Texture and flavor evaluation of peanut butter stabilized with natural waxes.

Natural peanut butter was stabilized with 1.0%-2.0% (w/w) beeswax (BW), candelilla wax (CLW), rice bran wax (RBW), or sunflower wax (SFW). The appearance, spreadability, mouthfeel, and flavor attributes of these samples were evaluated by a trained sensory panel using commercial stabilized peanut butter and a sample stabilized with hydrogenated cottonseed oil as references. The waxes and their blend ratio significantly (p < 0.05) influenced appearance, spreadability, firmness, mouthfeel, and flavor attributes. Samples with 1.5%-2.0% CLW, or 1.0%-1.5% RBW had the fewest differences in appearance and texture from the reference and commercial samples. However, an off-flavor was attributed to 1.5% or higher CLW. Samples stabilized with BW or with 1.0%-1.5% RBW had the fewest difference in flavor compared to the reference sample. Overall, samples stabilized with 1.0%-1.5% RBW scored closest to the commercial and reference samples. The response of CLW, RBW, and SFW (which was only evaluated for appearance and spreadability) indicates that amounts of these waxes could be tailored in different products to achieve a product with desirable texture and flavor as well as stability to oil loss. PRACTICAL APPLICATION: This research provides information that could be used by food companies that make seed or nut butters as spreads or as ingredients for use in foods. It shows the impact of the use of four types of waxes as stabilizers, at commercially relevant levels (< 3.0%), and at levels previously shown to be effective for stabilization, on the firmness, spreadability, and other texture and flavor attributes, and thus provides a starting point for optimization for commercial product specifications.

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-2, normal: 20-25 kg·m-2, overweight: 25- <30 kg·m-2, obese class I: 30- <35 kg·m-2, class II: 35- <40 kg·m-2 and class III: ≥40 kg·m-2), 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. The association between BMI category and time to event was modelled via proportional hazards (reference normal weight) adjusted for demographics and cardiorespiratory disease. Consistent with the paradox, underweight individuals demonstrated higher mortality (hazard ratio (HR) 1.31 (95% CI 1.04-1.64)), with lower mortality among overweight (HR 0.62 (95% CI 0.52-0.73)) and obese class I (HR 0.75 (95% CI 0.62-0.90)). However, mortality increased in obese class III (HR 1.36 (95% CI 1.00-1.86)). Death was primarily attributable to cardiovascular causes. Within a large, multinational cohort with moderate COPD and increased cardiovascular risk, the phenomenon of reduced mortality with obesity did not persist at BMI >40 kg·m-2, suggesting that obesity may not remain protective at the extremes in this population.

Targeted Endodontic Microsurgery: Implications of the Greater Palatine Artery.

INTRODUCTION: Targeted Endodontic Microsurgery (TEMS) combines trephine burs and 3D-printed guides to make flapless maxillary palatal root-end surgery possible. This study assessed the location of the greater palatine artery (GPA), the relationship of the GPA to maxillary molar root ends, and the feasibility of flapless palatal-approach TEMS. METHODS: Three endodontists analyzed 250 cone-beam computed tomographic images of maxillary molars for (1) transition morphology between the hard palate and the alveolar process adjacent to first and second molars as an indication of the most likely location of the GPA, (2) the superior-inferior relationship between the GPA and root ends, and (3) the feasibility of palatal-approach TEMS. RESULTS: Palatal transition morphology included 20% Spine, 72% Bridge, and 8% Smooth. GPA position as related to palatal root ends was classified as 34% superior, 40% adjacent, and 21% inferior. Five percent of classifications were undefined. TEMS was deemed feasible for 47% of maxillary first molars and 52% of second molars, and was significantly more feasible with GPAs superior to palatal root ends. Reasons for infeasibility included GPA proximity and unfavorable resection angle or level. Maxillary first molar palatal roots were 11.13 ± 2.68 mm from the greater palatine foramen (GPF) and 2.37 ± 1.46 mm from the GPA. Second molar palatal roots were 4.94 ± 2.55 mm from the GPF and 2.53 ± 1.77 mm from the GPA. CONCLUSIONS: Palatal transition morphology and GPA position adjacent to maxillary molars, as manifested in cone-beam computed tomographic coronal views, suggested maxillary palatal root TEMS could be accomplished with a 2-mm safety margin in 47% of first molars and 52% of second molars. Historical paradigms that do not consider flapless palatal surgical approaches may need to be revised.

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

Rationale: Whether pharmacological therapy alters decline in FEV1 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 FEV1 decline.Objectives: We conducted a systematic review of placebo-controlled pharmacological trials lasting ≥1 year to address the question of whether therapy alters FEV1 decline.Methods: A literature search for randomized trials that included repeated spirometry with at least one active and one placebo arm was conducted. Articles were excluded if study duration was <1 year, <3 spirometric measurements, or <100 subjects per arm. Study design was assessed using the Jadad score. To combine studies and find the estimated effect, we used random effects methodology to account for both within-study and between-study variation.Measurements and Main Results: There were 33,051 patients in the analysis (active component, n = 21,941; placebo, n = 11,110 in nine studies). The active treatment arms demonstrated a 5.0 ml/yr reduction (95% confidence interval, 0.8-9.1 ml/yr; P < 0.001) in the rate of FEV1 decline compared with the placebo arms. The relative FEV1 differences between active and placebo arms were within the range of differences reported for health status and for the exacerbation rate in the same studies.Conclusions: In chronic obstructive pulmonary disease, pharmacotherapy ameliorates rate of lung function decline. The relative benefit observed is within the range of those reported for health status and exacerbations in the same studies. Guidelines should be adjusted according to these findings.

FEV1 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 (FEV1) and forced vital capacity (FVC) differ in predictive value. Patients and Methods: Data from 16,485 participants in the Study to Understand Mortality and Morbidity (SUMMIT) in COPD were analyzed. Patients were grouped into quintiles for each lung function parameter (FEV1 %predicted, FVC %predicted, FEV1/FVC). The four highest quintiles (Q2-Q5) were compared to the lowest (Q1) to assess their relationship with all-cause mortality, cardiovascular events, and moderate-to-severe and severe exacerbations. Cox-regression was used, adjusted for age, sex, ethnicity, body-mass index, smoking status, previous exacerbations, cardiovascular disease, treatment, and modified Medical Research Council dyspnea score. Results: Compared to Q1 (<53.5% FEV1 predicted), increasing FEV1 quintiles (Q2 53.5-457.5% predicted, Q3 57.5-461.6% predicted, Q4 61.6-465.8% predicted, and Q5 ≥65.8%) were all associated with significantly decreased all-cause mortality (20% (4-34%), 28% (13-40%), 23% (7-36%), and 30% (15-42%) risk reduction, respectively). In contrast, a significant risk reduction (21% (4-35%)) was seen only between Q1 and Q5 quintiles of FVC. Neither FEV1 nor FVC was associated with cardiovascular risk. Increased FEV1 and FEV1/FVC quintiles were also associated with the reduction of moderate-to-severe and severe exacerbations while, surprisingly, the highest FVC quintile was related to the heightened exacerbation risk (28% (8-52%) risk increase). Conclusion: Our results suggest that FEV1 is a stronger predictor for all-cause mortality than FVC in moderate COPD patients with heightened cardiovascular risk and that subjects with moderate COPD have very different risks.

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. METHODS AND RESULTS: A six-member Clinical Endpoint Committee reviewed adverse event and serious adverse event reports included in a list of 204 Medical Dictionary for Regulatory Activities terms. Adverse events were triaged by one Clinical Endpoint Committee member, and then reviewed by three reviewers (round 1). If these three disagreed on the adjudication, the event was discussed by the full committee to reach a consensus (round 2). Among 16,485 participants, 48,105 adverse events were reported, among which 3314 were reviewed by the Clinical Endpoint Committee. After triage, 1827 were adjudicated in round 1; 338 required committee consensus in round 2, yielding 450 myocardial infarctions, strokes, unstable anginas or transient ischaemic attacks. Only 20/1627 (1%) non-serious adverse events were adjudicated as cardiovascular events. Only 45/204 Medical Dictionary for Regulatory Activities terms reviewed yielded cardiovascular events. A total of 430 deaths were adjudicated in round 1 and 631 in round 2, yielding 459 cardiovascular deaths. Adjudication of chest pain and sudden death often required additional information from site investigators. Site assessment of cardiovascular death was moderately specific (501/602 = 83%) but not sensitive (256/459 = 56%). CONCLUSION: A Clinical Endpoint Committee is useful for adjudication of major adverse cardiovascular events in chronic obstructive pulmonary disease trials but requires considerable resources and effort by investigators. This process can be streamlined by reviewing only serious adverse events and filtering by selected Medical Dictionary for Regulatory Activities terms.

VarSight: prioritizing clinically reported variants with binary classification algorithms.

BACKGROUND: When applying genomic medicine to a rare disease patient, the primary goal is to identify one or more genomic variants that may explain the patient's phenotypes. Typically, this is done through annotation, filtering, and then prioritization of variants for manual curation. However, prioritization of variants in rare disease patients remains a challenging task due to the high degree of variability in phenotype presentation and molecular source of disease. Thus, methods that can identify and/or prioritize variants to be clinically reported in the presence of such variability are of critical importance. METHODS: We tested the application of classification algorithms that ingest variant annotations along with phenotype information for predicting whether a variant will ultimately be clinically reported and returned to a patient. To test the classifiers, we performed a retrospective study on variants that were clinically reported to 237 patients in the Undiagnosed Diseases Network. RESULTS: We treated the classifiers as variant prioritization systems and compared them to four variant prioritization algorithms and two single-measure controls. We showed that the trained classifiers outperformed all other tested methods with the best classifiers ranking 72% of all reported variants and 94% of reported pathogenic variants in the top 20. CONCLUSIONS: We demonstrated how freely available binary classification algorithms can be used to prioritize variants even in the presence of real-world variability. Furthermore, these classifiers outperformed all other tested methods, suggesting that they may be well suited for working with real rare disease patient datasets.

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 (FEV1) decline, exacerbations, hospitalisations and mortality in COPD patients (FEV1 of ≥50 and ≤70% predicted) and heightened cardiovascular risk in a substudy of the Study to Understand Mortality and MorbidITy trial. Methods: Participants were randomised to daily inhalations of placebo, vilanterol 25 µg (VI), fluticasone furoate 100 µg (FF) or their combination (VI 25/FF 100) and followed quarterly until 1000 deaths in the overall 16 485 participants occurred. Biomarker blood samples were available from 1673 patients. The FEV1 decline (mL/year), COPD exacerbations, hospitalisations and death were determined. Associations between biomarker levels and outcomes were adjusted by age and gender. Results: Systemic levels of CC-16, CRP, sRAGE, SPD and fibrinogen did not relate to baseline FEV1, FEV1 decline, exacerbations or hospitalisations. Fibrinogen and CRP were related to mortality over a median follow-up of 2.3 years. Only the CC-16 changed with study therapy (VI, FF and FF/VI, p<0.01) at 3 months. Conclusions: In COPD, systemic levels of CC-16, CRP, sRAGE, SPD and fibrinogen were not associated with FEV1 decline, exacerbations or hospitalisations. These results cast doubts about the clinical usefulness of the systemic levels of these proteins as surrogate markers of these COPD outcomes. The study confirms that CRP and fibrinogen are associated with increased risk of death in patients with COPD. Trial registration number: NCT01313676.

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. Participants were current or former smokers, 40-80 years old with moderate COPD and history or increased risk of cardiovascular (CV) disease. The primary outcome was on and post-treatment all-cause mortality. Secondary outcomes included first-on-treatment moderate/severe AECOPD and on-treatment CV composite event (CV death, myocardial infarction, stroke, unstable angina and transient ischemic attack). Multivariable Cox proportional hazards models were used to investigate study endpoint associations with platelet count quintile grouping, continuous platelet count utilizing two-term fractional polynomials, and categories of low, normal and high platelet count (< 150, ≥150 to < 300, ≥300 × 109/L). RESULTS: Patients were followed for 2.3 ± 0.9 years for vital status and 1.6 ± 1.1 years for morbidity endpoints during which 105 (5.8%) died, 651 (36.2%) experienced AECOPD (159 with severe AECOPD) and 86 (4.8%) experienced a CV event. A U-shaped association between platelet count and all-cause mortality was observed. Compared to the third quintile group (Q3) of platelet count, risk of death was increased in the lowest quintile group (Q1; hazard ratio [HR]: 1.73; 95% confidence interval [CI]: 0.93-3.23) and highest quintile group (Q5; HR: 1.66; 95%CI: 0.89-3.10), though point estimates were imprecise. Using clinical cutoffs, compared with normal platelet counts (≥150 to < 300 × 109/L), risk of all-cause mortality was nominally increased among patients with thrombocytopenia (HR: 1.46; 95%CI: 0.81-2.64) and high platelet count (HR: 1.66; 95%CI: 0.96-2.86). Compared with Q3, CV events were nominally increased for Q5 (HR: 1.71; 95%CI: 0.83-3.49) and Q1 (HR: 1.41; 95%CI: 0.70, 2.85). There was no association between platelet count and AECOPD. CONCLUSIONS: In stable COPD platelet count demonstrated a U-shaped association with increased risk of 3-year all-cause mortality, though a platelet count level above or below which risk of mortality was increased could not be definitively identified. TRIAL REGISTRATION: ClinicalTrials.gov NCT01313676 .

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. The study was event-driven with a median study exposure of 1.8 years. This study was registered with ClinicalTrials.gov, number NCT01313676. There were no consistent associations between treatment prior to study entry and the effects of FF, VI or FF/VI on exacerbations during the study. However, patients taking inhaled corticosteroids and one or more bronchodilators prior to study entry seemed to have a better effect of active treatments than of placebo on mortality (hazard ratio for FF/VI 0.65, 95% CI 0.48-0.89). Survival in those randomised to placebo was independent of treatment prior to study enrolment. Prior treatment appears to affect treatment effects on mortality but not exacerbations in a randomised controlled trial of patients with COPD and heightened cardiovascular risk.

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. Plasma high-sensitivity cardiac troponin I concentrations were measured in a subgroup of 1,599 patients. Outcomes were on-treatment cardiovascular events and COPD exacerbations over a median of 18 months, and cardiovascular death over a median of 27 months. RESULTS: Baseline plasma cardiac troponin I concentrations were above the limit of detection (1.2 ng/l) in 1,542 (96%) patients. Concentrations were unaffected by inhaled therapies at 3 months (p > 0.05). Compared with the lowest quintile (cardiac troponin <2.3 ng/l), patients in the highest quintile (≥7.7 ng/l) were at greater risk of cardiovascular events (hazard ratio [HR] 3.7; 95% confidence interval [CI]: 1.3 to 10.1; p = 0.012) and cardiovascular death (HR: 20.1; 95% CI: 2.4 to 165.2; p = 0.005) after adjustment for risk factors. By contrast, there were no differences in exacerbations between quintiles (HR: 1.1; 95% CI: 0.8 to 1.5; p = 0.548). CONCLUSIONS: In patients with COPD and heightened cardiovascular risk, plasma cardiac troponin I concentrations are a specific and major indicator of future cardiovascular events and cardiovascular death. Inhaled therapies did not affect cardiac troponin I concentrations consistent with their neutral effect on mortality and cardiovascular outcomes. (Study to Evaluate the Effect of Fluticasone Furoate/Vilanterol on Survival in Subjects With Chronic Obstructive Pulmonary Disease [SUMMIT]; NCT01313676).

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. Participants with moderate COPD with or at risk for cardiovascular disease (CVD) were randomized to placebo, long-acting beta agonist, inhaled corticosteroid, or their combination. All-cause mortality increased in relation to high systolic [≥140 mmHg; hazard ratio (HR) 1.27, 95% confidence interval (CI) 1.12-1.45] or diastolic (≥90 mmHg; HR 1.35, 95% CI 1.14-1.59) BP and low systolic (<120 mmHg; HR 1.36, 95% CI 1.13-1.63) or diastolic (<80 mmHg; HR 1.15, 95% CI 1.00-1.32) BP. Higher heart rates (≥80 per minute; HR 1.39, 95% CI 1.21-1.60) and pulse pressures (≥80 mmHg; HR 1.39, 95% CI 1.07-1.80) were more linearly related to increases in all-cause mortality. The risks of cardiovascular events followed similar patterns to all-cause mortality. Similar findings were observed in subgroups of patients without established CVD. Conclusion: A 'U-shaped' relationship between BP and all-cause mortality and cardiovascular events exists in patients with COPD and heightened cardiovascular risk. A linear relationship exists between heart rate and all-cause mortality and cardiovascular events in this population. These findings extend the prognostic importance of BP to this growing group of patients and raise concerns that both high and low BP may pose health risks.

Exacerbations of Chronic Obstructive Pulmonary Disease and Cardiac Events. A Post Hoc Cohort Analysis from the SUMMIT Randomized Clinical Trial.

RATIONALE: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are common, associated with acute inflammation, and may increase subsequent cardiovascular disease (CVD) risk. OBJECTIVES: Determine whether AECOPD events are associated with increased risk of subsequent CVD. METHODS: We performed a secondary cohort analysis of the SUMMIT (Study to Understand Mortality and Morbidity) trial, a convenience sample of current/former smokers with moderate COPD from 1,368 centers in 43 countries. All had CVD or increased CVD risk. AECOPD was defined as an increase in respiratory symptoms requiring treatment with antibiotics, systemic corticosteroids, and/or hospitalization. CVD events were a composite outcome of cardiovascular death, myocardial infarction, stroke, unstable angina, and transient ischemic attack. All CVD events were adjudicated. Cox proportional hazards models compared the hazard for a CVD event before AECOPD versus after AECOPD. MEASUREMENTS AND MAIN RESULTS: Among 16,485 participants in SUMMIT, 4,704 participants had at least one AECOPD and 688 had at least one CVD event. The hazard ratio (HR) for CVD events after AECOPD was increased, particularly in the first 30 days after AECOPD (HR, 3.8; 95% confidence interval, 2.7-5.5) and was elevated up to 1 year after AECOPD. The 30-day HR after hospitalized AECOPD was more than twofold greater (HR, 9.9; 95% confidence interval, 6.6-14.9). CONCLUSIONS: In patients with COPD with CVD or risk factors for CVD, exacerbations confer an increased risk of subsequent CVD events, especially in hospitalized patients and within the first 30 days after exacerbation. Patients and clinicians should have heightened vigilance for early CVD events after AECOPD. Clinical trial registered with www.clinicaltrials.gov (NCT 01313676).

ß-Blocker Therapy and Clinical Outcomes in Patients with Moderate Chronic Obstructive Pulmonary Disease and Heightened Cardiovascular Risk. An Observational Substudy of SUMMIT.

RATIONALE: Cardiovascular disease is a common comorbidity in patients with chronic obstructive pulmonary disease. Although ß-blockers can be used safely in patients with chronic obstructive pulmonary disease, concerns remain regarding safety and efficacy interactions in patients using concomitant inhaled long-acting ß-agonists. OBJECTIVES: To compare the differential effects of long-acting ß-agonist or inhaled corticosteroid use on clinical outcomes in patients with heightened cardiovascular risk treated and not treated with ß-blockers. METHODS: We examined data from 16,485 participants in the SUMMIT study (Study to Understand Mortality and Morbidity in COPD) who were randomized to once-daily inhaled fluticasone furoate, vilanterol, fluticasone furoate/vilanterol combination, or placebo and examined the associations between treatment allocation and lung function, chronic obstructive pulmonary disease exacerbations, cardiovascular events, and all-cause mortality, stratified by baseline ß-blocker therapy. RESULTS: Baseline ß-blocker therapy was used by 31% (n = 5,159) of SUMMIT participants. There was no evidence of an interaction between baseline ß-blocker therapy and the association between inhaled treatments and forced expiratory volume in 1 second at 3 months (P = 0.27), 6 months (P = 0.14), or 12 months (P = 0.33). The placebo-adjusted mean differences in post-bronchodilator forced expiratory volume in 1 second at 3 months in the vilanterol-alone group were 58 ml (95% confidence interval, 38-78) in those receiving baseline ß-blocker therapy and 51 ml (95% confidence interval, 38-65) in those not receiving baseline ß-blocker therapy. The placebo-adjusted mean differences in post-bronchodilator forced expiratory volume in 1 second at 3 months in the combination fluticasone furoate/vilanterol group were 85 ml (95% confidence interval, 65-105) in those receiving baseline ß-blocker therapy and 68 ml (95% confidence interval, 54-82) in those not receiving baseline ß-blocker therapy. Overall, there was no evidence of interaction by randomized treatment, including vilanterol alone or in combination with fluticasone furoate, for chronic obstructive pulmonary disease exacerbations (P = 0.18), cardiovascular composite events (P = 0.33), and all-cause mortality (P = 0.41). CONCLUSIONS: There is no evidence to suggest that baseline ß-blocker therapy reduces the respiratory benefits or increases the cardiovascular risk of inhaled long-acting ß-agonists in patients with chronic obstructive pulmonary disease and heightened cardiovascular risk. Clinical trial registered with www.clinicaltrials.gov (NCT01313676).

Fluticasone Furoate, Vilanterol, and Lung Function Decline in Patients with Moderate Chronic Obstructive Pulmonary Disease and Heightened Cardiovascular Risk.

RATIONALE: Many patients with chronic obstructive pulmonary disease (COPD) have an accelerated loss of lung function. It is unclear whether drug treatment can modify this in patients with moderately severe disease. OBJECTIVES: In a prespecified analysis of the key secondary outcome in SUMMIT (Study to Understand Mortality and Morbidity), we investigated whether the inhaled corticosteroid fluticasone furoate (FF; 100 µg), the long-acting ß-agonist vilanterol (VI; 25 µg), or their combination (FF/VI) modified the rate of decline in FEV1 compared with placebo. We also investigated how baseline covariates affected this decline. METHODS: Spirometry was measured every 12 weeks in this event-driven, randomized, placebo-controlled trial of 16,485 patients with moderate COPD and heightened cardiovascular risk. An average of seven spirometric assessments per subject among the 15,457 patients with at least one on-treatment measurement were used in the analysis of rate of FEV1 decline. All statistical comparisons are considered nominal. MEASUREMENTS AND MAIN RESULTS: The adjusted rates of FEV1 decline were -46 ml/yr (-3.0% of baseline) with placebo, -47 ml/yr (-3.1%) with VI, -38 ml/yr (-2.5%) with FF, and -38 ml/yr (-2.3%) with FF/VI. FF-containing regimens had lower rates of decline than placebo (P < 0.03), and FF/VI had a lower rate of decline than VI alone (P < 0.005). The FEV1 decline was faster in current smokers, those with a lower body mass index, males, and patients with established cardiovascular disease. CONCLUSIONS: In patients with moderate COPD and heightened cardiovascular risk, FF alone or in combination with VI appears to reduce the rate of FEV1 decline. Clinical trial registered with www.clinicaltrials.gov (NCT01313676).

Pneumonia risk with inhaled fluticasone furoate and vilanterol in COPD patients with moderate airflow limitation: The SUMMIT trial.

RATIONALE: Pneumonia risk with inhaled corticosteroid use in chronic obstructive pulmonary disease (COPD) has not been thoroughly assessed in patients with moderate airflow limitation. OBJECTIVES: To determine the incidence of pneumonia and risk factors in COPD patients with moderate airflow limitation who had, or were at high risk for cardiovascular disease. METHODS: In the Study to Understand Mortality and MorbidITy in COPD (SUMMIT), 16,590 subjects with moderate airflow limitation (50% ≤ FEV1 ≤ 70% predicted) and heightened cardiovascular risk were randomized double-blind 1:1:1:1 to inhaled once-daily vilanterol 25 µg (VI), fluticasone furoate 100 µg (FF), vilanterol 25 µg combined with 100 µg fluticasone furoate (FF/VI), or matched placebo. In a pre-specified analysis, we assessed investigator-reported adverse pneumonia events, and independently-adjudicated fatal events. MEASUREMENTS AND MAIN RESULTS: The safety population comprised 16,568 subjects who actually received study medication. There were 1017 pneumonia events reported from 842 subjects. For placebo, FF, VI and FF/VI, reported pneumonia incidence was 5%, 5%, 4% and 6%, respectively. When adjusted for time on treatment, event rates were similar in the placebo, FF and FF/VI containing arms (3.84, 4.24 and 3.95/100 treatment years, respectively) but lower in the VI group (2.77/100 treatment years). Risk factors for pneumonia risk included: greater degree of airflow limitation (i.e. FEV1 <60% predicted), prior exacerbation history, and BMI <25 kg/m2. CONCLUSIONS: In contrast to previous studies in patients with severe disease, increased pneumonia risk with inhaled corticosteroid use was not evident in COPD subjects with moderate airflow limitation and heightened cardiovascular risk.