The occurrence of non-melanoma malignant skin lesions and non-cutaneous squamous-cell carcinoma among metastatic melanoma patients: an observational cohort study in Denmark.

BACKGROUND: Inhibitors of mutant BRAF are emerging as standard of care in patients with metastatic melanoma who carry relevant oncogenic mutations. However, BRAF inhibitors are found to induce cutaneous squamous cell carcinoma (cuSCC). Population-based background rates of cuSCC and non-cutaneous squamous cell carcinoma (non-cuSCC) in the metastatic melanoma population may contextualize safety signals from randomized clinical trials or the clinics. However, these background rates are lacking. METHODS: We conducted a historical cohort study to evaluate the background rates of new-onset non-melanoma skin lesions and non-cuSCC among 2,814 metastatic malignant melanoma patients diagnosed in 1997-2010, identified through the Danish Cancer Registry and the National Pathology Registry. Patients were excluded if they had a history of cancer before the metastatic melanoma diagnosis, other than skin cancers. We determined the incidence of non-melanoma malignant skin lesions and non-cuSCC that occurred post metastatic melanoma diagnosis, censoring patients at death, emigration, or December 31, 2011 (end of study period), whichever came first. RESULTS: The median age at metastatic melanoma diagnosis was 64 years. Over 40% of patients died within one year of metastatic diagnosis and ~70% died within 5 years. The percentages of patients with prior history or prevalent disease at metastatic melanoma diagnosis included: 8.6% with cuSCC or basal cell carcinoma (BCC), 3.9% with actinic keratosis (AK), and 0.7% with Bowen's disease. No patients had past or current non-cuSCC per study exclusion criterion. The incidence of non-melanoma skin lesions during the 6 months post-metastatic melanoma diagnosis was as follows: BCC, 1.8% (42.5 per 1000 person-years [PY]); AK, 0.8% (18.6 per 1000 PY); cuSCC, 0.1% (1.7 per 1000 PY); Bowen's disease, 0.04% (0.8 per 1000 PY); and keratoacanthoma (KA), 0%. Non-cuSCC was observed in 3 patients (0.1%; 2.5 per 1000 PY) at 3 sites: bronchi, heart and lung. CONCLUSION: CuSCC and non-cuSCC were rare events among metastatic melanoma patients.

A proposed modification to Hy's law and Edish criteria in oncology clinical trials using aggregated historical data.

PURPOSE: Identifying drug-induced liver injury is a critical task in drug development and postapproval real-world care. Severe liver injury is identified by the liver chemistry threshold of alanine aminotransferase (ALT) >3× upper limit of normal (ULN) and bilirubin >2× ULN, termed Hy's law by the Food and Drug Administration. These thresholds require discontinuation of the causative drug and are seldom exceeded in most patient populations. However, because maintenance of therapy is critical in the treatment of advanced cancer, customized thresholds may be useful in oncology patient populations, particularly for those with baseline liver chemistries elevations. METHODS: Liver chemistry data from 31 aggregated oncology clinical trials were modeled through a truncated robust multivariate outlier detection (TRMOD) method to develop the decision boundary or threshold for examining liver injury in oncology clinical trials. RESULTS: The boundary of TRMOD identified outliers with an ALT limit 5.0× ULN and total bilirubin limit 2.7× ULN. In addition, TRMOD was applied to the aggregated oncology data to examine fold-baseline ALT and total bilirubin, revealing limits of ALT 6.9× baseline and bilirubin 6.5× baseline. Similar ALT and bilirubin threshold limits were observed for oncology patients both with and without liver metastases. CONCLUSIONS: These higher liver chemistry thresholds examining fold-ULN and fold-baseline data may be valuable in identifying potential severe liver injury and detecting liver safety signals of clinical concern in oncology clinical trials and postapproval settings while helping to avoid premature discontinuation of curative therapy.

Eight genetic loci associated with variation in lipoprotein-associated phospholipase A2 mass and activity and coronary heart disease: meta-analysis of genome-wide association studies from five community-based studies.

AIMS: Lipoprotein-associated phospholipase A2 (Lp-PLA2) generates proinflammatory and proatherogenic compounds in the arterial vascular wall and is a potential therapeutic target in coronary heart disease (CHD). We searched for genetic loci related to Lp-PLA2 mass or activity by a genome-wide association study as part of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. METHODS AND RESULTS: In meta-analyses of findings from five population-based studies, comprising 13 664 subjects, variants at two loci (PLA2G7, CETP) were associated with Lp-PLA2 mass. The strongest signal was at rs1805017 in PLA2G7 [P = 2.4 × 10(-23), log Lp-PLA2 difference per allele (beta): 0.043]. Variants at six loci were associated with Lp-PLA2 activity (PLA2G7, APOC1, CELSR2, LDL, ZNF259, SCARB1), among which the strongest signals were at rs4420638, near the APOE-APOC1-APOC4-APOC2 cluster [P = 4.9 × 10(-30); log Lp-PLA2 difference per allele (beta): -0.054]. There were no significant gene-environment interactions between these eight polymorphisms associated with Lp-PLA2 mass or activity and age, sex, body mass index, or smoking status. Four of the polymorphisms (in APOC1, CELSR2, SCARB1, ZNF259), but not PLA2G7, were significantly associated with CHD in a second study. CONCLUSION: Levels of Lp-PLA2 mass and activity were associated with PLA2G7, the gene coding for this protein. Lipoprotein-associated phospholipase A2 activity was also strongly associated with genetic variants related to low-density lipoprotein cholesterol levels.

Lipoprotein-associated phospholipase A2 activity improves risk discrimination of incident coronary heart disease among women.

BACKGROUND: This study sought to determine the relation between and discriminative capability of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) and coronary heart disease (CHD) in a large population of disease-free women. METHODS: Among participants of the Nurses' Health Study who provided a blood sample, there were 421 cases of incident myocardial infarction during 14 years of follow-up. Controls were matched to cases 2:1 using risk set sampling based on age, smoking, and blood draw date. RESULTS: After conditioning on the matching factors, Lp-PLA(2) activity was significantly associated with myocardial infarction (relative risk [RR] 2.86 for extreme quartiles, 95% CI 1.98-4.12). Upon additional adjustment for lipid, inflammatory, and clinical risk factors, the RR remained statistically significant (RR 1.75, 95% CI 1.09-2.84). The discriminative capability of Lp-PLA(2) was assessed by comparing the area below the receiver operating characteristic curves for models with and without Lp-PLA(2) and by calculating the net reclassification improvement index. The addition of Lp-PLA(2) activity to a multivariable-adjusted model increased the receiver operating characteristic curves from 0.720 to 0.733 and significantly improved the net reclassification improvement index (P = .004). CONCLUSIONS: Levels of Lp-PLA(2) activity were significantly associated with incident CHD among women. In addition, Lp-PLA(2) activity added significantly to CHD risk discrimination.

Recent real-world treatment patterns and outcomes in US patients with relapsed/refractory multiple myeloma.

BACKGROUND: In patients with relapsed/refractory multiple myeloma (RRMM) previously receiving 1-3 therapy lines, newer agents demonstrated improved outcomes versus older agents. Real-world treatment pattern data are limited. We assessed real-world treatment patterns and outcomes in patients with RRMM (≥2 prior therapy lines). RESEARCH DESIGN AND METHODS: An electronic medical record (EMR) analysis and chart review were conducted using International Oncology Network (ION) EMR data. Patients ≥18 years old initiating first-line MM treatment 1 January 2011, to 31 May 2017, were stratified into older/newer treatment cohorts (approval date before vs during/after 2012). Treatment patterns and outcomes were described; no statistical tests were performed. RESULTS: In the EMR analysis (n = 1601) and chart review (n = 456), bortezomib, lenalidomide, and bortezomib-lenalidomide combinations dominated first-line treatment. Median real-world progression-free survival (rwPFS) was 12.0 to 3.5 months (first- to fifth-line), and median real-world overall survival (rwOS) was 48.2 to 5.8 months. A trend for increased rwPFS/rwOS with newer versus older treatments was observed. Most common AEs were fatigue, bone pain, and anemia. EXPERT OPINION: Real-world data describing treatment patterns in relapsed/refractory multiple myeloma are limited. Evaluation of new treatments on patient outcomes will influence treatment patterns and patient outcomes in the real-world setting. CONCLUSIONS: Although a trend for improved rwPFS and rwOS with newer versus older treatments was suggested, additional treatment options to improve patient outcomes are needed.

An Anatomical Site and Genetic-Based Prognostic Model for Patients With Nuclear Protein in Testis (NUT) Midline Carcinoma: Analysis of 124 Patients.

BACKGROUND: NUT midline carcinoma, renamed NUT carcinoma (NC), is an aggressive squamous cancer defined by rearrangement of the NUTM1 gene. Although a subset of patients can be cured, for the majority of patients the prognosis is grim. We sought to classify patients into risk groups based on molecular and clinicopathologic factors at the time of diagnosis. METHODS: Clinicopathologic variables and survival outcomes were extracted for a total of 141 NC patients from the NUT midline carcinoma Registry using questionnaires and medical records. Translocation type was identified by molecular analyses. Survival tree regression analysis was performed to determine risk factors associated with overall survival (OS). RESULTS: For 141 patients, the median age at diagnosis was 23.6 years. Fifty-one percent had thoracic origin compared with 49% nonthoracic sites (41% head and neck, 6% bone or soft tissue, 1% other). The median OS was 6.5 months (95% confidence interval [CI] = 5.8 to 9.1 months). Most patients had the BRD4-NUTM1 fusion (78%), followed by BRD3-NUTM1 (15%) and NSD3-NUTM1 (6%). Survival tree regression identified three statistically distinct risk groups among 124 patients classified by anatomical site and genetics: group A is nonthoracic primary, BRD3-, or NSD3-NUT (n = 12, median OS = 36.5 months, 95% CI = 12.5 to not reported months); group B is nonthoracic primary, BRD4-NUT (n = 45, median OS = 10 months, 95% CI = 7 to 14.6 months); and group C is thoracic primary (n = 67, median OS = 4.4 months, 95% CI = 3.5 to 5.6 months). Only groups A and B had long-term (≥3 years, n = 12) survivors. CONCLUSIONS: We identify three risk groups defined by anatomic site and NUT fusion type. Nonthoracic primary with non-BRD4-NUT fusion confers the best prognosis, followed by nonthoracic primary with BRD4-NUT. Thoracic NC patients, regardless of the NUT fusion, have the worst survival.

Cardiovascular events with increased lipoprotein-associated phospholipase A(2) and low high-density lipoprotein-cholesterol: the Veterans Affairs HDL Intervention Trial.

OBJECTIVE: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), a proinflammatory enzyme that predominantly circulates with low-density lipoprotein (LDL), has been shown in general populations to predict cardiovascular (CV) events. We sought to determine whether increased Lp-PLA(2) would also predict CV events in the absence of high LDL-cholesterol (LDL-C), in a population with low high-density lipoprotein-cholesterol (HDL-C). METHODS AND RESULTS: Plasma Lp-PLA(2) activity was measured at baseline and after 6 months on-trial in 1451 men with low HDL-C (mean, 32 mg/dL) and low LDL-C (mean 110 mg/dL), randomized to either placebo or gemfibrozil therapy in the Veterans Affairs HDL Intervention Trial (VA-HIT). Over a quartile range of increasing Lp-PLA(2) there was a significant increase in LDL-C and decrease in HDL-C (P < 0.0001), and an increased percentage of myocardial infarction (MI), stroke, or CHD death (P=0.03 for trend). In Cox models, adjusted for major CV risk factors, a 1-SD increase in Lp-PLA(2) was associated with a significant increase in CV events (hazard ratio [HR] 1.17 95% CI 1.04 to 1.32). Although gemfibrozil reduced Lp-PLA(2) only modestly (6.6%), at higher levels of Lp-PLA(2) gemfibrozil produced a significant reduction in CV events. CONCLUSIONS: In VA-HIT, a population with low HDL-C and LDL-C, high Lp-PLA(2) independently predicted CV events that were reduced by gemfibrozil.

Prescriber Compliance With Liver Monitoring Guidelines for Pazopanib in the Postapproval Setting: Results From a Distributed Research Network.

OBJECTIVES: Pazopanib received US Food and Drug Administration approval in 2009 for advanced renal cell carcinoma. During clinical development, liver chemistry abnormalities and adverse hepatic events were observed, leading to a boxed warning for hepatotoxicity and detailed label prescriber guidelines for liver monitoring. As part of postapproval regulatory commitments, a cohort study was conducted to assess prescriber compliance with liver monitoring guidelines. METHODS: Over a 4-year period, a distributed network approach was used across 3 databases: US Veterans Affairs Healthcare System, a US outpatient oncology community practice database, and the Dutch PHARMO Database Network. Measures of prescriber compliance were designed using the original pazopanib label guidelines for liver monitoring. RESULTS: Results from the VA (n = 288) and oncology databases (n = 283) indicate that prescriber liver chemistry monitoring was less than 100%: 73% to 74% compliance with baseline testing and 37% to 39% compliance with testing every 4 weeks. Compliance was highest near drug initiation and decreased over time. Among patients who should have had weekly testing, the compliance was 56% in both databases. The more serious elevations examined, including combinations of liver enzyme elevations meeting the laboratory definition of Hy's law were infrequent but always led to appropriate discontinuation of pazopanib. Only 4 patients were identified for analysis in the Dutch database; none had recorded baseline testing. CONCLUSIONS: In this population-based study, prescriber compliance was reasonable near pazopanib initiation but low during subsequent weeks of treatment. This study provides information from real-world community practice settings and offers feedback to regulators on the effectiveness of label monitoring guidelines.

Elevated Lp-PLA2 levels add prognostic information to the metabolic syndrome on incidence of cardiovascular events among middle-aged nondiabetic subjects.

BACKGROUND: To explore potential interrelationships between lipoprotein-associated phospholipase A2 (Lp-PLA2), the metabolic syndrome (MetS), and incident cardiovascular disease (CVD). METHODS AND RESULTS: MetS was defined by the National Cholesterol Education Program Adult treatment Panel III criteria in 4480 nondiabetic Malmö Diet and Cancer Study subjects without history of CVD. Incidence of first CVD event (stroke [130 cases] or myocardial infarction [131]) was monitored over 10 years of follow-up. Lp-PLA2 activity and mass were significantly higher in subjects with MetS. Lp-PLA2 activity compared with Lp-PLA2 mass was more strongly correlated to individual components and increased more linearly with number of MetS components. Elevated Lp-PLA2 activity (top compared with bottom tertile), but not elevated Lp-PLA2 mass, increased risk for incident CVD (relative risk, RR: 1.54, 95% CI 1.07 to 2.24), as did MetS (1.42, 1.06 to 1.90) after taking possible confounders into account. Relative to those without either elevated Lp-PLA2 activity or MetS, combination of MetS and elevated Lp-PLA2 activity increased risk for CVD (1.97, 1.34 to 2.90). Elevated Lp-PLA2 activity without MetS increased risk for CVD (1.40, 1.03 to 1.92) but not MetS without elevated Lp-PLA2 activity (1.46, 0.94 to 2.27). CONCLUSION: Lp-PLA2 is associated to the MetS. Higher plasma levels of Lp-PLA2 increased risk for incident CVD regardless of MetS. The simultaneous presence of elevated Lp-PLA2 activity and MetS may identify an especially high risk individual.

The epidemiology of Lp-PLA(2): distribution and correlation with cardiovascular risk factors in a population-based cohort.

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an enzyme that is produced by inflammatory cells (macrophages, T-lymphocytes and mast cells) and hydrolyzes oxidized phospholipids in LDL. Several epidemiology studies indicate that Lp-PLA(2) appears to be an independent marker of cardiovascular risk. This study was conducted to define the distribution of Lp-PLA(2) in a large population-based cohort and to determine associations between Lp-PLA(2) and other risk factors for CVD. The study group consisted of participants from the Malmö Diet and Cancer study (1992-1994). Lp-PLA(2) (activity and mass) was measured from samples obtained at baseline for 5402 participants (3167 women). A strong correlation was observed between Lp-PLA(2) activity and mass in this study (r=0.57). Highest correlations were observed between Lp-PLA(2) activity and LDL (r=0.45) and LDL/HDL ratio (r=0.54) and a strong inverse correlation to HDL (r=-0.31). The correlations between Lp-PLA(2) mass and lipids were not as strong as the correlation between activity and lipids. Lp-PLA(2) activity and mass were correlated with increased ultrasound determined carotid intima-media thickness. We conclude that Lp-PLA(2) is strongly correlated with several cardiovascular risk factors, especially lipid fractions, and with the degree of carotid artery atherosclerosis. However, the measured variables accounted for only 19% and 35% of the variation in Lp-PLA(2) mass and activity respectively.

Beta-blocker dosing in community-based treatment of heart failure.

BACKGROUND: Community patients with heart failure (HF) are older, less often treated by HF specialists, and have more comorbidity than those in randomized clinical trials. These differences might affect beta-blocker prescribing in HF. METHODS: To explore patterns of beta-blocker prescribing for HF in the community and their association with outcomes, we determined carvedilol doses at end titration in 4113 patients from a community-based beta-blocker HF registry according to physician and patient characteristics, HF severity, and rates of hospitalization and death. RESULTS: Female sex, age > or = 65 years, and left ventricular ejection fraction > or = 35% were associated with lower beta-blocker doses. Average daily dose of beta-blocker was lower with worse baseline New York Heart Association class. More patients of cardiologists achieved carvedilol doses > or = 25 mg twice daily, whereas in those of noncardiologists lower doses were more common. Relative risk of HF hospitalizations or all-cause death was significantly lower with higher doses of beta-blocker. CONCLUSIONS: Beta-blocker dosing in community HF appears lower than in randomized clinical trials, especially when prescribed by noncardiologists. At all doses, patients taking the beta-blocker carvedilol have a lower incidence of death and HF hospitalization than those discontinuing it, regardless of physician type in the community setting.

Comparison of outcomes and usefulness of carvedilol across a spectrum of left ventricular ejection fractions in patients with heart failure in clinical practice.

Heart failure (HF) in the community differs meaningfully from that in clinical trials, particularly the higher prevalence of patients with preserved left ventricular (LV) ejection fraction (EF) typically excluded from clinical trials, thus limiting knowledge of their responsiveness to beta-blocker therapy. From a community-based registry of 4,280 patients with HF starting treatment with the beta blocker carvedilol, we compared characteristics, carvedilol titration, and outcomes of patients according to LVEF >40% or <40% (as in clinical trials) and across the spectrum of LVEF <21%, 21% to 30%, 31% to 40%, and >40%. Patients with preserved EF (LVEF >40%) were older and more often women and hypertensive. Lower LVEF was associated with worse functional class and more HF hospitalizations in the previous year. Carvedilol dose decreased with increasing LVEF. Hospitalization rates for HF related inversely to LVEF before starting carvedilol therapy and decreased from the previous year in all LVEF groups during follow-up. Although 1-year mortality rate decreased from 8% with LVEF < or =20% to 6% with LVEF >40%, adjusted hazard ratios were not significantly different across LVEF groups. Thus, characteristics of community patients with HF vary across the spectrum of LVEF. Patients with HF and preserved EF treated with carvedilol in the community improve symptomatically and experience fewer HF hospitalizations after initiating carvedilol. In conclusion, without a control group, the effect of carvedilol on outcomes is not conclusive and trials of carvedilol in patients with HF and preserved EF should be undertaken.

Tolerability, safety, and efficacy of beta-blockade in black patients with heart failure in the community setting: insights from a large prospective beta-blocker registry.

Heart failure (HF) clinical trials suggest different responses of blacks and whites to beta-blockers. Differences between clinical trial and community settings may also have an impact. The Carvedilol Heart Failure Registry (COHERE) observed experience with carvedilol in 4280 patients with HF in a community setting. This analysis compares characteristics, outcomes, and carvedilol dosing of blacks and whites in COHERE. Compared with whites (n=3433), blacks (n=523) had more severe HF symptoms despite similar systolic function. At similar carvedilol maintenance doses, symptoms improved in 33% of blacks vs 28% of whites, while worsening in 10% and 11%, respectively (both nonsignificant), and HF hospitalization rates were reduced comparably in both groups (-58% vs -56%, respectively; both P<.001). Incidence and hazard ratios of death were similar in blacks and whites (6.9% vs 7.5%, hazard ratio 1.2 vs 1.0, P=.276). Thus carvedilol was similarly effective in blacks and whites with HF in the community setting, consistent with carvedilol clinical trials.

The association of the ankle-brachial index with incident coronary heart disease: the Atherosclerosis Risk In Communities (ARIC) study, 1987-2001.

BACKGROUND: Peripheral arterial disease (PAD), defined by a low ankle-brachial index (ABI), is associated with an increased risk of cardiovascular events, but the risk of coronary heart disease (CHD) over the range of the ABI is not well characterized, nor described for African Americans. METHODS: The ABI was measured in 12186 white and African American men and women in the Atherosclerosis Risk in Communities Study in 1987-89. Fatal and non-fatal CHD events were ascertained through annual telephone contacts, surveys of hospital discharge lists and death certificate data, and clinical examinations, including electrocardiograms, every 3 years. Participants were followed for a median of 13.1 years. Age- and field-center-adjusted hazard ratios (HRs) were estimated using Cox regression models. RESULTS: Over a median 13.1 years follow-up, 964 fatal or non-fatal CHD events accrued. In whites, the age- and field-center-adjusted CHD hazard ratio (HR, 95% CI) for PAD (ABI<0.90) was 2.81 (1.77-4.45) for men and 2.05 (1.20-3.53) for women. In African Americans, the HR for men was 4.86 (2.76-8.47) and for women was 2.34 (1.26-4.35). The CHD risk increased exponentially with decreasing ABI as a continuous function, and continued to decline at ABI values > 1.0, in all race-gender subgroups. The association between the ABI and CHD relative risk was similar for men and women in both race groups. A 0.10 lower ABI increased the CHD hazard by 25% (95% CI 17-34%) in white men, by 20% (8-33%) in white women, by 34% (19-50%) in African American men, and by 32% (17-50%) in African American women. CONCLUSION: African American members of the ARIC cohort had higher prevalences of PAD and greater risk of CHD associated with ABI-defined PAD than did white participants. Unlike in other cohorts, in ARIC the CHD risk failed to increase at high (>1.3) ABI values. We conclude that at this time high ABI values should not be routinely considered a marker for increased CVD risk in the general population. Further research is needed on the value of the ABI at specific cutpoints for risk stratification in the context of traditional risk factors.

Predictors of clinical outcomes in patients given carvedilol for heart failure.

Risk factors for outcomes in heart failure (HF) were derived from populations in clinical trials, at hospital discharge, or in localized geographic or socioeconomic strata before the widespread use of beta blockers. This study observed 4,280 patients in a community-based HF registry for 1 year after completing carvedilol titration. Independent risk factors for death, hospitalization for HF, or hospitalization for cardiovascular reasons other than HF were first identified by age-, gender-, and race-adjusted analyses, then by multivariate analysis adjusted simultaneously for all factors. Over this period, 7% of patients died, 11% were hospitalized for HF, 12% were hospitalized for other cardiovascular reasons, and 27% had > or =1 of these events. The most significant outcome predictors were New York Heart Association class III or IV, history of hospitalization for HF or other cardiovascular reasons, and angina pectoris, all associated with increased odds of having an adverse outcome (all p < or =0.001). The left ventricular ejection fraction was not a significant outcome predictor by multivariate analysis. The odds ratio for an adverse outcome was significantly reduced for patients with hypertensive or idiopathic causes of HF and for those whose physicians had graduated from medical school > or =24 years earlier compared with <14 years earlier (all p <0.005). In conclusion, easily obtained historical information predicts clinical outcomes in patients with HF in the year after initiating carvedilol. In this unselected community population, these historical factors were better predictors of risk than the left ventricular ejection fraction.

Heart failure in community practice: relationship to age and sex in a beta-blocker registry.

Women and the elderly are underrepresented in clinical trials of heart failure (HF). The authors analyzed, by sex and age groups, a registry of 4280 community patients initiating carvedilol for HF. Women (n=1485) were older than men (n=2793) and had worse functional class with higher left ventricular ejection fraction and blood pressure. Women also had more HF hospitalizations, less use of angiotensin-converting enzyme inhibitors, and lower doses of carvedilol. Nevertheless, during 1-year follow-up, both groups experienced greater than 40% reductions in HF hospitalizations (P<.001), with mortality of 7.3% in women vs 9.1% in men (P=.085). With increasing age, left ventricular ejection fraction, blood pressure, and functional class increased, whereas angiotensin-converting enzyme inhibitor use and carvedilol doses decreased. HF hospitalizations fell at least 40% in all age groups after starting carvedilol (P<.001). Characteristics of women and the elderly with HF in the community suggest increased risk, but both populations respond well after initiating carvedilol.

Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina.

OBJECTIVES: The primary objective of the Monotherapy Assessment of Ranolazine In Stable Angina (MARISA) trial was to determine the dose-response relationship of ranolazine, a potentially new anti-anginal compound, on symptom-limited exercise duration. BACKGROUND: Fatty acids rise precipitously in response to stress, including acute myocardial ischemia. Ranolazine is believed to partially inhibit fatty acid oxidation, shift metabolism toward carbohydrate oxidation, and increase the efficiency of oxygen use. METHODS: Patients (n = 191) with angina-limited exercise discontinued anti-anginal medications and were randomized into a double-blind four-period crossover study of sustained-release ranolazine 500, 1,000, or 1,500 mg, or placebo, each administered twice daily for one week. Exercise testing was performed at the end of each treatment during both trough and peak ranolazine plasma concentrations. RESULTS: Exercise duration at trough increased with ranolazine 500, 1,000, and 1,500 mg twice daily by 94, 103, and 116 s, respectively, all greater (p < 0.005) than the 70-s increase on placebo. Dose-related increases in exercise duration at peak and in times to 1 mm ST-segment depression at trough and peak and to angina at trough and peak were also demonstrated (all p < 0.005). Ranolazine had negligible effects on heart rate and blood pressure. One year survival rate combining data from the MARISA trial and its open-label follow-on study was 96.3 +/- 1.7%. CONCLUSIONS: In chronic angina patients, ranolazine monotherapy was well tolerated and increased exercise performance throughout its dosing interval at all doses studied without clinically meaningful hemodynamic effects. One-year survival was not lower than expected in this high-risk patient population. This metabolic approach to treating myocardial ischemia may offer a new therapeutic option for chronic angina patients.

Beta-blocker therapy for heart failure outside the clinical trial setting: findings of a community-based registry.

BACKGROUND: beta-Blockers reduce morbidity and mortality rates in heart failure (HF) clinical trials, but it is unknown whether these findings persist in the community setting. METHODS: A registry was created to survey tolerability and outcomes during initiation and 1-year follow-up of beta-blocker treatment with carvedilol in patients with HF treated by cardiologists (CARD) and primary care physicians (PCP) in the community. RESULTS: A total 4280 patients were enrolled (3121 by 259 CARD, 1159 by 129 PCP). Patient age averaged 67 +/- 13 years; 35% were women and 12% were black. The left ventricular ejection fraction averaged 31 +/- 12; New York Heart Association class was II-III in 86% and IV in 3%. Patients of PCP had higher left ventricular ejection fraction, were older, and more frequently were female, black, diabetic, hypertensive, and in New York Heart Association class III/IV. Minimal difficulty titrating carvedilol was noted by >80% of CARD and PCP. Significantly more CARD-treated patients reached carvedilol doses of 25 mg twice daily (49% vs 27%). Kaplan-Meier all-cause mortality rate was 8.5% at 1 year and did not differ between CARD-treated and PCP-treated patients (8.2% vs 9.3%, P =.254). At least one HF hospitalization occurred in 11% of patients during follow-up, compared with 28% in the preceding year. CONCLUSIONS: Community-based physicians use carvedilol with success approaching that of clinical trials. Overall mortality rates and HF hospitalizations were in the same low range as in clinical trials. Thus, it appears that results of clinical trials with carvedilol for HF can be translated to the community setting.

Disruptions in Liver Function among Cancer Patients and Patients Treated with Tyrosine Kinase Inhibiting Drugs: Comparisons of Two Population-Based Databases.

Liver toxicity is a recognized adverse event associated with small molecule tyrosine kinase inhibitors (TKIs). Electronic Medical Record (EMR) databases offer the most precise data to investigate the rate of liver function test (LFT) elevations; however, they can be limited in sample size and costly to access and analyze. Health insurance claims databases often contain larger samples sizes but may lack key health information. We evaluated the feasibility of utilizing a large claims database to calculate incidence rates (IRs) of LFT elevations among a general cohort of cancer patients and a cohort of patients treated with TKIs by comparing the results to a "gold standard" oncology-specific EMR database. IRs for the TKI cohorts were very similar between the two databases; however, IRs were higher in the EMR database for the cancer cohorts. Possible explanations for these differences include lack of specificity when defining a cancer case, poor capture of laboratory data, or inaccurate assessment of person-time in the insurance claims database. This study suggests that insurance claims data may provide reliable results when investigating liver toxicities associated with oncology drug exposure; however, there are limitations when assessing laboratory outcomes for cohorts defined solely by disease status.

Cardiovascular events in cancer patients treated with highly or moderately emetogenic chemotherapy: results from a population-based study.

Studies on cardiovascular safety in cancer patients treated with highly or moderately emetogenic chemotherapy (HEC or MEC), who may have taken the antiemetic, aprepitant, have been limited to clinical trials and postmarketing spontaneous reports. Our study explored background rates of cardiovascular disease (CVD) events among HEC- or MEC-treated cancer patients in a population-based setting to contextualize events seen in a new drug development program and to determine at a high level whether rates differed by aprepitant usage. Medical and pharmacy claims data from the 2005-2007 IMPACT National Benchmark Database were classified into emetogenic chemotherapy categories and CVD outcomes. Among 5827 HEC/MEC-treated patients, frequencies were highest for hypertension (16-21%) and composites of venous (7-12%) and arterial thromboembolic events (4-7%). Aprepitant users generally did not experience higher frequencies of events compared to nonusers. Our study serves as a useful benchmark of background CVD event rates in a population-based setting of cancer patients.