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.

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.

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.

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.

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.

Comorbidities and Concomitant Medication Use in Men with Prostate Cancer or High Levels of PSA Compared to Matched Controls: A GPRD Analysis.

Comorbidity influences screening practice, treatment choice, quality of life, and survival. The presence of comorbidities and medication use could place patients at greater risks of adverse effects from certain interventions. We conducted a longitudinal cohort study in the General Practice Research Database to better understand comorbidities and medication use in men with or at risk of prostate cancer (CaP). Compared with men with similar age but no CaP, CaP patients had higher incidence of urinary tract infection, impotence and breast disorder, and 2.6-fold higher all-cause mortality. Among men with elevated prostate-specific antigen (PSA) but no CaP, the mortality rates were slightly lower, and fewer differences in comorbidities and medication use were noted compared to men without elevated PSA. Many prevalent comorbidities and medications were consistent across groups and are typical of an older male population. These real-world data are broadly applicable throughout the drug development cycle and subsequent patient management.

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.

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.

Lipoprotein-associated phospholipase A2 activity and incident coronary heart disease among men and women with type 2 diabetes.

OBJECTIVE: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) has been shown to be associated with increased risk of coronary heart disease (CHD) in general adult populations. Because men and women with type 2 diabetes are at particularly high risk for CHD, the aim of this study was to assess the association of Lp-PLA(2) with future coronary events among diabetic men and women. RESEARCH DESIGN AND METHODS: We measured Lp-PLA(2) activity among 740 men and 777 women with confirmed diabetes enrolled in the Health Professionals Follow-Up Study (HPFS) and Nurses' Health Study (NHS). Participants were free of all cardiovascular disease and cancer at baseline. RESULTS: During 10 years of follow-up among men and 14 years among women, we documented 178 and 146 cases of CHD, respectively. We defined CHD as coronary artery bypass graft, angioplasty, nonfatal myocardial infarction, and fatal CHD. After adjustment for age, smoking, medical history, and biomarkers including C-reactive protein, HDL, and LDL, the relative risk of total CHD comparing extreme tertiles of Lp-PLA(2) was 1.39 (95% CI 1.01-1.90; P trend = 0.03). When we restricted analyses to only nonfatal myocardial infarction and fatal CHD, the relative risk was 1.75 (95% CI 1.05-2.92; P for trend = 0.001). LDL, HDL, C-reactive protein, hormone replacement therapy use, and diabetes duration did not modify these relationships. CONCLUSIONS: Levels of Lp-PLA(2) activity were significantly associated with incident CHD among men and women with type 2 diabetes, independent of traditional and inflammatory risk factors. This positive association was strongest for more severe clinical end points.

Dietary, lifestyle, and clinical predictors of lipoprotein-associated phospholipase A2 activity in individuals without coronary artery disease.

BACKGROUND: Elevated lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) may be positively associated with risk of coronary artery disease, yet little is known about potentially modifiable factors related to Lp-PLA(2). OBJECTIVE: The aim of this study was to determine dietary, lifestyle, and clinical measures associated with Lp-PLA(2) activity. DESIGN: We measured Lp-PLA(2) activity in 853 female participants of the Nurses' Health Study and 878 male participants of the Health Professionals Follow-Up Study who were free of cancer and cardiovascular disease. Multivariable linear regression models were used to assess the relation between potentially modifiable factors and Lp-PLA(2). RESULTS: The replacement of 5% of energy from carbohydrates with energy from protein was associated with 2.2 nmol . min(-1) . mL(-1) lower levels of Lp-PLA(2) (95% CI: -3.1, -0.4) activity, and every 15-g/d increase in alcohol consumption was associated with 4.4 nmol . min(-1) . mL(-1) lower levels of Lp-PLA(2) activity (95% CI: -6.4, -2.4). Smoking (beta = 10.2; 95% CI: 4.8, 15.5), being overweight (beta = 7.5; 95% CI: 3.6, 11.3), aspirin use (beta = 6.0; 95% CI: 2.1, 10.0), hypercholesterolemia (beta = 15.0; 95% CI: 11.3, 18.8), and age (beta = 2.5; 95% CI: 1.34, 3.74) were associated with elevated Lp-PLA(2) activity, whereas postmenopausal hormone use (beta = -15.8; 95% CI: -19.4, -12.1) and cholesterol medication use (beta = -9.6; 95% CI: -18.2, -1.1) were inversely associated. CONCLUSION: We found that not smoking, use of postmenopausal hormones, having a body mass index (in kg/m(2)) < or =25, increased alcohol consumption, and increased protein consumption all represent potential modifiable factors that may favorably influence Lp-PLA(2) activity.

Lipoprotein-associated phospholipase A(2) and risk of congestive heart failure in older adults: the Cardiovascular Health Study.

BACKGROUND: Inflammation may be a causative factor in congestive heart failure (CHF). Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an inflammation marker associated with vascular risk. One previous study showed an association of Lp-PLA(2) activity with CHF risk, but there were only 94 CHF cases and Lp-PLA(2) antigen, which is available clinically in the United States, was not measured. METHODS AND RESULTS: We measured baseline Lp-PLA(2) antigen and activity in 3991 men and women without baseline CHF or cardiovascular disease who were participating in the Cardiovascular Health Study, a prospective observational study of adults 65 years or older. Cox proportional hazards models adjusted for age, sex, clinic site, race, low-density and high-density lipoprotein cholesterol, body mass index, systolic and diastolic blood pressure, hypertension, smoking status, pack-years, and diabetes were used to calculate hazard ratios and 95% CIs for incident CHF. Further models adjusted for coronary disease events during follow-up and C-reactive protein. Eight hundred twenty-nine participants developed CHF during 12.1 years. Adjusted hazard ratios for CHF with Lp-PLA(2) in the fourth compared with the first quartile were 1.44 (95% CI, 1.16 to 1.79) for Lp-PLA(2) antigen and 1.06 (95% CI, 0.84 to 1.32) for activity. Adjustment for incident coronary disease attenuated the hazard ratio for Lp-PLA(2) antigen to 1.26 (95% CI, 1.02 to 1.57), adjustment for C-reactive protein had minimal impact. CONCLUSIONS: Lp-PLA(2) antigen was associated with risk of future CHF in older people, independent of CHF and coronary risk factors, and partly mediated by coronary disease events. Further clinical and basic research is needed to better understand the role of Lp-PLA(2) in CHF.

Lp-PLA2 activity and mass are associated with increased incidence of ischemic stroke: a population-based cohort study from Malmö, Sweden.

BACKGROUND: Data regarding the association between lipoprotein-associated phospholipase A2 (Lp-PLA(2)) level and incidence of cardiovascular (CV) events are conflicting. This prospective urban population-based study explored the relationship between baseline Lp-PLA(2) activity and mass, respectively, levels and incidence of first coronary heart disease (CHD) and ischemic stroke, respectively. METHODS: Lp-PLA(2) activity and mass were assessed in 5393 (60% women) subjects who participated in the Malmö Diet and Cancer Study cardiovascular program during 1991-1994. RESULTS: In all 347 subjects had an event (195 CHD and 152 ischemic strokes) during the follow-up period (mean 10.6+/-1.7 years). In an age-, sex- and CV risk factors-adjusted Cox regression analysis, comparing top to bottom tertile of Lp-PLA(2) activity, the relative risk [RR; 95% confidence interval (CI)] for incident CHD and ischemic stroke events were 1.48; 0.92-2.37 and RR: 1.94; 1.15-3.26, respectively. The corresponding figures for Lp-PLA(2) mass were 0.95; 0.65-1.40 and RR: 1.92; 1.20-3.10. CONCLUSION: Elevated levels of Lp-PLA(2) activity and mass, respectively, were in this study, independently of established risk factors related to the incidence of ischemic stroke but after adjustment for lipids not significant related to incident CHD.

The association between lipoprotein-associated phospholipase A2 and cardiovascular disease and total mortality in vascular medicine patients.

INTRODUCTION: In some community-based studies, lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) has been shown to be independently predictive of future fatal and nonfatal cardiovascular disease (CVD) events. We tested the hypothesis that Lp-PLA(2) is independently predictive of mortality in high-risk patients from a vascular laboratory. METHODS: Between 1990 and 1994, patients seen in the previous 10 years for noninvasive lower extremity arterial testing were invited to return for a vascular examination of the lower extremities. By medical record review, we identified 2265 eligible patients; of these, 508 returned for interviews, blood collection, and arterial examination and represent those who had survived, could be located, and were willing to participate. The 508 subjects were followed up for an average of 6.7 years until the end of the study period on December 31, 2001. Vital status was ascertained by multiple searches of the Social Security Death Index. The primary outcomes for this study were time to any, CVD, and coronary heart disease (CHD) mortality. RESULTS: The mean age was 68.2 years, 88% were men, 87% were non-Hispanic white, 39.1% were diagnosed with peripheral arterial disease only, 9.2% with other CVD only, and 28.5% with both peripheral arterial disease and other CVD. During the entire follow-up period, 299 (59.7%) patients died, 167 from CVD, of which 88 deaths were due to coronary heart disease. With adjustment for CVD risk factors and baseline peripheral arterial disease and other CVD, an increment of one standard deviation in Lp-PLA(2) activity was associated with a 40% higher risk for CHD mortality at 5 years of follow-up (P = .04). Additional adjustment for triglycerides, high-density lipoprotein, and low-density lipoprotein cholesterol reduced this association to nonsignificance (hazard risk, 1.12). CONCLUSION: In a vascular laboratory patient population, higher levels of LpPLA(2) mass and activity were not significantly associated with total, CVD, or CHD mortality at 5 years of follow-up and after adjustment for traditional CVD risk factors and the presence of PAD and other CVD at baseline. An apparent elevated risk of CHD death associated with elevated Lp-PLA2 was largely explained by associated elevations in lipids and lipoproteins.

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.

Lipoprotein-associated phospholipase A2 as a target of therapy.

PURPOSE OF REVIEW: Considerable discussion continues regarding the precise role that secreted lipoprotein-associated phospholipase A2 (Lp-PLA2), also called platelet-activating factor acetylhydrolase, plays in atherosclerosis. Since interest in this enzyme as a putative drug target has been based primarily upon its association with low-density lipoprotein (LDL) in human plasma, this review will focus on Lp-PLA2 and human coronary heart disease. RECENT FINDINGS: Recent reports have linked Lp-PLA2 enrichment not only to the most atherogenic of LDL particles but also to the most advanced, rupture-prone, plaques. Electronegative LDL has been shown to be highly enriched in Lp-PLA2; and in advanced atheroma, Lp-PLA2 levels are highly upregulated, colocalizing with macrophages in both the necrotic core and fibrous cap. Lp-PLA2 is well placed, whether on an oxidation susceptible LDL particle or in the highly oxidative environment of an advanced rupture-prone plaque, to hydrolyse oxidized phospholipid and generate significant quantities of the two pro-inflammatory mediators, lysophosphatidylcholine and oxidized nonesterified fatty acid. Several studies have confirmed that Lp-PLA2 is an independent risk factor for cardiovascular events (i.e. myocardial infarction and stroke). Although epidemiology studies consistently support a relationship between plasma Lp-PLA2 levels and susceptibility to coronary heart disease this is not the case for Lp-PLA2 polymorphisms. Two clinical studies have linked the Ala-379-->Val polymorphism with a reduced risk of myocardial infarction, but functional differences between the AA and VV polymorphs have yet to be demonstrated. SUMMARY: Lp-PLA2 is intimately associated with several aspects of human atherogenesis. Although various lipid-lowering therapies, such as statins, have been shown to reduce plasma levels of Lp-PLA2, none has been studied in terms of its ability to lower the large macrophage-mediated upregulation of Lp-PLA2 within advanced plaques.