Cardiovascular safety in patients receiving roflumilast for the treatment of COPD.

BACKGROUND: Evaluation of cardiovascular safety for new therapies for COPD is important because of a high prevalence of cardiac comorbidities in the COPD population. Hence, we evaluated the effects of roflumilast, a novel oral phosphodiesterase 4 inhibitor developed for the treatment and prevention of COPD exacerbations, on major adverse cardiovascular events (MACEs). METHODS: Intermediate- and long-term placebo-controlled clinical trials of roflumilast in COPD were pooled and assessed for potential cardiovascular events. Studies comprised 14 12- to 52-week placebo-controlled trials in patients with moderate to very severe COPD. All deaths and serious nonfatal cardiovascular events were evaluated by an independent adjudication committee blinded to study and treatment. The MACE composite of cardiovascular death, nonfatal myocardial infarction, and stroke was analyzed according to treatment group. RESULTS: Of 6,563 patients receiving roflumilast, 52 experienced MACEs (14.3 per 1,000 patient-years), and of 5,491 patients receiving placebo, 76 experienced MACEs (22.3 per 1,000 patient-years). The MACE composite rate was significantly lower for roflumilast compared with placebo (hazard ratio, 0.65; 95% CI, 0.45-0.93; P = .019). CONCLUSIONS: A lower rate of cardiovascular events was observed with roflumilast than with placebo in patients with COPD, indicating the lack of a cardiovascular safety signal when treating patients with COPD. Potential cardiovascular benefits of roflumilast should be evaluated in future controlled clinical trials.

Evidence for the role of Epstein Barr Virus infections in the pathogenesis of acute coronary events.

BACKGROUND: The role of viral infections in the pathogenesis of atherosclerosis remains controversial largely due to inconsistent detection of the virus in atherosclerotic lesions. However, viral infections elicit a pro-inflammatory cascade known to be atherogenic and to precipitate acute ischemic events. We have published in vitro data that provide the foundation for a mechanism that reconciles these conflicting observations. To determine the relation between an early viral protein, deoxyuridine triphosphate nucleotidohydrolase (dUTPase), produced following reactivation of Epstein Barr Virus (EBV) to circulating pro-inflammatory cytokines, intercellular adhesion molecule-1 (ICAM-1) and acute coronary events. METHODOLOGY/PRINCIPAL FINDINGS: Blood samples were obtained from 299 patients undergoing percutaneous coronary intervention for stable angina (SA), unstable angina (UA), or acute myocardial infarction (AMI). Plasma concentrations of pro-inflammatory cytokines and neutralizing antibody against EBV-encoded dUTPase were compared in the three patient groups. AMI was associated with the highest measures of interleukin-6 (ANOVA p<0.05; 4.6 ± 2.6 pg/mL in patients with AMI vs. 3.2 ± 2.3 pg/mL in SA). ICAM-1 was significantly higher in patients with AMI (ANOVA p<0.05; 304 ± 116 pg/mL in AMI vs. 265 ± 86 pg/mL SA). The highest values of ICAM-1 were found in patients having an AMI and who were antibody positive for dUTPase (ANOVA p=0.008; 369 ± 183 pg/mL in AMI and positive for dUTPase vs. 249 ± 70 pg/mL in SA negative for dUTPase antibody). CONCLUSIONS/SIGNIFICANCE: These clinical data support a model, based on in vitro studies, by which EBV may precipitate AMI even under conditions of low viral load through the pro-inflammatory action of the early protein dUTPase that is produced even during incomplete viral replication. They further support the putative role of viral infections in the pathogenesis of atherosclerosis and coronary artery events.

Post-menopausal hormone therapy and cardiovascular events: a new paradigm based on pharmacogenetics?

The risk of coronary heart disease (CHD) events increases in women after menopause and it was thought that hormone therapy (HT) would decrease this risk. However, numerous large randomized clinical trials have not demonstrated decreased risk in secondary prevention and some have actually shown increased risk of cardiovascular events with HT in primary prevention. Platelets are involved in CHD events and platelet glycoprotein single-nucleotide polymorphisms may help to identify risk and treatment efficacy. It may become a plausible strategy in the future for clinicians to identify, by genotyping, high-risk patients who would benefit from HT to reduce CHD risk as well as to identify patients with neutral risk for whom HT could be harmful.

Recovery of normal ventricular function in patients with dilated cardiomyopathy: predictors of an increasingly prevalent clinical event.

BACKGROUND: This investigation was designed to identify clinical variables associated with recovery of normal ventricular function in patients with dilated cardiomyopathy treated with medical therapy. Recovery of normal ventricular function with medical treatment of patients with dilated cardiomyopathy is observed with increasing frequency. However, the clinical variables associated with such dramatic improvement of ventricular performance are poorly defined. METHODS: Fifty-three patients with dilated cardiomyopathy and reduced ejection fractions who achieved an increase in ejection fraction to > or = 40% with medical therapy were identified during follow-up in a dedicated heart failure clinic. A cohort of patients frequency-matched on baseline ejection fraction who did not recover ventricular systolic function to this magnitude constituted the control group. Clinical variables characterizing the 2 groups were compared by univariable analysis. Variables that significantly differed between the 2 groups were entered in a stepwise logistic regression analysis to identify factors independently associated with recovery of ejection fraction to > or = 40%. RESULTS: In the final logistic regression model, QRS duration, sex, etiology of cardiomyopathy, diabetes, and systolic blood pressure were significantly associated with improvement of ejection fraction to > or = 40%. CONCLUSIONS: Five clinical variables that are independently associated with improvement of left ventricular ejection fraction to normal or near-normal values with medical therapy alone were identified by this modeling process. These variables may be used to discriminate between patients in whom ventricular function will normalize with medical therapy alone and those who will require more aggressive pharmacologic or device therapy.

Endothelial nitric oxide synthase gene: prospects for treatment of heart disease.

Nitric oxide functions as a signaling molecule with a well-established role in vascular homeostasis. It is synthesized from the oxidation of L-arginine by the enzyme, endothelial nitric oxide synthase (eNOS). The eNOS gene has a number of polymorphic sites, including SNPs, dinucleotide repeats and variable number tandem repeat sequences, and the opportunity exists to investigate polymorphic functional correlates as well as disease-specific associations, especially in cardiovascular disease, including coronary artery disease, and its most severe consequence, myocardial infarction. A number of clinical and functional correlative studies involving eNOS polymorphisms have been reported and are presented. The promise and complexity of pharmacogenetics is illustrated using eNOS as an example because of its relationship with cardiovascular biology and pathology. In this review, we will discuss the impact of nitric oxide, eNOS, genetic regulation, clinical investigation and, ultimately, prospects for treatment of heart disease.

Data mining tools for genotype-phenotype correlation.

Single Nucleotide Polymorphisms (SNPs) may be the key to diagnosing and treating certain diseases. A preliminary study was conducted at The Ohio State University Medical Center Information Warehouse to correlate such SNPs with a selected group of lab values for cardiology patients. Early results show that data mining tools can be valuable for understanding such correlations, but further refinement of the methodology and data preparation is needed to fully realize such value.

Detection of coronary artery disease in orthotopic heart transplant recipients with 64-detector row computed tomography angiography.

Cardiac transplant recipients develop coronary artery disease in the form of cardiac allograft vasculopathy (CAV), and still undergo annual left heart catheterizations for detection at most centers. We prospectively enrolled 20 cardiac transplant recipients scheduled for annual left heart catheterization with X-ray coronary angiography (XRA) to also undergo electrocardiographically gated coronary computed tomography angiography (CTA), which was performed on a 64-detector computed tomography scanner. CTA detected more CAV vs XRA in 4 patients and less CAV in 0 patient, resulting in good overall agreement between the two modalities (kappa = 0.69). CTA may be superior to conventional catheter-based angiography to identify non-obstructive vessel wall disease that may go unrecognized with catheter-based angiography alone.

The safety and efficacy of aspirin and clopidogrel as a combination treatment in patients with coronary heart disease.

The use of aspirin and clopidogrel in combination has become part of the standard clinical care of patients with coronary artery disease. The use of this combination provides significant benefits compared with the use of aspirin alone in patients with acute coronary syndromes, and in patients treated with percutaneous coronary intervention with stent placement (both bare metal and drug-eluting stents). Clinical trials have demonstrated significant efficacy of this dual therapy; however, there is the potential for significant bleeding complications from the synergistic antiplatelet effects. In total, it appears that when there is vessel injury (mechanical from perctutaneous coronary intervention or a ruptured plaque), dual antiplatelet therapy with aspirin and clopidogrel results in improved outcomes, albeit with a small but significant inherent risk of increased bleeding.

Estradiol increases platelet aggregation in Pl(A1/A1) individuals.

BACKGROUND: The platelet glycoprotein IIb/IIIa receptor is a key mediator of platelet aggregation and intracoronary thrombosis. Studies have suggested that hormone replacement therapy (HRT) may increase coronary events in postmenopausal women. OBJECTIVES: We sought to characterize the relationship between the estrogen concentration expected in HRT and platelet aggregation. DESIGN AND RESULTS: Platelet aggregation studies were performed using epinephrine on 30 healthy individuals (15 Pl(A1/A1) and 15 Pl(A1/A2)) before and after incubation with beta-estradiol (E2) (10(-11) mol/L). The effect of E2 10(-11) mol/L on Pl(A1/A1) platelets demonstrated a significant increase (P = .03) in aggregation compared with baseline. In contrast, with the same concentration of E2, aggregation of Pl(A1/A2) platelets decreased significantly compared with baseline (P < .0001). CONCLUSIONS: Estrogen concentration similar to that expected in HRT resulted in an increase in platelet aggregation in Pl(A1/A1) individuals, but not in Pl(A1/A2) individuals. The data may provide further insight for the increase in coronary events seen in HRT clinical trials and suggest that further evaluation is needed to better define the role of pharmacogenetics in HRT.

Effect of platelet antigen polymorphism on platelet inhibition by aspirin, clopidogrel, or their combination.

OBJECTIVES: We studied the modifier effect of platelet antigen polymorphism (PlA2) on platelet inhibition by acetylsalicylic acid (ASA, i.e., aspirin), clopidogrel, or their combination in patients with coronary heart disease. BACKGROUND: Clopidogrel, when administered with ASA, was shown to significantly improve the outcome of patients with acute coronary syndromes compared with patients receiving only ASA. We have shown previously that the effect of ASA on platelets is modified by the glycoprotein IIIa single nucleotide polymorphism PlA2. Hence, an important pharmacogenetic question remains whether the antiplatelet effect of clopidogrel is uniform for all patients or, like acetylsalicylic acid, more selective. METHODS: Thirty PlA1/A1 and 30 PlA1/A2 patients were assigned randomly to ASA 325 mg/day, clopidogrel 75 mg/day, or both. After 10 days, platelet function was studied. RESULTS: Clopidogrel provided stronger platelet inhibition than ASA with adenosine diphosphate as the agonist, and combination therapy resulted in greater inhibition than either inhibitor used alone (p < 0.0001). The use of ASA resulted in greater inhibition compared with clopidogrel with epinephrine (p < 0.0001) and collagen as agonists (p < 0.0001). With collagen as the agonist, platelets from PlA1/A2 donors were markedly and significantly less inhibited by ASA (p = 0.005). In contrast, with clopidogrel, no significant difference could be detected between inhibition of Pl(A1/A1) and Pl(A1/A2) platelets. CONCLUSIONS: The combination of ASA and clopidogrel appears superior to either agent alone in inhibiting platelet function. Pl(A2) functions as an important modifier for platelet responsiveness to ASA but not to clopidogrel. These findings could have significant impact on the future design of pharmacogenetic antithrombotic strategies for patients with coronary heart disease.

Pharmacogenetics of multigenic disease: heart disease as an example.

We now have a greater understanding of the workings of the human genome as well as a wide assortment of pharmacological and mechanical therapies that clearly improve mortality and quality of life for our patients with cardiovascular disease, but these areas of therapeutics and genomics have essentially advanced independently with little interaction up until recently. Pharmacogenetics is the study of the effect of a medication as it relates to single or defined sets of genes. A major goal will be to integrate the two so that true personalized therapy can be delivered. This review explores the clinical implications of the complex interactions in multigenic disease and pharmacology with examples of atherosclerosis and heart failure. The therapies of today are the direct result of understanding the epidemiological, molecular and genetic basis of cardiovascular disease with the application to clinical practice. The complexity of multigenic disease and the promise of pharmacogenetics will require that we improve on the methods of drug evaluation and this includes the need for new statistical methods, bioinformatics, and novel clinical trial design with sufficient power to detect differences in therapy. There must be a continued effort to apply biological and mechanistic plausibility in understanding disease and pharmacology but openness to new ideas and concepts, especially in understanding the workings of the genome.

A meta-analysis of studies on the association of the platelet PlA polymorphism of glycoprotein IIIa and risk of coronary heart disease.

The Pl(A2) polymorphism of the glycoprotein IIIa subunit of the fibrinogen receptor (GPIIb-IIIa) has been reported by some studies to be associated with an increased risk of coronary thrombosis. Following the first paper on the subject in 1996, a large number of studies have investigated the relationship between this polymorphism and coronary thrombosis, either at the epidemiological or at the cellular and molecular levels. The cellular and molecular studies have shown in a consistent manner that this polymorphism increases platelet responsiveness. In contrast, epidemiological studies have generated inconsistent results regarding the clinical impact of Pl(A2). We consider 12 epidemiological studies that investigate the link between presence/absence of this polymorphism and presence/absence of coronary heart disease. Each is a case-control study that reports an odds ratio. The studies are not directly comparable because they differ greatly in their patient pools and also in the way the data are analysed. We present several meta-analyses of these 12 studies. The simplest one is based on a standard frequentist random effects model with a normal distribution for the study effects (the per-study population log-odds ratios). We also consider a Bayesian version of this model, with a diffuse prior for the mean and variance of the normal distribution of the study effects. The conclusions from both of these analyses is about the same, and is that there is evidence that the Pl(A2) polymorphism is associated with an increased risk of coronary heart disease. A look at the reported log-odds ratios across studies suggests that the study effects do not come from a symmetric distribution. For this reason, we also consider semi-parametric priors for the distribution of the study effects. These priors are specifically designed for this kind of meta-analysis, and are based on a certain class of mixtures of Dirichlet priors. They can be designed to concentrate most of their mass around the family of normal distributions, but still allow for any other distribution. The semi-parametric Bayesian model continues to give evidence of an association between the Pl(A2) polymorphism and the risk of coronary heart disease.