A pre-specified statistical analysis plan for the VERIFY study: Vildagliptin efficacy in combination with metformin for early treatment of T2DM.

AIMS: To ensure the integrity of the planned analyses and maximize the clinical utility of the VERIFY study results by describing the detailed concepts behind its statistical analysis plan (SAP) before completion of data collection and study database lock. The SAP will be adhered to for the final primary data analysis of the VERIFY trial. MATERIALS AND METHODS: Vildagliptin efficacy in combination with metformin for early treatment of T2DM (VERIFY) is an ongoing, multicentre, randomized controlled trial aiming to demonstrate the clinical benefits of glycaemic durability and glucose control achieved with an early combination therapy in newly-diagnosed type 2 diabetes (T2DM) patients. RESULTS: The SAP was initially designed at the study protocol conception phase and later modified, as reported here, in collaboration between the steering committee members, statisticians, and the VERIFY study leadership team. All authors were blinded to treatment allocation. An independent statistician has additionally retrieved and presented unblinded data to the independent data safety monitoring committee. An overview of the trial design with a focus on describing the fine-tuning of the analysis plan for the primary efficacy endpoint, risk of initial treatment failure, and secondary, exploratory and pre-specified subgroup analyses is provided here. CONCLUSION: According to optimal trial practice, the details of the statistical analysis and data-handling plan prior to locking the database are reported here. The SAP accords with high-quality standards of internal validity to minimize analysis bias and will enhance the utility of the reported results for improved outcomes in the management of T2DM.

Effect of angiotensin receptor blockers on blood pressure and renal function in patients with concomitant hypertension and chronic kidney disease: a systematic review and meta-analysis.

Objective: Angiotensin receptor blockers (ARB) are among the recommended first-line treatment options in patients with hypertension and chronic kidney disease (CKD). This meta-analysis evaluated the effect of ARB on blood pressure (BP) and renal function in patients with concomitant hypertension and CKD with or without diabetes.Methods: Literature search was performed in PubMed/MEDLINE, EMBASE and BIOSIS to identify parallel-group, randomized controlled trials (≥8 weeks) reporting the effects of ARB on office systolic/diastolic BP (SBP/DBP), estimated glomerular filtration rate (eGFR), serum creatinine (SCr), creatinine clearance (CrCl) or proteinuria in adults with hypertension and CKD. Mean difference (MD, generic inverse variance) with 95% confidence intervals (CIs) was used to report an outcome.Results: Among the 24 studies identified, 19 evaluated ARB as monotherapy, 4 evaluated ARB as combination therapy and one evaluated ARB both as monotherapy and combination therapy. Median (range) duration of the studies was 12 (1.84-54.0) months. ARB monotherapy significantly (p < 0.01) reduced BP (treatment ≥1 year: SBP [MD: -14.84 mmHg; 95% CI: -17.82 to -11.85]/DBP [-10.27 mmHg; -12.26 to -8.27]) and proteinuria (≥1 year [-0.90 g/L; -1.22 to -0.59]). Results were consistent for combination therapy. In these studies, non-significant changes were observed for eGFR, CrCl and SCr. The impact of SBP changes on eGFR was not significant; however, studies were of a relatively short duration.Conclusion: ARB had a favorable impact on BP and renal parameters such as proteinuria with monotherapy as well as with combination therapy, highlighting their potential benefits in patients with hypertension and CKD. During the short follow-up of these studies, no significant change in eGFR was observed.

Efficacy of vildagliptin versus sulfonylureas as add-on therapy to metformin: comparison of results from randomised controlled and observational studies.

AIMS/HYPOTHESIS: Randomised control trials (RCTs) do not always reflect real-life outcomes for glucose-lowering drugs. In this work we compared RCT and real-life data on the efficacy of the dipeptidyl peptidase-IV (DPP-4) inhibitor vildagliptin or sulfonylureas when added to metformin. METHODS: Data were pooled from five RCTs examining vildagliptin (n = 2,788) and sulfonylureas (glimepiride [n = 1,259] or gliclazide [n = 433]), added to metformin. For real-life conditions, data were extracted from an observational study examining vildagliptin (n = 7,002) or sulfonylureas (n = 3,702), added to metformin monotherapy. Linear regression analyses were performed between the baseline HbA1c and the change in HbA1c (Δ HbA1c) after 24 weeks. RESULTS: Baseline HbA1c correlated to Δ HbA1c (r (2) = 0.36, slope = -0.54 [95% CI -0.55, -0.53; p < 0.0001]) for both treatments. With sulfonylureas, the slope of the correlation was steeper in the observational study than in RCTs (interaction coefficient = -0.327, p < 0.001), whereas for vildagliptin, the slope was virtually identical in the observational study and the RCTs (interaction coefficient = 0.024, p = 0.175). For any given baseline HbA1c, Δ HbA1c with sulfonylureas was smaller in real life than in RCTs, whereas Δ HbA1c with vildagliptin was the same. CONCLUSIONS/INTERPRETATIONS: When comparing RCT to real-life data, the decrease in HbA1c from baseline with sulfonylurea treatment is smaller in real life than in RCTs, whereas the reduction with vildagliptin is essentially the same, suggesting that the full power of treatment is retained in real life for vildagliptin but not for sulfonylureas, possibly due to fear of hypoglycaemia.

Health and Productivity Benefits with Early Intensified Treatment in Patients with Type 2 Diabetes: Results from Korea.

The available evidence suggests positive health outcomes associated with early treatment intensification in Type 2 diabetes mellitus (T2DM). Our study estimated the productivity effects arising from improved health correlated with early intensified treatment in T2DM in Korea. Using a recently published methodology and model, we investigated the association between early intensified treatment and the probability of experiencing fewer diabetes-related complication events. Treatment strategies leading to better health outcomes are expected to be associated with social value through increased participation in paid and unpaid work activities. Therefore, we translated the lower incidence of complications into monetary terms related to productivity for the Korean population. We quantified productivity by considering (a) absenteeism, (b) presenteeism, (c) permanent loss of labor force, and (d) activity restriction. Deterministic and probabilistic sensitivity analyses in the base case parameter were performed. Approximately, 1.7 thousand (standard deviation [SD] ±580 events) micro- and macrovascular complication events could potentially be avoided by early treatment intensification. This led to a societal gain attributed to increased productivity of 23 million USD (SD ± $8.2 million). This article demonstrates the likelihood of achieving better health and productivity through early intensified treatment in diabetes.

Demonstrating the burden of hypoglycemia on patients' quality of life in diabetes clinical trials: measurement considerations for hypoglycemia.

OBJECTIVES: To evaluate the association between hypoglycemia and health-related quality of life (HRQoL) in the context of a clinical trial using both an objectively confirmed and a patient-reported measure of hypoglycemia. METHODS: During a phase III, double-arm, randomized study, patients completed the short form 36 health survey (SF-36), a generic HRQoL questionnaire, at baseline and at weeks 24, 52, and 104. The objectively confirmed measure of hypoglycemia was based on a combination of plasma glucose measure and presence of hypoglycemia-related symptoms. The patient-reported frequency of hypoglycemia was defined as the following item: "How often have you felt that your blood sugars have been unacceptably low recently?" The association between hypoglycemia and HRQoL was evaluated in intent-to-treat patients (N = 3059) by using repeated-measurements analyses, with SF-36 scores used as explained variables and baseline SF-36 score, age, sex, country, time, and either number of objectively confirmed hypoglycemic events (0, ≥1) or patient-reported frequency of hypoglycemia (continuous variable 0-6) as explanatory variables. RESULTS: During study duration, less than 6% of patients experienced at least one objectively confirmed hypoglycemic event and about half the patients reported unacceptably low blood sugars "none of the time." The association between the number of objectively confirmed hypoglycemic events and HRQoL was not statistically significant, while the patient-reported frequency of hypoglycemia was statistically significantly related to all SF-36 scores (P < 0.001), except physical functioning; patients reporting greater perceived frequency of hypoglycemia had worse HRQoL. CONCLUSIONS: Using a patient-reported measure of hypoglycemia in the context of a clinical trial could enable the burden of hypoglycemia for patients to be demonstrated.

The societal impact of early intensified treatment in patients with type 2 diabetes mellitus.

Aim: The current study estimates the societal impact of early intensified treatment compared with initial monotherapy with subsequent treatment intensification in newly diagnosed adults with type 2 diabetes mellitus in Mexico. Methods: An individual patient-level simulation and a static cohort model were employed to simulate the treatment pathway and the probability of experiencing complications of diabetes. The avoided number of events was translated into avoided productivity losses, which were monetized using wages. Results: Patients on early intensified treatment experienced approximately 13,000 fewer complication events over 10 years. This was translated into a societal impact of $54 million (USD). Conclusion: Early treatment intensification is likely to be of particular benefit to health outcomes and productivity losses.

Re: Association Between Renal Dysfunction and Major Adverse Cardiac Events After Liver Transplantation: Evidence From an International Randomized Trial of Everolimus-Based Immunosuppression.

Ann Transplant. 2018 Oct 26;23:751-757. doi: 10.12659/AOT.911030. PMID: 30361470, PMCID: PMC6248043 In the paper, the sentence on page 754, first column, lines 4, 5, and 6 has been incorrectly written:  At the month 24 study visit, mean (SD) eGFR was 74.7 (26.1), 67.8 (21.0), and 77.5 (26.2) mL/min/1.73 m2 in the EVR/rTAC, TAC Elimination, and TAC Control groups, respectively (p=0.007). The corrected sentence should read:  At the 24-month study visit, mean (SD) eGFR was 74.7 (26.1), 67.8 (21.0), and 77.5 (26.2) mL/min/1.73 m2 in the EVR/rTAC, TAC Control, and TAC Elimination groups, respectively (p=0.007).

Carotid intima media thickness and plaques can predict the occurrence of ischemic cerebrovascular events.

BACKGROUND AND PURPOSE: The clinical usefulness of noninvasive measurement of carotid intima media thickness and plaque visualization in the general population is still uncertain. METHODS: We evaluated the age-specific incidence rates of cerebrovascular events in a cohort of 1348 subjects randomly taken from the census list of San Daniele Township and followed for a mean period of 12.7 years. The association among common carotid intima media thickness, measured at baseline, arterial risk factors, and incidence of ischemic cerebrovascular events was modeled using Poisson regression. The predictive ability of common carotid intima media thickness over arterial risk factors (summarized in the Framingham Stroke Risk Score) was evaluated by receiver operating characteristic curve analysis. RESULTS: During the follow-up, 115 subjects developed nonfatal ischemic stroke, transient ischemic attack, or vascular death, which were the predefined study end points. After adjustment for age and sex, hypertension, diabetes, common carotid intima media thickness above 1 mm, and carotid plaques were all independent risk factors for development of vascular events. Inclusion of carotid findings (presence of common carotid intima media thickness above 1 mm or carotid plaques) resulted in a predictive power higher than Framingham Stroke Risk Score alone only on for those subjects with a Framingham Stroke Risk Score over 20%. CONCLUSIONS: Although common carotid intima media thickness and presence of carotid plaques are known to be risk factors for the development of vascular events and to be independent from the conventional risk factors summarized in the Framingham Stroke Risk Score, their contribution to individual risk prediction is limited. Further studies will be required to address the role of carotid ultrasonography in the primary prevention of high-risk subjects.

Association Between Renal Dysfunction and Major Adverse Cardiac Events After Liver Transplantation: Evidence from an International Randomized Trial of Everolimus-Based Immunosuppression.

BACKGROUND Prospective evidence is lacking regarding the association between renal dysfunction and cardiovascular events after liver transplantation. MATERIAL AND METHODS Data were analyzed post hoc regarding renal function and major adverse cardiac events in a two-year prospective trial of de novo liver transplant recipients randomized at 30 days post-transplant to (i) everolimus [EVR]/reduced tacrolimus [EVR/rTAC] (ii) EVR with tacrolimus discontinued [TAC Elimination] or (iii) standard tacrolimus [TAC Control]. RESULTS By month 24 post-transplant, 32/716 patients had experienced a first major cardiac event (4.5%): 4.1% (10/245), 2.2% (5/229) and 7.0% (17/242) of patients in the EVR/rTAC, TAC Elimination and TAC Control groups, respectively (p=0.043). The cumulative eGFR area under the curve (AUC) from randomization to month 24 was 119 706, 123 082, and 105 946 mL in the EVR/rTAC, TAC Elimination, and TAC Control groups, respectively, corresponding to a mean eGFR AUC of 82.4, 83.0, and 71.9 mL/min/1.73 m². Cox regression modeling showed that mean eGFR AUC was inversely associated with time to first major cardiac event: the hazard ratio per mL/min/1.73 m² was -0.0000015 [95% CI -0.00000078; -0.0000024] (p<0.001). CONCLUSIONS These findings confirm retrospective evidence that the risk of major cardiac events increases with deteriorating renal function after liver transplantation and demonstrate the need for careful cardiovascular risk management in patients with renal impairment. Immunosuppression based on everolimus with tacrolimus withdrawal, or to a lesser extent tacrolimus reduction, improves both renal function and the risk of major cardiac events compared to standard tacrolimus therapy in liver transplant recipients.

Efficacy and effectiveness of valsartan/amlodipine and valsartan/amlodipine/hydrochlorothiazide in hypertension: randomized controlled versus observational studies.

OBJECTIVE: The aim of this post-hoc analysis was to compare the results from randomized controlled trials (RCTs) and real-world evidence (RWE) studies of valsartan/amlodipine (Val/Aml) and valsartan/amlodipine/hydrochlorothiazide (Val/Aml/HCTZ) in patients with uncontrolled hypertension (>140/90 mmHg). METHODS: Data was pooled from 15 RCTs (N = 5542) and 8 RWE studies (N = 1397) for Val/Aml; and 2 RCTs (N = 804) and 5 RWE studies (N = 9380) for Val/Aml/HCTZ. Patients who received Val/Aml (80/5, 160/5, 160/10, 320/5, or 320/10 mg), Val/Aml/HCTZ (160/5/12.5, 160/5/25, 160/10/12.5, 160/10/25, or 320/10/25 mg) or placebo were considered for this analysis. Only patients with both baseline and follow-up assessment within 60-90 days after baseline had been included in the analysis. Patients with missing values were excluded from the analysis. Using fitted linear mixed-effects model and random factors, treatment interactions and study design with mean sitting systolic blood pressure (msSBP), diastolic BP (msDBP) and pulse pressure (msPP) reductions from baseline to Week 8-12 of treatment were compared. RESULTS: Baseline demographics and patient characteristics were comparable between RCT and RWE datasets and within Val/Aml and Val/Aml/HCTZ treatment groups. In both RCT and RWE studies, least-squares mean (LSM) reduction in msSBP/msDBP and msPP from baseline were significant (p < .05) across all dosages. The efficacy of Val/Aml in RCTs was statistically significantly greater than in RWE studies for msSBP/msDBP (-23.1/-13.8 vs. -17.9/-9.1 mmHg) but the difference was non-significant for msPP (-8.6 vs. -9.3 mmHg; p = .77). For Val/Aml/HCTZ, no direct comparison was available but a similar trend was observed. The difference observed for msSBP and msDBP may be due to routine practice setting, larger populations may have more confounders and different behaviors towards treatment adherence. CONCLUSION: These findings demonstrate that the efficacy of Val/Aml and Val/Aml/HCTZ in RCTs was more pronounced compared with their effectiveness in RWE studies in different ethnic populations although the overall benefit was not different.

Comparison of glycopyrronium versus tiotropium on the time to clinically important deteriorations in patients with COPD: a post-hoc analysis of randomized trials.

Glycopyrronium is a once-daily, inhaled long-acting muscarinic antagonist (LAMA) demonstrating similar efficacy to inhaled tiotropium in patients with moderate-to-severe COPD; however, the benefit of LAMAs on COPD symptoms has been variable. COPD is a progressive disease in which many patients develop an acute or sustained deterioration. Data on the prevention of clinically important deteriorations (CID) using LAMAs are limited. A pooled analysis was performed on four Phase III trials (n = 2936) that compared the efficacy of glycopyrronium (n = 1859) with tiotropium (n = 1077). The primary endpoint was significant delay and/or reduction in the occurrence of CID. CID was defined as any of the following: ≥100 mL decrease from baseline in pre-dose forced expiratory volume in 1 second (FEV1), ≥4 point increase in St George's Respiratory Questionnaire score or a moderate-to-severe COPD exacerbation occurring after the first dose of study medication. A sustained CID was a CID occurring on ≥2 consecutive visits 4 weeks apart or for ≥50% of all available subsequent visits. Baseline characteristics for the overall population were similar. Patients had moderate (62%) or severe (38%) COPD. Mean post-bronchodilator FEV1 was approximately 55% predicted, and mean FEV1 reversibility was 16.7 and 18.6% in the glycopyrronium and tiotropium groups, respectively. Both glycopyrronium and tiotropium significantly reduced time to CID and sustained CID versus placebo (p < 0.001). No statistically significant differences were found between the glycopyrronium and tiotropium treatment groups in time to CID or sustained CID. Glycopyrronium is effective in delaying time to clinically important deteriorations, with similar efficacy to tiotropium.

Human lecithin:cholesterol acyltransferase deficiency: in vivo kinetics of low-density lipoprotein and lipoprotein-X.

OBJECTIVE: Lecithin:cholesterol acyltransferase deficiency (LCAT-def) is characterized by low levels of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) and the accumulation of lipoprotein-X (LpX). Despite the low HDL, atherosclerosis is uncommon in LCAT-def. The decreased LDL would be a possible explanation but the underlying mechanism is not clear. In addition, the mechanism(s) for LpX accumulation is not known. The aim of the present study is to elucidate the mechanism(s) responsible for the low LDL and determine the plasma kinetics of LpX in LCAT-def. METHODS AND RESULTS: We conducted a radiotracer study in LCAT-def (n=2) and normal controls (n=10) and a stable isotope study in one patient and other controls (n=7). LCAT-def LDL was catabolized faster than control LDL in the control subjects as well as in LCAT-def patients. Control LDL was catabolized faster in LCAT-def patients than the controls. The production rate of LDL apolipoprotein B-100 was normal in LCAT-def. The increased LDL apoB-100 catabolism was confirmed by a stable isotope study. LpX was catabolized more slowly in LCAT-def. CONCLUSIONS: The decreased LDL in LCAT-def is attributable to an increased catabolism caused by a rapid catabolism of abnormal LDL and an upregulation of LDL receptor pathway. The decreased catabolism of LpX contributes to its accumulation in LCAT-def.

Relationship Between Duration of Type 2 Diabetes and Effectiveness of DPP-4 Inhibitor Versus Sulfonylurea as Add-on Therapy: A Post Hoc Analysis.

INTRODUCTION: To assess the impact of duration of type 2 diabetes on glucose-lowering effectiveness of the dipeptidyl peptidase-4 (DPP-4) inhibitor vildagliptin versus sulfonylureas (SUs) in a real-life setting. METHODS: Data were extracted from the large 1-year, observational EDGE study (N = 45,868). Patients receiving either DPP-4 inhibitor or any SU as add-on to monotherapy were selected (N = 36,164). Impact of the disease duration on change in glycated hemoglobin (HbA1c) levels was evaluated by using a linear multiple regression model. Descriptive statistics assessed the proportion of patients achieving the composite endpoint (HbA1c <7.0%; 53.0 mmol/mol without hypoglycemia or weight gain), stratified by diabetes duration. RESULTS: At baseline, the overall mean (±SD) type 2 diabetes duration was 5.4 ± 5.24 years, and HbA1c was 8.2 ± 1.33% (66.0 ± 14.5 mmol/mol). HbA1c lowering was directly proportional to the baseline HbA1c (-0.69 per unit; 95% CI -0.696, -0.681; p < 0.0001) and inversely proportional to the disease duration (0.01 per year; 95% CI 0.01, 0.013). There was an increased loss of ß-cell function (less pronounced HbA1c drop with increasing disease duration) in patients treated with SU-based regimens (0.025; 95% CI 0.022, 0.027) compared with vildagliptin-based regimens (0.005; 95% CI 0.003, 0.007), with the mean adjusted difference being 0.10 (95% CI -0.122, -0.092; p < 0.0001). Consistently, a higher proportion of patients achieved the composite endpoint with vildagliptin over the diabetes duration (less than 2 to more than 10 years). CONCLUSION: Vildagliptin demonstrated less dependency on the duration of type 2 diabetes, whereas the effectiveness of SUs diminished faster with increasing duration of the disease in a real-life setting. FUNDING: Novartis Pharma AG.

The effect of indacaterol/glycopyrronium versus tiotropium or salmeterol/fluticasone on the prevention of clinically important deterioration in COPD.

BACKGROUND: Endpoints that evaluate deterioration rather than improvement of disease may have clinical utility in COPD. In this analysis, we compared the effects of different maintenance treatments on the prevention of clinically important deterioration (CID) in moderate-to-severe COPD patients. METHODS: Data were analyzed from three 26-week studies comparing indacaterol/glycopyrronium (IND/GLY) with tiotropium (TIO) or salmeterol/fluticasone (SFC). Two definitions of CID were used; each was a composite of three outcome measures typically associated with COPD. Definition 1 (D1) comprised a ≥100 mL decrease in forced expiratory volume in 1 second (FEV1), a ≥4-unit increase in St George's Respiratory Questionnaire, and a moderate-to-severe COPD exacerbation. In Definition 2 (D2), a ≥1-unit decrease in transition dyspnea index replaced FEV1. RESULTS: Using D1, IND/GLY significantly reduced the risk of first or sustained CID versus either TIO (hazard ratio 0.72 [0.61, 0.86], P=0.0003 and 0.73 [0.61, 0.89], P=0.001) or SFC (0.67 [0.57, 0.80] and 0.63 [0.52, 0.77], both P<0.0001). With D2, IND/GLY significantly reduced the risk of first, but not sustained, CID versus TIO (0.80 [0.64 to 0.99], P=0.0359 and 0.85 [0.66, 1.10], P=0.2208) and both first and sustained CID versus SFC (0.73 [0.61, 0.88], P=0.001 and 0.72 [0.58, 0.90], P=0.0036). CONCLUSION: These data confirm the utility of the CID endpoint as a means of monitoring COPD worsening in patients with moderate-to-severe COPD. Using the CID measure, we demonstrated that dual bronchodilation with IND/GLY significantly reduced the risk of CID versus either long-acting muscarinic antagonist or long-acting ß2-agonist/inhaled corticosteroid treatment, providing further evidence for the benefit of dual bronchodilation in this patient population.

LABA/LAMA combinations versus LAMA monotherapy or LABA/ICS in COPD: a systematic review and meta-analysis.

BACKGROUND: Randomized controlled trials (RCTs) indicate that long-acting bronchodilator combinations, such as ß2-agonist (LABA)/muscarinic antagonist (LAMA), have favorable efficacy compared with commonly used COPD treatments. The objective of this analysis was to compare the efficacy and safety of LABA/LAMA with LAMA or LABA/inhaled corticosteroid (ICS) in adults with stable moderate-to-very-severe COPD. METHODS: This systematic review and meta-analysis (PubMed/MEDLINE, Embase, Cochrane Library and clinical trial/manufacturer databases) included RCTs comparing ≥12 weeks' LABA/LAMA treatment with LAMA and/or LABA/ICS (approved doses only). Eligible studies were independently selected by two authors using predefined data fields; the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. RESULTS: Eighteen studies (23 trials) were eligible (N=20,185). LABA/LAMA significantly improved trough forced expiratory volume in 1 second (FEV1) from baseline to week 12 versus both LAMA and LABA/ICS (0.07 L and 0.08 L, P<0.0001), with patients more likely to achieve clinically important improvements in FEV1 of >100 mL (risk ratio [RR]: 1.33, 95% confidence interval [CI]: [1.20, 1.46] and RR: 1.44, 95% CI: [1.33, 1.56], respectively, the number needed to treat being eight and six, respectively). LABA/LAMA improved transitional dyspnea index and St George's Respiratory Questionnaire scores at week 12 versus LAMA (both P<0.0001), but not versus LABA/ICS, and reduced rescue medication use versus both (P<0.0001 and P=0.001, respectively). LABA/LAMA significantly reduced moderate/severe exacerbation rate compared with LABA/ICS (RR 0.82, 95% CI: [0.75, 0.91]). Adverse event (AE) incidence was no different for LABA/LAMA versus LAMA treatment, but it was lower versus LABA/ICS (RR 0.94, 95% CI: [0.89, 0.99]), including a lower pneumonia risk (RR 0.59, 95% CI: [0.43, 0.81]). LABA/LAMA presented a lower risk for withdrawals due to lack of efficacy versus LAMA (RR: 0.66, 95% CI: [0.51, 0.87]) and due to AEs versus LABA/ICS (RR: 0.83, 95% CI: [0.69, 0.99]). CONCLUSION: The greater efficacy and comparable safety profiles observed with LABA/LAMA combinations versus LAMA or LABA/ICS support their potential role as first-line treatment options in COPD. These findings are of direct relevance to clinical practice because we included all currently available LABA/LAMAs and comparators, only at doses approved for clinical use.

Indacaterol/glycopyrronium in symptomatic patients with COPD (GOLD B and GOLD D) versus salmeterol/fluticasone: ILLUMINATE/LANTERN pooled analysis.

BACKGROUND: Indacaterol/glycopyrronium (IND/GLY) is approved for maintenance treatment of adult patients with COPD. This post hoc analysis explored the efficacy and safety of IND/GLY versus salmeterol/fluticasone (SFC) in symptomatic (Global Initiative for Chronic Obstructive Lung Disease [GOLD] B and GOLD D) patients with moderate-to-severe COPD. PATIENTS AND METHODS: Data from LANTERN and ILLUMINATE studies were pooled and analyzed. In both studies, symptomatic COPD patients were randomized to once-daily IND/GLY 110 µg/50 µg or twice-daily SFC 50 µg/500 µg. End points were pre-dose trough forced expiratory volume in one second (FEV1), standardized area under the curve for FEV1 from 0 to 12 hours (FEV1 AUC0-12 hours), peak FEV1, peak forced vital capacity (FVC), pre-dose trough FVC, Transition Dyspnea Index (TDI) total score, St George's Respiratory Questionnaire total score, rescue medication use and safety. RESULTS: A total of 1,263 patients were classified as either GOLD B (n=809) or GOLD D (n=454). At week 26, IND/GLY demonstrated statistically significant improvement in all lung function parameters versus SFC in patients in both the GOLD B and GOLD D subgroups. TDI total score and rescue medication use were significantly improved with IND/GLY versus SFC in the overall population and in the GOLD B (TDI total score only) and GOLD D (rescue medication only) subgroups. IND/GLY also reduced the rate of exacerbations in the pooled population. Overall safety profile was comparable with a higher incidence of pneumonia in the SFC-treated group. CONCLUSION: In this pooled analysis, IND/GLY demonstrated superior efficacy compared with SFC in patients in the GOLD B and GOLD D subgroups and supported its use in symptomatic COPD patients.

Number of lymph nodes examined and prognosis of TNM stage II colorectal cancer.

The diagnosis of a lymph node-negative colorectal carcinoma should imply a good prognosis; however, the outcomes for TNM stage II patients remain variable. Few studies have examined the relationship of the number of lymph nodes examined to the prognosis of this stage. The aim of this study was to determine whether the number of lymph nodes examined has an effect on prognosis of a relatively large sample of patients undergoing curative surgery for stage II colorectal cancer at a single institution. Data on patients who underwent surgery for colorectal cancer between January 1980 and April 2000 were prospectively collected in a database. Patients with TNM stage II or stage III tumours who were treated with curative intent were removed. Patients over 80 years of age were excluded from the survival analysis. Survival comparisons were made using Kaplan-Meier curves and the log-rank test. Multivariate analysis was performed using a Cox regression model. A total of 625 cases of TNM stage II cases and, for comparison purposes, 415 stage III cases, were analysed. Lymph node retrieval in stage II cases was affected by the patient's age (P=0.04) and gender (P=0.02), tumour grade (P<0.0001), tumour site (P<0.0001), and necessity to carry out extended resection (P<0.0001). In stage III cases, lymph node retrieval was affected by patient age (P<0.0001), tumour grade (P=0.02), and tumour site (P=0.002). Decreased lymph node detection was associated with increasing hazard ratios among the 480 TNM stage II patients under 80 years of age, but not among the 345 patients with TNM stage III tumours. Five year survival rate for patients with stage III tumours with only 1-3 positive lymph nodes (52.6%) was similar to that of patients with stage II tumour who had nine or fewer lymph nodes examined (51.3%). These results demonstrate that the prognosis of TNM stage II colorectal cancer is dependent on the number of lymph nodes examined. Patients with few nodes examined have a poorer prognosis. It is possible that a smaller number of lymph nodes examined reflects a diminished immune response. It can be presumed that those patients with stage II tumour with only a few nodes examined should be offered postoperative chemotherapy on a routine basis.

Evidence against the widespread use of angiography of noncoronary arteries during coronary artery angiography and cardiac catheterization.

PURPOSE: Although the most widely used screening techniques for extracardiac atherosclerotic distributions are noninvasive, in patients undergoing coronary arteriography, the question as to whether angiography of extracardiac arteries at the time of cardiac catheterization is really effective or if it should be considered malpractice is still open. We sought to determine the safety and real usefulness of angiography of extracardiac arteries performed by trained invasive cardiologists during cardiac catheterization. METHODS: Medical records of all patients undergoing combined coronary and noncoronary angiography between May 1998 and December 2002 were retrospectively reviewed. Moderate to severe arterial stenosis (>50% stenosis), vessel occlusion, aneurysmal, or severe ectasia were noted as significant angiographic findings. RESULTS: Two hundred and seventy patients (165 males, mean age = 67.7+/-9.2 years, mean serum creatinine = 1.1+/-0.8 mg/dl) underwent combined cardiac catheterization and angiography of extracardiac arteries following specific indications. Significant findings were reported in 66 (24.4%) patients. Logistic regression analyses revealed three-vessel coronary artery disease [CAD; odds ratio (OR)=9.917; 95% confidence interval (CI) = 2.2 to 43.8; P = .002) and hypercholesterolemia (OR = 2.851; 95% CI=1.03 to 7.9; P = .044) to be independent predictors of extracardiac atherosclerotic involvement. Complications rate was negligible. The detection of significant angiographic findings led to endovascular treatment in 37.8% and surgical vascular repair in 33.3% of cases. CONCLUSIONS: Angiography of extracardiac arteries at the time of coronary angiography appears justified only in patients with specific indications, multivessel CAD, and hypercholesterolemia.

Effects of treatment withdrawal on brachial and central aortic pressure after direct renin inhibition or angiotensin receptor blockade.

INTRODUCTION: Whilst sustained lowering of brachial systolic blood pressure (Br-SBP) and central aortic systolic pressure (CASP) have been demonstrated in patients with hypertension, effects of treatment withdrawal on these parameters have not been investigated. The ASSERTIVE study previously reported more sustained control of Br-SBP with aliskiren versus telmisartan in patients with hypertension, following 7-days treatment withdrawal. In this ASSERTIVE sub-study, we hypothesised that aliskiren would similarly exert more sustained control of CASP than telmisartan during treatment withdrawal. METHODS: We investigated the effects of treatment withdrawal on both Br-SBP and CASP following 12-weeks treatment with either aliskiren (300 mg) or telmisartan (80 mg). Br-SBP and CASP were measured at the end of treatment, and at days 2 and 7 following treatment withdrawal in 303 patients (CASP randomised set). RESULTS: Of the CASP randomised set, 94 patients completed CASP measurements at all time points (CASP completer set). After 7 days of treatment withdrawal, aliskiren demonstrated lesser increases in both Br-SBP and CASP than telmisartan; Br-SBP change: -2.0±1.6 vs. +5.6±1.7 mmHg, p = 0.001; CASP change: -0.4±1.6 vs. +4.6±1.7 mmHg, p = 0.041, n = 94. Similar findings were obtained for the CASP randomised set. CONCLUSIONS: Following treatment withdrawal, aliskiren demonstrated more sustained control of both brachial and central SBP than telmisartan.