Implementation of pharmacogenetics: the University of Maryland Personalized Anti-platelet Pharmacogenetics Program.

Despite a substantial evidence base, implementation of pharmacogenetics into routine patient care has been slow due to a number of non-trivial practical barriers. We implemented a Personalized Anti-platelet Pharmacogenetics Program (PAP3) for cardiac catheterization patients at the University of Maryland Medical Center and the Baltimore Veterans Administration Medical Center Patients' are offered CYP2C19 genetic testing, which is performed in our Clinical Laboratory Improvement Amendment (CLIA)-certified Translational Genomics Laboratory. Results are returned within 5 hr along with clinical decision support that includes interpretation of results and prescribing recommendations for anti-platelet therapy based on the Clinical Pharmacogenetics Implementation Consortium guidelines. Now with a working template for PAP3, implementation of other drug-gene pairs is in process. Lessons learned as described in this article may prove useful to other medical centers as they implement pharmacogenetics into patient care, a critical step in the pathway to personalized and genomic medicine.

Multisite Investigation of Outcomes With Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention.

OBJECTIVES: This multicenter pragmatic investigation assessed outcomes following clinical implementation of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention (PCI). BACKGROUND: CYP2C19 loss-of-function alleles impair clopidogrel effectiveness after PCI. METHODS: After clinical genotyping, each institution recommended alternative antiplatelet therapy (prasugrel, ticagrelor) in PCI patients with a loss-of-function allele. Major adverse cardiovascular events (defined as myocardial infarction, stroke, or death) within 12 months of PCI were compared between patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy. Risk was also compared between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy. Cox regression was performed, adjusting for group differences with inverse probability of treatment weights. RESULTS: Among 1,815 patients, 572 (31.5%) had a loss-of-function allele. The risk for major adverse cardiovascular events was significantly higher in patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy (23.4 vs. 8.7 per 100 patient-years; adjusted hazard ratio: 2.26; 95% confidence interval: 1.18 to 4.32; p = 0.013). Similar results were observed among 1,210 patients with acute coronary syndromes at the time of PCI (adjusted hazard ratio: 2.87; 95% confidence interval: 1.35 to 6.09; p = 0.013). There was no difference in major adverse cardiovascular events between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy (adjusted hazard ratio: 1.14; 95% confidence interval: 0.69 to 1.88; p = 0.60). CONCLUSIONS: These data from real-world observations demonstrate a higher risk for cardiovascular events in patients with a CYP2C19 loss-of-function allele if clopidogrel versus alternative therapy is prescribed. A future randomized study of genotype-guided antiplatelet therapy may be of value.

Fasting plasma glucose predicts survival and angiographic progression in high-risk postmenopausal women with coronary artery disease.

BACKGROUND: We studied the association of baseline fasting plasma glucose (FPG) levels with survival and coronary artery disease (CAD) progression among postmenopausal women without unstable angina. METHODS: Women were recruited from seven centers in the Women's Angiographic Vitamin and Estrogen Trial (WAVE) (n = 423). Event follow-up was available for 400 women (65.1 +/- 8.5 years, 66% white, 92% hypertensive, 19% smokers, 67% hypercholesterolemic). Thirty-eight percent of the women had diabetes or FPG > 125 mg/dL, and 21% had a fasting glucose 100-125 mg/dL. Follow-up angiography was performed in 304 women. Cox regression was used to model survival from a composite outcome of death or myocardial infarction (D/MI, 26 events; median follow-up 2.4 years). Angiographic progression was analyzed quantitatively using linear regression accounting for baseline minimum lumen diameter (MLD), follow-up time, and intrasubject correlations using generalized estimating equations. Regression analyses were adjusted for follow-up time, baseline age, treatment assignment, and Framingham risk (excluding diabetes). RESULTS: Women with impaired fasting glucose/diabetes mellitus (IFG/DM) had a relative risk (RR) of D/MI of 4.2 ( p = 0.009). In all women, each 10 mg/dL increase in FPG was associated with an 11% increase ( p < 0.001) in the hazard of D/MI. Each 10 mg/dL increase in FPG was associated with a 6.8 mum decrease in MLD over the follow-up period ( p = 0.005). CONCLUSIONS: Higher FPG is associated with increased risk of D/MI and greater narrowing of the coronary lumen in women with CAD. Aggressive monitoring of glucose levels may be beneficial for secondary CAD prevention.

Acute coronary syndromes in the elderly.

Elderly patients with acute coronary syndromes suffer higher mortality and more morbidity than their younger counterparts because they have higher prevalence of cardiac risk factors and have lived with those risk factors longer, physiologic effects of aging lead to sicker patients at presentation and impaired healing processes, they are more sensitive to some of the side effects of some of our higher risk therapies, and they are less likely to receive therapies that have been proven to improve outcome. Close attention must be paid to risk assessment. We must continue to strive to match risky therapies to high-risk patients, those more likely to derive benefit. Age remains one of the most powerful cardiac risk factors of all.

Angina pectoris: evaluation in the office.

Angina pectoris is a clinical manifestation of myocardial ischemia. Complete evaluation consists of a review of risk factors, a careful history, and, typically, a provocative test. Stress testing can be performed with exercise(treadmill, bicycle, or arm ergometry) or pharmacologic agents that increase cardiac work (dobutamine) or dilate the coronary vessels (adenosine or dipyridamole). Patients who have high-risk features found by clinical history or by stress testing should be referred for coronary angiography and possible revascularization. Comprehensive management of patients who have angina (with or without revascularization) includes smoking cessation,diet and weight control, vasculoprotective drugs (aspirin, statins, and possibly ACE inhibitors), and antianginal medications (nitrates, D-blockers, and calcium channel blockers). These strategies have led to an important reduction in morbidity and mortality over the past 2 decades, and the focus on implementing guidelines for patients who are currently undertreated is expected to improve outcomes further.

Early management of ST-segment elevation myocardial infarction.

Improvements in the management of ST-segment elevation myocardial infarction(STEMI) have led to a reduction in the acute and long-term mortality rates. The first important decision in the care of patients who have STEMI is the method of reperfusion. Whether percutaneous intervention (PCI) or fibrinolytic therapy is chosen depends on a number of factors. This article reviews the data on PCI and fibrinolytics in the context of consensus guidelines, outlines adjunctive medical therapies important in the first 24 hours, and discusses a strategy for making the decisions and a hypothetical construct for evaluating new drugs and procedures in the future.

Cardiac risk assessment: matching intensity of therapy to risk.

Simple RSS allow for rapid decision making in the emergency department. The data presented in this article suggest that for patients at the highest risk and the lowest risk for complications of NSTEACS, the scoring systems work well and allow effective triage and treatment. For patients at intermediate risk (30%-40% of all patients who have ACS), however, it is not clear whether early aggressive treatment with cardiac catheterization or routine conservative management should be the standard of care. The consensus guidelines are vague, and the scoring systems discriminate less well for these patients. The authors think that patients at intermediate risk are best served by initial screening with an RSS like the TRS (with risk scores of 3-4), followed by a multimarker strategy to define risk better. They also think that the next step is to design clinical trials to test strategies of care defined prospectively by risk. This step would, in the authors' opinion, begin the next round of the cycle of clinical therapeutics [31]. The treatment of patients who have NSTE ACS has been characterized in the past 2 decades by care based on evidence from many excellent clinical tri-als. The consensus panels have convened and guide patient management. Quality-improvement initiatives such as CRUSADE and GRACE give feedback to improve compliance with guidelines. The understanding of risk is developing with the help of these scoring systems. Discovery is ongoing. The next decade of acute cardiac care will focus on early identification of patients at high risk and on matching the most intensive treatments to the patients most in need. Excessive testing and care promotes cost inefficiency and, perhaps, increased hazard for some patients. New trials are needed to move these new hypotheses back into practice.

L-arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial.

CONTEXT: The amino acid L-arginine is a substrate for nitric oxide synthase and is increasingly used as a health supplement. Prior studies suggest that L-arginine has the potential to reduce vascular stiffness. OBJECTIVE: To determine whether the addition of L-arginine to standard postinfarction therapy reduces vascular stiffness and improves ejection fraction over 6-month follow-up in patients following acute ST-segment elevation myocardial infarction. DESIGN AND SETTING: Single-center, randomized, double-blind, placebo-controlled trial with enrollment from February 2002 to June 2004. PATIENTS: A total of 153 patients following a first ST-segment elevation myocardial infarction were enrolled; 77 patients were 60 years or older. INTERVENTION: Patients were randomly assigned to receive L-arginine (goal dose of 3 g 3 times a day) or matching placebo for 6 months. MAIN OUTCOME MEASURES: Change in gated blood pool-derived ejection fraction over 6 months in patients 60 years or older randomized to receive L-arginine compared with those assigned to receive placebo. Secondary outcomes included change in ejection fraction in all patients enrolled, change in noninvasive measures of vascular stiffness, and clinical events. RESULTS: Baseline characteristics, vascular stiffness measurements, and left ventricular function were similar between participants randomized to receive placebo or L-arginine. The mean (SD) age was 60 (13.6) years; of the participants, 104 (68%) were men. There was no significant change from baseline to 6 months in the vascular stiffness measurements or left ventricular ejection fraction in either of the 2 groups, including those 60 years or older and the entire study group. However, 6 participants (8.6%) in the L-arginine group died during the 6-month study period vs none in the placebo group (P = .01). Because of the safety concerns, the data and safety monitoring committee closed enrollment. CONCLUSIONS: L-arginine, when added to standard postinfarction therapies, does not improve vascular stiffness measurements or ejection fraction and may be associated with higher postinfarction mortality. L-arginine should not be recommended following acute myocardial infarction. Clinical Trial Registration ClinicalTrials.gov, NCT00051376.

Exaggerated exercise blood pressure is related to impaired endothelial vasodilator function.

BACKGROUND: Persons with high normal blood pressure (BP) or mild hypertension who also have an exaggerated BP response to exercise are at risk for worsening hypertension. The mechanisms that explain this relationship are unknown. We examined the relationships of endothelial vasodilator function and of aortic stiffness with exercise BP. METHODS: Subjects were 38 men and 44 women, aged 55 to 75 years, with untreated high normal BP or mild hypertension but otherwise healthy. Exercise was performed on a treadmill. Endothelial vasodilator function was assessed as brachial artery flow-mediated vasodilation (FMD) during reactive hyperemia. Aortic stiffness was measured as pulse wave velocity (PWV). RESULTS: Among men, resting systolic BP explained 34% of the variance (P < .01) in maximal exercise systolic BP and FMD explained an additional 11% (P < .01); resting systolic BP explained 23% of the variance in maximal pulse pressure (PP) (P < .01), and FMD explained an additional 10% (P < .01). Among women, resting systolic BP was the only independent correlate of maximal systolic BP (R2 = 0.12, P < .03) and FMD correlated negatively with maximal PP (R2 = 0.12, P < .03). Among men, FMD was the only independent correlate of the difference between resting and maximal systolic BP (R2 = 0.20, P < .02). The FMD was the only independent correlate of the difference between resting and maximal PP among men (R2 = 0.17, P < .03) and among women (R2 = 0.12, P < .03). The PWV did not correlate with exercise BP responses. CONCLUSIONS: These results suggest that impaired endothelial vasodilator function may be a mechanism contributing to exercise hypertension and may also be one link between exaggerated exercise BP and worsening hypertension.

Relationships of insulin sensitivity with fatness and fitness and in older men and women.

PURPOSE: Increased body fatness, especially abdominal obesity, and low levels of fitness are associated with decreased insulin sensitivity. Men and women differ in obesity, body fat distribution, and fitness levels. This cross-sectional study evaluated sex differences in the relationships of insulin sensitivity with fatness and fitness and obesity. METHODS: Subjects were nonsmoking, nondiabetic, sedentary men (n = 50) and women (n = 61) aged 55-75 years with mild hypertension. Study measures were insulin sensitivity (QUICKI: 1/[log(fasting insulin) + log(fasting glucose)]), lipids and lipoproteins, total body fatness using dual energy x-ray absorptiometry (DXA), anthropometrics, abdominal obesity using magnetic resonance imaging (MRI), and aerobic fitness assessed as Vo(2) peak during treadmill testing. RESULTS: Women had a higher percentage of body fat and more abdominal subcutaneous and less visceral fat than men. Among women, QUICKI correlated negatively with body mass index (BMI), percent body fat, abdominal total fat, subcutaneous fat, and visceral fat but not with lipids. Among men, QUICKI correlated negatively with total and abdominal fatness and triglycerides. QUICKI correlated with fitness in men only. Using stepwise regression, among women, decreased total abdominal fat accounted for 33%, and postmenopausal hormone therapy accounted for an additional 5% of the variance in QUICKI. Among men, only a higher level of fitness independently correlated with insulin sensitivity, accounting for 21% of the variance (p < 0.01). CONCLUSIONS: Abdominal obesity among women and fitness among men were the strongest determinants of insulin sensitivity in this older cohort. This raises the question whether there are sex differences in the lifestyle changes that would be most effective in improving insulin sensitivity.

Development of an observational tool on computer use during rounds.

We present an observational tool to capture computer usage patterns during rounds to inform designs of information and communication technology to support clinical discourse during rounds. The tool captures choreography and logistics of information exchanges supported by clinical information systems during rounds. We developed the tool as part of an ongoing video-recording study of communication to under-stand how, when, and why computers are used during multidisciplinary clinical rounds.