The Computerized Cognitive Composite (C3) in A4, an Alzheimer’s Disease Secondary Prevention Trial

Background: Computerized cognitive assessments may improve Alzheimer’s disease (AD) secondary prevention trial efficiency and accuracy. However, they require validation against standard outcomes and relevant biomarkers. Objective: To assess the feasibility and validity of the tablet-based Computerized Cognitive Composite (C3). Design: Cross-sectional analysis of cognitive screening data from the A4 study (Anti-Amyloid in Asymptomatic AD). Setting: Multi-center international study. Participants: Clinically normal (CN) older adults (65-85; n=4486). Measurements: Participants underwent florbetapir-Positron Emission Tomography for Aβ+/- classification. They completed the C3 and standard paper and pencil measures included in the Preclinical Alzheimer’s Cognitive Composite (PACC). The C3 combines memory measures sensitive to change over time (Cogstate Brief Battery-One Card Learning) and measures shown to be declining early in AD including pattern separation (Behavioral Pattern Separation Test- Object- Lure Discrimination Index) and associative memory (Face Name Associative Memory Exam- Face-Name Matching). C3 acceptability and completion rates were assessed using qualitative and quantitative methods. C3 performance was explored in relation to Aβ+/- groups (n=1323/3163) and PACC. Results: C3 was feasible for CN older adults to complete. Rates of incomplete or invalid administrations were extremely low, even in the bottom quartile of cognitive performers (PACC). C3 was moderately correlated with PACC (r=0.39). Aβ+ performed worse on C3 compared with Aβ- [unadjusted Cohen’s d=-0.22 (95%CI: -0.31,-0.13) p<0.001] and at a magnitude comparable to the PACC [d=-0.32 (95%CI: -0.41,-0.23) p<0.001]. Better C3 performance was observed in younger, more educated, and female participants. Conclusions: These findings provide support for both the feasibility and validity of C3 and computerized cognitive outcomes more generally in AD secondary prevention trials.

Abstract P304: High Cardiovascular Health Metrics Score Predicts Slower Cognitive Performance Decline in Coronary Patients

Introduction: In 2010, the American Heart Association introduced a metric defining the concept of ideal cardiovascular health (CVH) metrics as part of its 2020 Impact Goals definition designed for the health general population. Several studies have demonstrated that a higher number of ideal CVH metrics were associated with a lower rate of cardiovascular events, stroke and all-cause mortality. Hypothesis: We hypothesized that a modified cardiovascular health (CVH) metrics score among patients with CHD may be associated with the change in cognitive functions two decades later in patients. Methods: CVH metrics were assessed in a subgroup of men, who had previously participated in a secondary prevention trial and two successive examinations of cognitive function (N=200, mean age at baseline 57.3±6.3 yrs.). A CVH metrics score at baseline was calculated including 3 health parameters, glucose, LDL-cholesterol, blood-pressure; and 4 health behaviors, smoking, obesity, physical-activity and adherence to Mediterranean diet. We scored each of these CVH metrics into best (2 points), intermediate (1 point), and poor levels (0 points). Cognitive performance was evaluated 14.7±1.9 and 19.9±1.0 years after entry to the trial. Cognitive function was assessed using the NeuroTrax Computerized Cognitive Battery. Linear mixed model was used to assess change in cognitive functions between T1 and T2 cognitive evaluations. Results: Among the 200 patients, 68 (34.0%) had less than 7 (bottom group), 85 (42.5%) had 8-9 (middle group) and 47 (23.5%) had at least 10 CVH metrics points (top group). After adjustments, the top group of CVH score vs. others was associated with slower decline in overall cognitive performance composite z-score [0.23±0.09; p=0.009] and on tests of executive and visual spatial functions [0.23±0.11; p=0.047 and 0.49±0.17; p=0.004, respectively]. A 3 point-Increment in the health behaviors component was related to a slower decline in visuospatial functions [0.325±0.12; p=0.01]. Conclusion: an inverse association was observed between the score of best CVH metrics and cognitive decline among men with pre-existing CHD.

Abstract W P369: International Variability in Stroke Preventive Care

Introduction: Research protocols for stroke prevention trials commonly specify goals for preventive care. We report variability in goal achievement between 3 countries participating in an on-going stroke secondary prevention trial. Methods: The Insulin Resistance Intervention after Stroke (IRIS) trial is testing pioglitazone, compared with placebo, for prevention of stroke and myocardial infarction among non-diabetic patients with a recent ischemic stroke/TIA. Preventive care is provided by personal physicians, although achievement of prevention goals is monitored and reported to participants and their physicians annually. Goals are from the American Heart Association guidelines: blood pressure (BP) <140/90 mmHg, statin therapy, and anti-platelet or anticoagulation depending on clinical indications. At baseline and year 1, we compared the proportions of participants meeting these goals in the largest enrolling countries: Canada (CA), United Kingdom (UK) and United States (US). Results: Participant characteristics were similar across countries, except the proportions of women and blacks were lower in the UK and CA than the US, and self-reported hypertension was more common in US than CA or UK. At baseline, achievement of BP goal was lower in the UK (53%) compared with the US (66%) and CA (75%) (Chi 2 p<0.0001). Statin therapy was used more commonly in the UK (91%) and CA (88%) compared with the US (80%) (Chi 2 p<0.0001). Differences persisted at year 1. At baseline, use of antithrombotic therapy was high (99%) in all countries. However, at year 1, use fell in US (96%) compared to CA and UK (p=0.02). Conclusions: Secondary preventive care for stroke varied among 3 countries for BP, statin therapy and antithrombotic therapies despite the IRIS protocol specifying uniform goals. These findings may be the result of disagreement among practitioners in the 3 countries for secondary prevention goals, variability in care delivery, or variability in research implementation. Understanding and resolving variability may lead to more efficient research and improved care for patients.

Abstract 117: Apolipoprotein E and use of Statins in Intracerebral Hemorrhage

Background: Apolipoprotein E (ApoE) genotypes have been associated with lobar intracerebral hemorrhage (ICH), and HMG-CoA Reductase Inhibitors (statins) were associated with risk of ICH in a secondary prevention trial. Yet, large meta-analyses of statin use have not consistently identified an increased risk of ICH with statin use. We evaluated whether ApoE genotypes were differentially associated with ICH risk according to statin use. Methods: The Genetic and Environmental Risk Factors for Hemorrhagic Stroke study is a prospective ICH study which recruits cases and controls from the same population. Study physicians adjudicated cases and determined ICH location. Subjects were classified as normocholesterolemia (NC), hypercholesterolemia without statin (HC-NS), and hypercholesterolemia with statin use (HC-S) based on chart review. Genotyping for ApoE ( rs429358 and rs7412) was performed using standard methods. Statistical comparisons were performed using Fisher’s exact test and Mantel-Haenszel tests for homogeneity. Results: From 1997-2008, the study recruited 597 cases of ICH and 1,548 controls. Of these, 26 cases/ 8 controls were excluded for unknown history of hypercholesterolemia, and 13 cases/ 96 controls were excluded for missing ApoE result. Of the 554 cases included, 204 were lobar in location. For non-lobar ICH cases, no significant differences were observed in ApoE genotype and statin use between NC, HC-NS and HC-S cases and controls. However, for lobar ICH, a marked increased risk of ICH was seen in HC-S patients with Apo E4/E4 (OR=4.5; 95% CI 1.3-16; p=0.02) and E2/E4 (OR=11.3; 95%CI 2.0-64; p=0.005), and there was a trend for Apo E2/E3 (OR=2.8; 95% CI 1.1-7.5, p=0.06) compared with Apo E3/E3. Apo E4/E4 did not demonstrate an increased odds of ICH without statin use (OR=1.6; 95% CI 0.27-9.4; p=0.63). The p-value for heterogeneity of odds ratios did not reach statistical significance between the HC-NS vs. HC-S group. Conclusion: Our data support a gene-by-drug effect for lobar ICH and, if confirmed, may indicate a utility for ApoE genotyping to identify patients who would bear the highest risk of ICH with statin use. However, further study is required to determine if an interaction exists or if the finding is associative.

The Cardiologist’s Role in the Management of Type 2 Diabetes—A Review

Evidence-based medicine is key to the cardiologist’s role in the management of type 2 diabetes. Proven therapies that reduce cardiovascular (cV) events with few off-target effects are imperative. evidence from epidemiology studies supports the concept that increased blood sugar is correlated with increased cV events. unfortunately, the lowering of glucose with current agents shows limited benefit in reducing cV events. Metformin in the obese individual reduced cV events and is currently first-line therapy in most clinical practice guidelines. recently, a meta-analysis reported that current hypoglycemic agents did not improve cV outcomes and were possibly harmful. Possible exceptions come from the Prospective pioglitazone clinical trial in macrovascular events (Proactive), a secondary prevention trial in patients with prior myocardial infarction in which pioglitazone was found to reduce cV events. glucagon-like peptide-1 (gLP-1) agonists appear to be the most exciting new cV agents, but a dipeptidyl peptidase-4 (DPP4) inhibitor (sitagliptin) combined with a high-dose angiotensin-converting enzyme inhibitor (Acei) (enalapril) may increase blood pressure and heart rate. Lifestyle modification and proven global risk reduction are still the number one ways to reduce cV events in type 2 diabetes.