International Differences in the Frequency of Chronic Obstructive Pulmonary Disease Exacerbations Reported in Three Clinical Trials.

Exacerbations of chronic obstructive pulmonary disease (COPD) are an important endpoint in multinational clinical treatment trials, but the observed event rate is often lower than anticipated and appears to vary between countries. We investigated whether systematic differences in national exacerbation rates might explain this observed variation. We reviewed data from three large multicenter international randomized trials conducted over an 18-year period with different designs and clinical severities of COPD, comparing bronchodilator and/or inhaled corticosteroids with bronchodilators alone and/or placebo.

Challenging the obesity paradox: extreme obesity and COPD mortality in the SUMMIT trial.

Populations with COPD demonstrate higher survival in overweight and obese compared with normal weight; the "obesity paradox". Relationships in less-severe COPD are unclear, as is the impact of cardiovascular risk, and few studies include individuals at extremes of obesity.  We examined the relationship between body mass index (BMI; defined as underweight: <20 kg·m, normal: 20-25 kg·m, overweight: 25- <30 kg·m, obese class I: 30- <35 kg·m, class II: 35- <40 kg·m and class III: ≥40 kg·m), morbidity, and mortality in the SUMMIT trial population (n=16 485), characterised by moderate COPD and heightened cardiovascular risk with a substantial proportion with class III obesity.

Pharmacotherapy and Lung Function Decline in Patients with Chronic Obstructive Pulmonary Disease. A Systematic Review.

Whether pharmacological therapy alters decline in FEV in chronic obstructive pulmonary disease remains controversial. Because pharmacotherapy improves health status, exacerbation rate, and symptoms, it may be unethical to complete placebo-controlled long-term studies aimed at modifying FEV decline. We conducted a systematic review of placebo-controlled pharmacological trials lasting ≥1 year to address the question of whether therapy alters FEV decline.

FEV is a stronger mortality predictor than FVC in patients with moderate COPD and with an increased risk for cardiovascular disease.

Purpose: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death worldwide. Impaired lung function is associated with heightened risk for death, cardiovascular events, and COPD exacerbations. However, it is unclear if forced expiratory volume in one second (FEV) and forced vital capacity (FVC) differ in predictive value.

Adjudication of cardiovascular events in patients with chronic obstructive pulmonary disease: SUMMIT trial.

Background: Adjudicated cause-specific mortality has been used in major trials of chronic obstructive pulmonary disease. However, there is less experience with adjudicated major adverse cardiovascular events as a key efficacy outcome in chronic obstructive pulmonary disease trials. The Study to Understand Mortality and Morbidity in chronic obstructive pulmonary disease trial required a Clinical Endpoint Committee to adjudicate the outcomes of modified major adverse cardiovascular events and cause-specific mortality.

Serum biomarkers and outcomes in patients with moderate COPD: a substudy of the randomised SUMMIT trial.

Rationale: Systemic levels of C reactive protein (CRP), surfactant protein D (SPD), fibrinogen, soluble receptor of activated glycogen end-product (sRAGE) and club cell protein 16 (CC-16) have been associated with chronic obstructive pulmonary disease (COPD) outcomes. However, they require validation in different cohorts.

Objectives: Relate systemic levels of those proteins to forced expiratory volume in 1 s (FEV) decline, exacerbations, hospitalisations and mortality in COPD patients (FEV of ≥50 and ≤70% predicted) and heightened cardiovascular risk in a substudy of the Study to Understand Mortality and MorbidITy trial.

Association of platelet count with all-cause mortality and risk of cardiovascular and respiratory morbidity in stable COPD.

Background: Platelet count is a prognostic indicator in the general population and elderly. Thrombocytosis during acute exacerbation of COPD (AECOPD) has been associated with mortality; however, the relationship between platelet count and mortality in stable COPD is unknown.

Methods: We performed post hoc secondary analysis on a subsample of 1797 patients in the Study to Understand Mortality and Morbidity in COPD (SUMMIT) who had blood samples drawn at baseline.

Impact of pre-enrolment medication use on clinical outcomes in SUMMIT.

The impact of prior treatment on results of clinical trials in chronic obstructive pulmonary disease (COPD) has been debated. We used data from the Study to Understand Mortality and Morbidity in COPD Trial to examine the impact of prior treatment on the effects of randomised study drugs on mortality and exacerbations. We used data on 16 417 patients with moderate COPD and heightened cardiovascular risk and information on prior medications to examine the effects of fluticasone furoate (FF), vilanterol (VI) and combined FF/VI compared to placebo on moderate and severe exacerbation as well as mortality.

Cardiac Troponin I and Cardiovascular Risk in Patients With Chronic Obstructive Pulmonary Disease.

Background: Patients with chronic obstructive pulmonary disease (COPD) have increased risk of cardiovascular events.

Objectives: This study evaluated the association between high-sensitivity cardiac troponin I concentration and cardiovascular events in patients with COPD and heightened cardiovascular risk.

Methods: In a double-blind randomized controlled trial, 16,485 patients with COPD and cardiovascular disease or risk factors were randomized to once daily inhaled placebo, fluticasone furoate (100 μg), vilanterol (25 μg), or their combination.

Blood pressure, heart rate, and mortality in chronic obstructive pulmonary disease: the SUMMIT trial.

Aims: To characterize the relationship between blood pressure (BP) or heart rate and mortality and morbidity in chronic obstructive pulmonary disease (COPD).

Methods And Results: We performed post hoc analysis of baseline BP or heart rate and all-cause mortality and cardiovascular events in the SUMMIT trial. SUMMIT was a randomized double-blind outcome trial of 16 485 participants (65 ± 8 years, 75% male, and 47% active smokers) enrolled at 1368 sites in 43 countries.

Effect of Fluticasone Furoate and Vilanterol on Exacerbations of Chronic Obstructive Pulmonary Disease in Patients with Moderate Airflow Obstruction.

Rationale: Inhaled corticosteroids have been shown to decrease exacerbations in patients with moderate to severe chronic obstructive pulmonary disease (COPD). Their effects in patients with milder airflow obstruction remain unclear.

Objectives: This was an analysis of exacerbations in the SUMMIT (Study to Understand Mortality and Morbidity) study.

First trimester maternal serum placental growth factor levels in twin pregnancies.

Background: An understanding of the normal behavior of biochemical markers in twin pregnancies is necessary in order to offer prenatal screening to this subgroup. This study investigates the levels of first trimester maternal serum placental growth factor (PlGF) in twin and singleton pregnancies.

Methods: The PlGF concentrations were measured by an automated assay in the first trimester maternal serum of 440 dichorionic twin, 116 monochorionic twin, and 607 singleton pregnancy samples thawed from frozen storage.

The association between gestational diabetes mellitus and first trimester aneuploidy screening markers.

Objective: To establish whether maternal serum first trimester concentrations of PAPP-A and free hCGβ are altered in pregnancies that subsequently are diagnosed by an oral glucose tolerance test (OGTT) with gestational diabetes mellitus (GDM).

Methods: Over the period 2009 and 2011, the results for women who had first trimester screening for aneuploidy were matched with those having an oral glucose tolerance test at 22-26 weeks for suspected GDM. Free hCGβ, PAPP-A and NT MoMs were compared amongst the group having an OGTT with confirmed GDM and those in which GDM was not confirmed.

Evaluation of a dried blood spot assay to measure prenatal screening markers pregnancy-associated plasma protein a and free β-subunit of human chorionic gonadotropin.

Background: First-trimester prenatal screening for aneuploidy by use of dried blood spots (DBSs) may offer practical benefits in settings where the instability of intact human chorionic gonadotropin (hCG) is problematic. We evaluated a DBS pregnancy-associated plasma protein A (PAPP-A) and free β-subunit of hCG (free hCGβ) dual assay and compared it to serum screening.

Methods: Hematocrit-corrected DBS PAPP-A and free-hCGβ concentrations were measured and compared with serum concentrations in 252 first-trimester samples.

Accuracy of self-reported smoking status in first trimester aneuploidy screening.

Objectives: To review the accuracy of self-reporting of smoking status in our first trimester screening population and to assess the levels of pregnancy-associated plasma protein-A (PAPP-A) and free-β human chorionic gonadotropin (free-hCGβ) in women who were classified for smoking status by serum cotinine concentrations and self-reporting.

Methods: Cotinine concentration was determined in the stored serum 696 self-reported smokers and 442 self-reported non-smokers. PAPP-A and free-hCGβ multiples of the medians (MoMs) determined at screening were reverted to uncorrected for self-reported smoking status.

Analytical goal setting in aneuploidy screening: within person biological variability of first trimester biochemical markers.

Objective: To determine the average within person biological variability of free-β human chorionic gonadotrophin (free hCGβ), intact hCG and pregnancy-associated plasma protein A (PAPP-A), and to establish analytical goals for the measurement of these markers when used in first trimester screening.

Methods: Free hCGβ, PAPP-A and intact hCG were measured on paired first trimester samples collected during the same pregnancy. Results were converted to Multiple of the Median (MoMs).

Effect of gestational age on first trimester maternal serum prenatal screening correction factors for ethnicity and IVF conception.

Objective: The aim of this study is to investigate gestational age effects of maternal ethnicity and in vitro fertilization (IVF) pregnancy correction factors of first trimester trisomy 21 screening markers pregnancy associated plasma protein A (PAPP-A) and free-β human chorionic gonadotropin (free hCGβ) in a large dataset.

Methods: Data from 205,341 normal singleton pregnancies were retrieved, and PAPP-A and free hCGβ concentrations were converted to multiples of the medians (MoMs) uncorrected for either maternal ethnicity or IVF pregnancy. Log(10) transformed MoMs were plotted against gestational age in each group to examine gestational age effects

Results: Significant gestational age effects were found for correction factors for PAPP-A in Afro-Caribbean, South Asian and East Asian, and for free hCGβ in Afro-Caribbean and IVF pregnancy.

Correction of first trimester biochemical aneuploidy screening markers for smoking status: influence of gestational age, maternal ethnicity and cigarette dosage.

Objective: To examine the gestational age, maternal ethnicity and cigarette dosage effects of the reduction of maternal serum pregnancy-associated plasma protein A (PAPP-A) and free-β human chorionic gonadotrophin (free hCGβ) in smokers.

Methods: Maternal serum PAPP-A and free hCGβ corrected for confounders, excluding smoking, in first trimester smokers and nonsmokers were compared by gestational age, maternal ethnicity and cigarette dosage. A small set of second trimester smokers and nonsmoker controls were analysed for PAPP-A along with free hCGβ and assessed for gestational age effects of smoking.

Maternal serum CA 19-9 and CA 15-3 levels in pregnancies affected by trisomy 21.

Objectives: To investigate the levels of tumour markers CA 19-9 and CA 15-3 in the first trimester maternal serum of euploid control and trisomy 21 pregnancies.

Methods: Maternal serum marker levels of 69 trisomy 21 and 388 euploid controls were quantified by the Kryptor analyser, and levels were compared between the two groups after analysis for confounding factors. Monte Carlo simulation was carried out to determine the effect of adding potential markers to the combined test.

A comparison of two immunoassay methods for the measurement of maternal serum placental growth factor in early pregnancy.

Objectives: To compare the DELFIA Xpress and Quantikine ELISA placental growth factor (PlGF) immunoassay platforms by analysing the same set of early first-trimester maternal serum samples from cases with trisomy 21 and euploid controls.

Methods: Thirty-seven trisomy 21 cases and 243 euploid control serum samples, drawn at 8(+0) to 10(+6) weeks of gestation, were reanalysed by Quantikine PlGF ELISA following original analysis on the DELFIA Xpress platform.

Results: PlGF levels increased with gestation in the euploid controls when measured on both platforms, although raw levels were in general lower on the DELFIA Xpress.