Faculty Bibliography

OBJECTIVE: Subjects with peripheral artery disease (PAD) are at increased risk of cardiovascular morbidity and mortality, perhaps in part, related to increased levels of inflammation, platelet activity, and lipids. We therefore sought to investigate the relationship between PAD and levels of inflammatory, platelet, and lipid biomarkers and the treatment effect of darapladib, a novel lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) inhibitor. METHODS: This is a post hoc analysis of the 959 patients with coronary disease or their risk equivalent receiving atorvastatin who were randomized to receive darapladib or placebo to examine the effects of an Lp-PLA(2) inhibitor on the biomarkers of cardiovascular risk. We conducted an exploratory analysis evaluating the levels of biomarkers in subjects with PAD (n = 172) compared with those without PAD (n = 787). RESULTS: After adjustment for age, sex, smoking, body mass index, and diabetes, subjects with PAD had greater levels of matrix metalloproteinase-9 (between group comparisons 22%, 95% confidence interval [10-31], P < .01), myeloperoxidase (12% [2-20], P = .01), interleukin-6 (13% [4-21], P = .01), adiponectin (17% [7-26], P < .01), intercellular adhesion molecule-1 (7% [2-11], P < .01), osteoprotegrin (6% [1-10], P = .02), CD40 ligand (15% [1-28], P = .04), high-sensitivity C-reactive protein (17% [1-31], P = .04), and triglycerides (11% [0.2-21], P = .05). No significant difference was detected for Lp-PLA(2) activity, P-selectin, urinary 11-dehydrothroboxane B2, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol between subjects with and without PAD. Darapladib produced highly significant inhibition of Lp-PLA(2) activity when compared with placebo at weeks 4 and 12 (P < .01) in patients with and without PAD. CONCLUSIONS: Subjects with PAD had elevated levels of matrix metalloproteinase-9, myeloperoxidase, interleukin-6, adiponectin, intercellular adhesion molecule-1, osteoprotegrin, CD40 ligand, high-sensitivity C-reactive protein, and triglycerides compared with those without PAD. Darapladib, a novel Lp-PLA(2) inhibitor, was equally effective in reducing Lp-PLA(2) activity levels in subjects with and without PAD

Background: Prasugrel is effective at decreasing cardiovascular events compared to clopidogrel, but increases the risk of bleeding. In 2010, the FDA issued a black box warning to consider genetic testing in clopidogrel users. Our aims were to evaluate (1) the balance of potential benefits and harms and (2) the cost-effectiveness that would result from adopting a genotype-guided strategy of dual anti-platelet therapy following PCI for ACS vs. no testing strategies of prasugrel plus aspirin (prasugrel) or clopidogrel plus aspirin (clopidogrel). Methods: A Markov state transition model was used to conduct a decision analysis and compare strategies. Probabilities of adverse outcomes were derived from TRITON-TIMI 38 trial. Event rates on clopidogrel for carriers of CYP2C19*2 vs. wild-type were derived from the TRITON genetic substudy and a recent meta-analysis. Costs are expressed in January 2011 US dollars and estimated based on Medicare reimbursements for diagnosis-related group codes. Medication costs were used from the net wholesale price for prasugrel ($5.45/d) and a generic estimate for clopidogrel ($1/d). Results: In base case analyses, the genetic testing guided strategy yielded more benefits than harms, and was less costly compared to both 'no testing' strategies. Over 15 months, total costs were $83.8 ($1200.9 at 10 yrs) lower with a gain of 0.0007 QALY (0.0216 QALY at 10 yrs) in the genotype-guided strategy compared to prasugrel. Compared to clopidogrel, it was $0.38 ($2168.8 at 10 yrs) lower with a gain of 0.0036 QALY (0.112 QALY at 10 yrs). The strongest predictor of the preferred strategy was the relative risk (RR) of a thrombotic event occurring in CYP2C19*2 carriers versus wild-type. Below a RR of 1.5, a genotype-guided strategy is no longer more effective (but is less expensive) when compared to prasugrel. Compared to clopidogrel, below a RR of 1.3 a genotype-guided strategy is no longer cost effective (>$100,000/QALY). Clopidogrel costs ($1-$4/d) did not alter our results. Conclusions: Among ACS patients undergoing PCI, a genotype-guided strategy is economically favorable in determining which anti-platelet regimen is used, assuming that the risk of thrombotic events in CYP2C19*2 carriers is approximately 30-50% higher than wild type patients

PURPOSE: Acetylsalicylic acid (ASA) dosing guidelines for ACS treatment are inconsistent and lack supporting data. This analysis evaluated the relationship between ASA maintenance dosing and clinical outcomes in patients with ACS who did not undergo revascularization and are managed medically. METHODS: A meta-analysis was conducted with random-effects modeling to estimate the frequency of clinical outcomes for low (75-149 mg) and high (150-325 mg) doses of ASA, using data from worldwide clinical and observational trials published from Jan 1995 to Feb 2010, available from PubMed, EMBASE and Current Contents. Clinical outcomes measured were: revascularization rate (overall rate, percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG]), cardiovascular (CV) death, all-cause death, myocardial infarction (MI), stroke, and bleeding at 1, 3, 6 and 12 months. RESULTS: Sixty-eight studies including 207,523 patients were accepted and appraised for quality using Oxford Centre for Evidence- Based Medicine scoring. Significant heterogeneity was seen in the results (quantified using the Cochran's Q statistics and the I² measures), due to differences in enrolment procedures, medical management regimens and timing of administration, study designs and some inconsistencies in the definitions of bleeding and MACE. At one month, the incidence of clinical outcomes with high- and low-dose ASA groups were 4.9% and 5.0% for MI; 6.3% and 3.7% for revascularization; 1.4% and 1.3% for stroke; 5.5% and 3.4% for CV death; 5.7% and 4.3% for all cause death; and 4.0% and 1.7% for major bleeding, respectively. Meta regression demonstrated a significant association between aspirin dose and major bleeding (p=0.037). Further data will be presented at the meeting. CONCLUSIONS: This analysis suggests that in patients receiving medical management for ACS, major bleeding occurred more frequently in patients who received higher doses of ASA. ASA dose does not have a statistically significant impact on the other outcomes analyzed

OBJECTIVES: We sought to determine whether mean platelet volume (MPV) is associated with the prevalence of peripheral artery disease (PAD). BACKGROUND: Platelets play a pivotal role in the pathogenesis of atherosclerosis and PAD. MPV, a measure of platelet size available in every blood count, is increasingly recognized as an important marker of platelet activity. METHODS: We analyzed data from 6354 participants aged 40 years and older from the 1999 to 2004 National Health and Nutrition Examination Survey (NHANES), a nationally representative sample of the US population. PAD was defined as an ankle brachial index </=0.90 in either leg. Odds ratios and 95% confidence intervals were estimated by logistic regression. RESULTS: The prevalence of PAD in the cohort was 5.7%. MPV was significantly associated with PAD prevalence (tertile 1 - 4.4%, tertile 2 - 6.1%, tertile 3 - 7.0%, P for trend=0.003). After adjustment for age, sex, and race, the odds ratio of PAD comparing the highest tertile to the lowest tertile was 1.57 (95% confidence interval 1.15-2.13). After further adjustment for smoking status, hypertension, hypercholesterolemia, diabetes, glomerular filtration rate, body mass index, and platelet count the corresponding odds ratio was 1.58 (95% confidence interval 1.14-2.19). The addition of triglycerides, hemoglobin A1c, and C-reactive protein did not affect the results. The significant association between MPV and PAD was unchanged when MPV was used as a continuous variable. CONCLUSIONS: Mean platelet volume is independently associated with PAD. These findings support the hypothesis that platelet size is an independent predictor of increased risk for PAD

Cardiovascular disease is the number 1 cause of death in the western world and 1 of the leading causes of death worldwide. The lifetime risk of atherosclerotic cardiovascular disease (CVD) for persons at age 50 years, on average, is estimated to be 52% for men and 39% for women, with a wide variation depending on risk factor burden. Assessing patients' cardiovascular risk may be used for the targeting of preventive treatments of individual patients who are asymptomatic but at sufficiently high risk for the development of CVD. Risk stratifying patients for CVD remains challenging, particularly for those with low or intermediate short-term risk. Several algorithms have been described to facilitate the assessment of risk in individual patients. We describe 6 risk algorithms (Framingham Risk Score for coronary heart disease events and for cardiovascular events, Adult Treatment Panel III, SCORE [Systematic Coronary Risk Evaluation] project, Reynolds Risk Score, ASSIGN [Assessing Cardiovascular Risk to Scottish Intercollegiate Guidelines Network/SIGN to Assign Preventative Treatment], and QRISK [QRESEARCH Cardiovascular Risk Algorithm]) for outcomes, population derived/validated, receiver-operating characteristic, variables included, and limitations. Areas of uncertainty include 10-year versus lifetime risk, prediction of CVD or coronary heart disease end points, nonlaboratory-based risk scores, age at which to start, race and sex differences, and whether a risk score should guide therapy. We believe that the best high-risk approach to CVD evaluation and prevention lies in routine testing for cardiovascular risk factors and risk score assessment. We recommend that health care providers discuss the global cardiovascular risk and lifetime cardiovascular risk score assessment with each patient to better explain each patient's future risk. Appropriate intervention, guided by risk assessment, has the potential to bring about a significant reduction in population levels of risk