Marlene Stewart

Aspirin for Prevention of Cardiovascular Events in a General Population Screened for a Low Ankle Brachial Index: A Randomized Controlled Trial

CONTEXT A low ankle brachial index (ABI) indicates atherosclerosis and an increased risk of cardiovascular and cerebrovascular events. Screening for a low ABI can identify an asymptomatic higher risk group potentially amenable to preventive treatments. OBJECTIVE To determine the effectiveness of aspirin in preventing events in people with a low ABI identified on screening the general population. DESIGN, SETTING, AND PARTICIPANTS The Aspirin for Asymptomatic Atherosclerosis trial was an intention-to-treat double-blind randomized controlled trial conducted from April 1998 to October 2008, involving 28,980 men and women aged 50 to 75 years living in central Scotland, free of clinical cardiovascular disease, recruited from a community health registry, and had an ABI screening test. Of those, 3350 with a low ABI (< or = 0.95) were entered into the trial, which was powered to detect a 25% proportional risk reduction in events. INTERVENTIONS Once daily 100 mg aspirin (enteric coated) or placebo. MAIN OUTCOME MEASURES The primary end point was a composite of initial fatal or nonfatal coronary event or stroke or revascularization. Two secondary end points were (1) all initial vascular events defined as a composite of a primary end point event or angina, intermittent claudication, or transient ischemic attack; and (2) all-cause mortality. RESULTS After a mean (SD) follow-up of 8.2 (1.6) years, 357 participants had a primary end point event (13.5 per 1000 person-years, 95% confidence interval [CI], 12.2-15.0). No statistically significant difference was found between groups (13.7 events per 1000 person-years in the aspirin group vs 13.3 in the placebo group; hazard ratio [HR], 1.03; 95% CI, 0.84-1.27). A vascular event comprising the secondary end point occurred in 578 participants (22.8 per 1000 person-years; 95% CI, 21.0-24.8) and no statistically significant difference between groups (22.8 events per 1000 person-years in the aspirin group vs 22.9 in the placebo group; HR, 1.00; 95% CI, 0.85-1.17). There was no significant difference in all-cause mortality between groups (176 vs 186 deaths, respectively; HR, 0.95; 95% CI, 0.77-1.16). An initial event of major hemorrhage requiring admission to hospital occurred in 34 participants (2.5 per 1000 person-years) in the aspirin group and 20 (1.5 per 1000 person-years) in the placebo group (HR, 1.71; 95% CI, 0.99-2.97). CONCLUSION Among participants without clinical cardiovascular disease, identified with a low ABI based on screening a general population, the administration of aspirin compared with placebo did not result in a significant reduction in vascular events. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN66587262.

Low dose aspirin and cognitive function in middle aged to elderly adults: randomised controlled trial

Objective To determine the effects of low dose aspirin on cognitive function in middle aged to elderly men and women at moderately increased cardiovascular risk. Design Randomised double blind placebo controlled trial. Setting Central Scotland. Participants 3350 men and women aged over 50 participating in the aspirin for asymptomatic atherosclerosis trial. Intervention Low dose aspirin (100 mg daily) or placebo for five years. Main outcome measures Tests of memory, executive function, non-verbal reasoning, mental flexibility, and information processing five years after randomisation, with scores used to create a summary cognitive score (general factor). Results At baseline, mean vocabulary scores (an indicator of previous cognitive ability) were similar in the aspirin (30.9, SD 4.7) and placebo (31.1, SD 4.7) groups. In the primary intention to treat analysis, there was no significant difference at follow-up between the groups in the proportion achieving over the median general factor cognitive score (32.7% and 34.8% respectively, odds ratio 0.91, 95% confidence interval 0.79 to 1.05, P=0.20) or in mean scores on the individual cognitive tests. There were also no significant differences in change in cognitive ability over the five years in a subset of 504 who underwent detailed cognitive testing at baseline. Conclusion Low dose aspirin does not affect cognitive function in middle aged to elderly people at increased cardiovascular risk. Trial registration ISRCTN 66587262.

Association of KIBRA and memory

We report on the association of KIBRA with memory in two samples of older individuals assessed on either memory for semantically unrelated word stimuli (Rey Auditory Verbal Learning Test, n=2091), or a measure of semantically related material (the WAIS Logical Memory Test of prose-passage recall, n=542). SNP rs17070145 was associated with delayed recall of semantically unrelated items, but not with immediate recall for these stimuli, nor with either immediate or delayed recall for semantically related material. The pattern of results suggests a role for the T-->C substitution in intron 9 of KIBRA in a component of episodic memory involved in long-term storage but independent of processes shared with immediate recall such as rehearsal involved in acquisition and rehearsal or processes.

Peripheral Levels of Fibrinogen, C-reactive Protein, and Plasma Viscosity Predict Future Cognitive Decline in Individuals Without Dementia

Objective: To determine whether circulating levels of the biomarkers C-reactive protein (CRP), fibrinogen, plasma viscosity, and hematocrit were associated with cognitive decline in middle-aged to elderly people. Methods: Subjects consisted of 2312 men and women aged 50 to 80 years participating in the Aspirin for Asymptomatic Atherosclerosis Trial, all of whom were free of symptomatic cardiovascular disease at baseline. Biomarker levels and cognitive ability were measured at baseline with cognition assessed in all subjects using the Mill Hill Vocabulary Scale and in a subgroup of 504 persons using tests of memory, nonverbal reasoning, information processing speed, executive function, and mental flexibility. After 5 years, the five-test battery was administered to all participants and scores were used to derive a general cognitive ability factor. Results: Baseline CRP and fibrinogen levels were associated negatively with age and sex-adjusted follow-up scores on the majority of the cognitive tests, and the general cognitive ability factor (correlations = −0.054 to 0.105, p < .05). In analyses adjusting for baseline cognitive scores, asymptomatic atherosclerotic disease, and cardiovascular risk factors, both markers predicted decline in several cognitive domains (excluding memory). Baseline plasma viscosity, but not hematocrit, was associated negatively with follow-up test scores for general cognitive ability, information processing speed, and mental flexibility (correlations = −0.050 to −0.098, p < .05) and with decline across the same domains (p < .05). Conclusions: Increased circulating levels of CRP, fibrinogen, and elevated plasma viscosity predicted poorer subsequent cognitive ability and were associated with age-related cognitive decline in several domains, including general ability. CRP = C-reactive protein; AAA = Aspirin for Asymptomatic Atherosclerosis; ABI = ankle-brachial index; AVLT = Auditory Verbal Learning Test; RAVENS = Raven’s Standard Progressive Matrices; DST = Digit Symbol Test; VFT = Verbal Fluency Test; TMT = Trail Making Test, Part B; MHVS = Mill Hill Vocabulary Scale; CVD = cardiovascular disease; BP = blood pressure; fib = fibrinogen.

Scottish smoke-free legislation and trends in smoking cessation

AIM To investigate trends in smoking cessation before and after the introduction of Scottish smoke-free legislation and to assess the perceived influence of the legislation on giving up smoking and perceptions of the legislation in smokers. DESIGN, SETTING AND PARTICIPANTS Longitudinal data on smoking cessation were obtained from 1998 to 2007 on a cohort of 3350 Scottish adults aged between 50 and 75 years at baseline. All members of the cohort were participating in a clinical trial of aspirin in people at moderately increased risk of cardiovascular events. A subgroup of 474 participants who had smoked in the year prior to the introduction of legislation in March 2006 also completed a questionnaire on the influence and perceptions of the smoke-free legislation following its introduction. MEASUREMENTS Smoking status was recorded yearly, including dates of quitting and restarting. Participants who gave up smoking for at least 3 months were recorded as having quit smoking. The questionnaire included scales on whether the smoke-free legislation had helped/influenced cessation, made the individual think about/prompt them to quit and perceptions of the legislation. FINDINGS The odds of smokers quitting annually increased throughout the 7-year period prior to introduction of the smoke-free legislation to 2 years afterwards (odds ratio 1.09, 95% confidence interval 1.05-1.12, P<0.001). During 2006, the pattern of quarterly quitting rates changed, with an increase in quit rates (to 5.1%) in the 3-month period prior to introduction of the legislation (January-March 2006). Socio-economic status was not related to smoking cessation. In the subgroup completing the questionnaire (n=474), 57 quit smoking between June 2005 and May 2007 and 43.9% of these said that the smoke-free legislation had helped them to quit. Most (>70%) smokers were positive about the legislation, especially those from more affluent compared with more deprived communities (P=0.01). CONCLUSIONS The Scottish smoke-free legislation was associated with an increase in the rate of smoking cessation in the 3-month period immediately prior to its introduction. Overall quit rates in the year the legislation was introduced and the subsequent year were consistent with a gradual increase in quit rates prior to introduction of the legislation. Socio-economic status was not related to smoking cessation, but individuals from more affluent communities were more positive about the legislation.

Relationship between Lifetime Smoking, Smoking Status at Older Age and Human Cognitive Function

Cigarette smoking is a major risk factor for clinical cardiovascular disease and may also be associated with poorer cognitive functioning in older age. We measured lifetime cigarette smoking, smoking status and cognitive function in over 2,000 men and women from the general population aged over 50 years with subclinical atherosclerosis (ankle brachial pressure index ≤0.95 but no history of clinical cardiovascular disease). In this population, an association was found between greater lifetime smoking and poorer cognitive function in men and between smoking cessation and better cognitive function in women. The former relationship appeared to reflect an association between smoking habit and prior cognitive function (in early life), whereas the latter remained significant after adjustment for tests of crystallised cognitive function, suggesting a relationship between continuing to smoke (as opposed to quitting) and age-related cognitive decline. Both relationships were inde pendent of the degree of atherosclerosis (as measured using the ankle brachial pressure index), suggesting alternative underlying mechanisms for the association between smoking and human adult cognitive function.

Ankle brachial index as a predictor of cognitive impairment in the general population : Ten-year follow-up of the edinburgh artery study

OBJECTIVES: To determine whether the ankle brachial index (ABI, a marker of generalized atherosclerosis) is associated with cognitive impairment after 10 years in older people.

Meta analysis of candidate gene variants outside the LPA locus with Lp(a) plasma levels in 14,500 participants of six White European cohorts.

BACKGROUND Both genome-wide association studies and candidate gene studies have reported that the major determinant of plasma levels of the Lipoprotein (a) [Lp(a)] reside within the LPA locus on chromosome 6. We have used data from the HumanCVD BeadChip to explore the contribution of other candidate genes determining Lp(a) levels. METHODS 48,032 single nucleotide polymorphisms (SNPs) from the Illumina HumanCVD BeadChip were genotyped in 5059 participants of the Whitehall II study (WHII) of randomly ascertained healthy men and women. SNPs showing association with Lp(a) levels of p<10(-4) outside the LPA locus were selected for replication in a total of an additional 9463 participants of five European based studies (EAS, EPIC-Norfolk, NPHSII, PROCARDIS, and SAPHIR). RESULTS In Whitehall II, apart from the LPA locus (where p values for several SNPs were <10(-30)) there was significant association at four loci GALNT2, FABP1, PPARGC1A and TNFRSFF11A. However, a meta-analysis of the six studies did not confirm any of these findings. CONCLUSION Results from this meta analysis of 14,522 participants revealed no candidate genes from the HumanCVD BeadChip outside the LPA locus to have an effect on Lp(a) levels. Further studies with genome-wide and denser SNP coverage are required to confirm or refute this finding.

Improvement in Prediction of Coronary Heart Disease Risk over Conventional Risk Factors Using SNPs Identified in Genome-Wide Association Studies

Objective We examined whether a panel of SNPs, systematically selected from genome-wide association studies (GWAS), could improve risk prediction of coronary heart disease (CHD), over-and-above conventional risk factors. These SNPs have already demonstrated reproducible associations with CHD; here we examined their use in long-term risk prediction. Study Design and Setting SNPs identified from meta-analyses of GWAS of CHD were tested in 840 men and women aged 55–75 from the Edinburgh Artery Study, a prospective, population-based study with 15 years of follow-up. Cox proportional hazards models were used to evaluate the addition of SNPs to conventional risk factors in prediction of CHD risk. CHD was classified as myocardial infarction (MI), coronary intervention (angioplasty, or coronary artery bypass surgery), angina and/or unspecified ischaemic heart disease as a cause of death; additional analyses were limited to MI or coronary intervention. Model performance was assessed by changes in discrimination and net reclassification improvement (NRI). Results There were significant improvements with addition of 27 SNPs to conventional risk factors for prediction of CHD (NRI of 54%, P<0.001; C-index 0.671 to 0.740, P = 0.001), as well as MI or coronary intervention, (NRI of 44%, P<0.001; C-index 0.717 to 0.750, P = 0.256). ROC curves showed that addition of SNPs better improved discrimination when the sensitivity of conventional risk factors was low for prediction of MI or coronary intervention. Conclusion There was significant improvement in risk prediction of CHD over 15 years when SNPs identified from GWAS were added to conventional risk factors. This effect may be particularly useful for identifying individuals with a low prognostic index who are in fact at increased risk of disease than indicated by conventional risk factors alone.

Accrual and drop out in a primary prevention randomised controlled trial: qualitative study

BackgroundRecruitment and retention of participants are critical to the success of a randomised controlled trial. Gaining the views of potential trial participants who decline to enter a trial and of trial participants who stop the trial treatment is important and can help to improve study processes. Limited research on these issues has been conducted on healthy individuals recruited for prevention trials in the community.MethodsSemi-structured interviews with people who were eligible but had declined to participate in the Aspirin for Asymptomatic Atherosclerosis (AAA) trial (N = 11), and AAA trial participants who had stopped taking the trial medication (N = 11). A focus group with further participants who had stopped taking the trial medication (N = 6). (Total participants N = 28).ResultsExplanations for declining to participate could be divided into two groups: the first group were characterised by a lack of necessity to participate and a tendency to prioritise other largely mundane problems. The second groups concern was with a high level of perceived risk from participating.Explanations for stopping trial medication fell into four categories: side effects attributed to the trial medication; starting on aspirin or medication contraindicating to aspirin; experiencing an outcome event, and changing ones mind.ConclusionsThese results indicate that when planning trials (especially in preventive medicine) particular attention should be given to designing appropriate recruitment materials and processes that fully inform potential recruits of the risks and benefits of participation.Trial registrationISRCTN66587262