Faculty Bibliography

OPINION STATEMENT: Triglycerides are routinely obtained with standard lipid testing, but their role in cardiovascular risk is controversial. An excess of triglycerides is commonly encountered in patients with the metabolic syndrome or diabetes, and represents an excess burden of small, dense low-density lipoproteins (LDLs), which confers additive risk for cardiovascular disease. Current guidelines prioritize LDL targets first, but treatment of triglycerides once LDL targets are achieved bears consideration. Beyond lifestyle modification, potential pharmacologic therapies include statins, fibrates, niacin, omega-3 fatty acids and antidiabetic drugs. There are few trials to date comparing these agents directly in the management of hypertriglyceridemia, but available data seems to demonstrate that the greatest benefit of triglyceride lowering is experienced in a subgroup of patients with an atherogenic lipid profile (elevated triglycerides, low high-density lipoprotein (HDL), elevated small, dense LDL particles). Here, we discuss the current understanding of how triglyceride elevations impart cardiovascular risk, current therapies and the data supporting their use, and ongoing studies to elucidate the degree to which treatment of triglycerides modifies risk of future cardiovascular events.

Increased platelet activity is associated with adverse cardiovascular events. The mean platelet volume (MPV) correlates with platelet activity; however, the relation between the MPV and long-term mortality in patients undergoing percutaneous coronary intervention (PCI) is not well established. Furthermore, the role of change in the MPV over time has not been previously evaluated. We evaluated the MPV at baseline, 30 days, 60 days, 90 days, 1 year, 2 years, and 3 years after the procedure in 1,512 patients who underwent PCI. The speed of change in the MPV was estimated using the slope of linear regression. Mortality was determined by query of the Social Security Death Index. During a median of 8.7 years, mortality was 49.3% after PCI. No significant difference was seen in mortality when stratified by MPV quartile (first quartile, 50.1%; second quartile, 47.7%; third quartile, 51.3%; fourth quartile, 48.3%; p = 0.74). For the 839 patients with available data to determine a change in the MPV over time after PCI, mortality was 49.1% and was significantly greater in patients with an increase (52.9%) than in those with a decrease (44.2%) or no change (49.1%) in the MPV over time (p <0.0001). In conclusion, no association was found between the baseline MPV and long-term mortality in patients undergoing PCI. However, increased mortality was found when the MPV increased over time after PCI. Monitoring the MPV after coronary revascularization might play a role in risk stratification.

The mechanism underlying a hyperreactive platelet phenotype remains unknown. Since serotonin has been shown to influence platelet biology and atherothrombosis, we sought to investigate the association of platelet serotonin transporter number, binding affinity, and uptake kinetics with platelet aggregation. A total of 542 healthy volunteers had light transmittance platelet aggregometry measured in response to varying concentrations of epinephrine, serotonin, epinephrine plus serotonin, ADP and collagen. Transporter-dependent serotonin uptake rate was determined (Vmax), as were serotonin transporter number (Bmax) and binding affinity (Kd) using 3H paroxetine binding in a homologous displacement assay, nonlinear regression and validated algorithms for kinetic modelling. Stimulation with submaximal (2muM) epinephrine concentration elicited a distinct, bimodal pattern of platelet aggregation in this population. In contrast, subjects exhibited minimal aggregation in response to serotonin alone. Co-stimulation with submaximal epinephrine and serotonin induced platelet aggregation to a level beyond that observed with either agonist alone and maintained a bimodal response distribution. Subjects with heightened (>60%) platelet aggregation to both epinephrine alone and epinephrine plus serotonin exhibited increased platelet serotonin uptake, and transporter number and affinity. In a population of healthy subjects, co-stimulation with submaximal concentrations of epinephrine and serotonin identifies a subset of individuals with a hyperreactive platelet aggregation profile that is associated with changes in platelet serotonin function.

Summary. Background: The CYP2C19 genotype is a predictor of adverse cardiovascular events in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) treated with clopidogrel. Objectives: We aimed to evaluate the cost-effectiveness of a CYP2C19*2 genotype-guided strategy of antiplatelet therapy in ACS patients undergoing PCI, compared with two 'no testing' strategies (empiric clopidogrel or prasugrel). Methods: We developed a Markov model to compare three strategies. The model captured adverse cardiovascular events and antiplatelet-related complications. Costs were expressed in 2010 US dollars and estimated using diagnosis-related group codes and Medicare reimbursement rates. The net wholesale price for prasugrel was estimated as $5.45 per day. A generic estimate for clopidogrel of $1.00 per day was used and genetic testing was assumed to cost $500. Results: Base case analyses demonstrated little difference between treatment strategies. The genetic testing-guided strategy yielded the most QALYs and was the least costly. Over 15 months, total costs were $18 lower with a gain of 0.004 QALY in the genotype-guided strategy compared with empiric clopidogrel, and $899 lower with a gain of 0.0005 QALY compared with empiric prasugrel. The strongest predictor of the preferred strategy was the relative risk of thrombotic events in carriers compared with wild-type individuals treated with clopidogrel. Above a 47% increased risk, a genotype-guided strategy was the dominant strategy. Above a clopidogrel cost of $3.96 per day, genetic testing was no longer dominant but remained cost-effective. Conclusions: Among ACS patients undergoing PCI, a genotype-guided strategy yields similar outcomes to empiric approaches to treatment, but is marginally less costly and more effective.

BACKGROUND: Current acetylsalicylic acid (ASA) dosing algorithms for the prevention of secondary thrombotic events in acute coronary syndrome (ACS) patients are inconsistent and lack sufficient data support. METHODS: We performed a systematic review of the literature for studies that assessed clinical outcomes in patients with ACS following coronary stent insertion (SI) or medical treatment (MT). Acetylsalicylic acid dosing was stratified into low- (<160 mg) and high- (>/=160 mg) dose categories. Outcomes were assessed at 1, 6, and 12 months and included major bleeding, myocardial infarction, and all-cause death. A random-effects meta-analysis was used to estimate the value of the mean for each outcome variable. RESULTS: Of 12,472 publications identified, 136 studies with 289,330 patients were analyzed. In the 1-month SI analysis, proportions of patients (95% CI) in the low- and high-dose ASA categories experiencing major bleeding were 2.1% (1.5-2.6) and 1.9% (0.0-3.8); proportions with myocardial infarction were 2.1% (1.3-2.8) and 1.8% (0.9-2.6); and proportions of all-cause death were 2.8% (2.2-3.4) and 2.4% (1.3-3.5), respectively. Results were similar in the MT analysis, except that major bleeding rates for low and high doses were 1.7% (1.3-2.2) and 4.0% (2.2-5.8), respectively. Regression analyses suggested that the proportion of patients reporting each of the outcomes evaluated were not significantly different between the low- and high-dose categories, with the exception of the 1-month major bleeding following MT. CONCLUSIONS: Our results suggest no improved clinical outcomes associated with higher ASA maintenance doses in ACS patients receiving SI or MT. In the MT analysis, there was more major bleeding in the first month after an ACS event with high-dose ASA.