95, p=0·02) and risk of metastasis on subsequent follow-up in patients without metastasis initially (HR 0·45, 95% CI 0·28-0·72, p=0·0009), particularly in patients with colorectal cancer (HR 0·26, 95% CI 0·11-0·57, p=0·0008) and in patients who remained on trial treatment up to or after diagnosis (HR 0·31, 95% CI 0·15-0·62, p=0·0009). Allocation to aspirin reduced death due to cancer in patients who developed adenocarcinoma, particularly in those without metastasis at diagnosis (HR 0·50, 95% CI 0·34-0·74, p=0·0006). Consequently, aspirin reduced the overall risk of fatal adenocarcinoma in the trial populations (HR 0·65, 95% CI 0·53-0·82, p=0·0002), but not the risk of other fatal cancers (HR 1·06, 95% CI 0·84-1·32, p=0·64; difference, p=0·003). Effects were independent of age and sex, but absolute benefit was greatest in smokers. A low-dose, slow-release formulation of aspirin designed to inhibit platelets but to have little systemic bioavailability was as effective as higher doses. INTERPRETATION That aspirin prevents distant metastasis could account for the early reduction in cancer deaths in trials of daily aspirin versus control. This finding suggests that aspirin might help in treatment of some cancers and provides proof of principle for pharmacological intervention specifically to prevent distant metastasis. FUNDING None.

Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: Analysis of the time course of risks and benefits in 51 randomised controlled trials

BACKGROUND Daily aspirin reduces the long-term risk of death due to cancer. However, the short-term effect is less certain, especially in women, effects on cancer incidence are largely unknown, and the time course of risk and benefit in primary prevention is unclear. We studied cancer deaths in all trials of daily aspirin versus control and the time course of effects of low-dose aspirin on cancer incidence and other outcomes in trials in primary prevention. METHODS We studied individual patient data from randomised trials of daily aspirin versus no aspirin in prevention of vascular events. Death due to cancer, all non-vascular death, vascular death, and all deaths were assessed in all eligible trials. In trials of low-dose aspirin in primary prevention, we also established the time course of effects on incident cancer, major vascular events, and major extracranial bleeds, with stratification by age, sex, and smoking status. RESULTS Allocation to aspirin reduced cancer deaths (562 vs 664 deaths; odds ratio [OR] 0·85, 95% CI 0·76-0·96, p=0·008; 34 trials, 69,224 participants), particularly from 5 years onwards (92 vs 145; OR 0·63, 95% CI 0·49-0·82, p=0·0005), resulting in fewer non-vascular deaths overall (1021 vs 1173; OR 0·88, 95% CI 0·78-0·96, p=0·003; 51 trials, 77,549 participants). In trials in primary prevention, the reduction in non-vascular deaths accounted for 87 (91%) of 96 deaths prevented. In six trials of daily low-dose aspirin in primary prevention (35,535 participants), aspirin reduced cancer incidence from 3 years onwards (324 vs 421 cases; OR 0·76, 95% CI 0·66-0·88, p=0·0003) in women (132 vs 176; OR 0·75, 95% CI 0·59-0·94, p=0·01) and in men (192 vs 245; OR 0·77, 95% CI 0·63-0·93, p=0·008). The reduced risk of major vascular events on aspirin was initially offset by an increased risk of major bleeding, but effects on both outcomes diminished with increasing follow-up, leaving only the reduced risk of cancer (absolute reduction 3·13 [95% CI 1·44-4·82] per 1000 patients per year) from 3 years onwards. Case-fatality from major extracranial bleeds was also lower on aspirin than on control (8/203 vs 15/132; OR 0·32, 95% CI 0·12-0·83, p=0·009). INTERPRETATION Alongside the previously reported reduction by aspirin of the long-term risk of cancer death, the short-term reductions in cancer incidence and mortality and the decrease in risk of major extracranial bleeds with extended use, and their low case-fatality, add to the case for daily aspirin in prevention of cancer. FUNDING None.

Blood viscosity and risk of cardiovascular events: the Edinburgh Artery Study.

We examined the relationships of whole blood viscosity and its major determinants to incident cardiovascular events (ischaemic heart disease and stroke) in a prospective study of a random population sample of 1592 men and women aged 55–74 years (the Edinburgh Artery Study). 272 fatal and non‐fatal cardiovascular events occurred during 5 years of follow‐up (cumulative incidence 17.1%). Age and sex adjusted mean levels of blood viscosity (3.70 v 3.55 mPa.s), haematocrit (46.2 v 45.7%), haematocrit‐corrected blood viscosity (3.57 v 3.48 mPa.s), plasma viscosity (1.35 v 1.33 mPa.s) and fibrinogen (2.88 v 2.67 g/l) were significantly higher in subjects who experienced events than in subjects who did not. The relationships of these rheological variables to cardiovascular events were at least as strong as those of conventional risk factors (smoking habit, diastolic blood pressure, and low‐density lipoprotein cholesterol). After adjustment for these conventional risk factors, the associations of blood viscosity and haematocrit remained significant for stroke, but not for total events; whereas the associations of plasma viscosity and fibrinogen remained significant for total events and for stroke.

Hemostatic Factors as Predictors of Ischemic Heart Disease and Stroke in the Edinburgh Artery Study

Plasma fibrinogen is a consistent predictor of ischemic heart disease (IHD) in prospective studies, but there are fewer data relating other hemostatic variables to IHD and also to stroke. We therefore studied the relationships of plasma fibrinogen, von Willebrand factor antigen, tissue plasminogen activator (TPA) antigen, factor VII, and fibrin D-dimer to incidence of IHD and stroke and determined whether any associations could be explained by conventional risk factors and baseline heart disease. In the Edinburgh Artery study, 1592 men and women aged 55 to 74 years, randomly sampled from the general population, were followed prospectively over 5 years to detect fatal and nonfatal IHD and stroke events. During the 5 years, 268 new vascular events were identified. Baseline plasma fibrinogen was independently related to risk of stroke in multivariate analysis that adjusted for cigarette smoking, LDL-cholesterol, systolic blood pressure, and preexisting IHD (relative risk [RR] 1.52, 95% confidence interval [CI] 1.17, 1.98). TPA antigen, and fibrin D-dimer were also independently associated with risk of stroke (RR 1.69,95% CI 1.22,2.35 and RR 1.96, 95% CI 1.12,3.41, respectively). Significant relationships were found between TPA antigen and myocardial infarction (P < or = .05). In older men and women, increased coagulation activity and disturbed fibrinolysis are predictors of future vascular events (both IHD and stroke).

Cognitive function, dementia and type 2 diabetes mellitus in the elderly

Increasing numbers of people are developing type 2 diabetes mellitus, but interventions to prevent and treat the classic microvascular and macrovascular complications have improved, so that people are living longer with the condition. This trend means that novel complications of type 2 diabetes mellitus, which are not targeted by current management strategies, could start to emerge. Cognitive impairment and dementia could come into this category. Type 2 diabetes mellitus is associated with a 1.5–2.5-fold increased risk of dementia. The etiology of dementia and cognitive impairment in people with type 2 diabetes mellitus is probably multifactorial. Chronic hyperglycemia is implicated, perhaps by promoting the development of cerebral microvascular disease. Data suggest that the brains of older people with type 2 diabetes mellitus might be vulnerable to the effects of recurrent, severe hypoglycemia. Other possible moderators of cognitive function include inflammatory mediators, rheological factors and dysregulation of the hypothalamic–pituitary–adrenal axis. Cognitive function should now be included as a standard end point in randomized trials of therapeutic interventions in patients with type 2 diabetes mellitus.

Improved Prediction of Fatal Myocardial Infarction Using the Ankle Brachial Index in Addition to Conventional Risk Factors The Edinburgh Artery Study

Background—Prediction of major cardiovascular and cerebrovascular events using conventional risk factor models is limited. Noninvasive measures of subclinical atherosclerosis such as the ankle brachial index (ABI) could improve risk prediction and provide more focused primary prevention strategies. We wished to determine the added value of a low ABI in the prediction of long-term risk of cardiovascular and cerebrovascular events and death. Methods and Results—In 1988, 1592 men and women 55 to 74 years of age were randomly selected from the age-sex registers of 11 general practices in Edinburgh, Scotland, and followed up over a period of 12 years for incident events. After adjustment for age and sex, an ABI ≤0.9 was predictive of an increased risk of fatal myocardial infarction (MI), cardiovascular death, all-cause death, combined fatal and nonfatal MI, and total cardiovascular events. After further adjustment for prevalent cardiovascular disease, diabetes, and conventional risk factors, a low ABI was independently predictive of the risk of fatal MI. Addition of the ABI significantly (P≤0.01) increased the predictive value of the model for fatal MI compared with a model containing risk factors alone. Comparison of areas under receiver operator characteristic curves confirmed that a model including the ABI discriminated marginally better than one without. Conclusions—Addition of the ABI significantly improved prediction of fatal MI over and above that of conventional risk factors. We recommend that the ABI be incorporated into routine cardiovascular screening and that the potential of its inclusion into cardiovascular scoring systems (with a view to improving their accuracy) now be examined.

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.

Interleukin-6 receptor pathways in abdominal aortic aneurysm

Methods We conducted a systematic review and meta-analysis of studies reporting circulating IL-6 in AAA, and new investigations of the association between a common non-synonymous functional variant (Asp358Ala) in the IL-6R gene (IL6R) and AAA, followed the analysis of the variant both in vitro and in vivo. Inflammation may play a role in the development of abdominal aortic aneurysms (AAA). Interleukin-6 (IL-6) signalling through its receptor (IL-6R) is one pathway that could be exploited pharmacologically. We investigated this using a Mendelian randomization approach. Results Up to October 2011, we identified seven studies (869 cases, 851 controls). Meta-analysis demonstrated that AAA cases had higher levels of IL-6 than controls [standardized mean difference (SMD) = 0.46 SD, 95% CI = 0.25–0.66, I2 = 70%, P = 1.1 × 10–5 random effects]. Meta-analysis of five studies (4524 cases/15 710 controls) demonstrated that rs7529229 (which tags the non-synonymous variant Asp358Ala, rs2228145) was associated with a lower risk of AAA, per Ala358 allele odds ratio 0.84, 95% CI: 0.80–0.89, I2 = 0%, P = 2.7 × 10–11). In vitro analyses in lymphoblastoid cell lines demonstrated a reduction in the expression of downstream targets (STAT3, MYC and ICAM1) in response to IL-6 stimulation in Ala358 carriers. Conclusions A Mendelian randomization approach provides robust evidence that signalling via the IL-6R is likely to be a causal pathway in AAA. Drugs that inhibit IL-6R may play a role in AAA management.

The relationship between type 2 diabetes and dementia

INTRODUCTION The prevalence of type 2 diabetes and dementia are set to rise inexorably over the next 30-40 years. There are now substantial data to suggest that type 2 diabetes is associated with an increased risk of dementia. SOURCES OF DATA This is a narrative review using data from individual studies and review articles known to the authors. A Medline search was also undertaken and reference lists were reviewed to identify additional relevant studies. AREAS OF AGREEMENT Type 2 diabetes is associated with an increased risk of both Alzheimers and Vascular dementia, although the reality is that many affected individuals have mixed forms of dementia. AREAS OF CONTROVERSY The mechanisms underpinning this association remain to be clearly delineated. Type 2 diabetes is a complex disorder and so it is likely that multiple different, synergistic processes may interact to promote cognitive decrements. GROWING POINTS Recent data suggest that glucocorticoids excess and elevated inflammatory markers may also have a role in the aetiology of diabetes-related cognitive impairment. AREAS TIMELY FOR DEVELOPING RESEARCH Large-scale, prospective epidemiological studies are now required to accurately delineate the pathogenesis of cognitive impairment in people with type 2 diabetes. These are underway and randomized trials of diabetes-specific interventions are also starting to include cognitive function as an outcome measure.