Increased circulating plasma urate concentration is associated with an increased risk of coronary heart disease, but the extent of any causative effect of urate on risk of coronary heart disease is ...still unclear. In this study, we aimed to clarify any causal role of urate on coronary heart disease risk using Mendelian randomisation analysis.
We first did a fixed-effects meta-analysis of the observational association of plasma urate and risk of coronary heart disease. We then used a conventional Mendelian randomisation approach to investigate the causal relevance using a genetic instrument based on 31 urate-associated single nucleotide polymorphisms (SNPs). To account for potential pleiotropic associations of certain SNPs with risk factors other than urate, we additionally did both a multivariable Mendelian randomisation analysis, in which the genetic associations of SNPs with systolic and diastolic blood pressure, HDL cholesterol, and triglycerides were included as covariates, and an Egger Mendelian randomisation (MR-Egger) analysis to estimate a causal effect accounting for unmeasured pleiotropy.
In the meta-analysis of 17 prospective observational studies (166 486 individuals; 9784 coronary heart disease events) a 1 SD higher urate concentration was associated with an odds ratio (OR) for coronary heart disease of 1·07 (95% CI 1·04–1·10). The corresponding OR estimates from the conventional, multivariable adjusted, and Egger Mendelian randomisation analysis (58 studies; 198 598 individuals; 65 877 events) were 1·18 (95% CI 1·08–1·29), 1·10 (1·00–1·22), and 1·05 (0·92–1·20), respectively, per 1 SD increment in plasma urate.
Conventional and multivariate Mendelian randomisation analysis implicates a causal role for urate in the development of coronary heart disease, but these estimates might be inflated by hidden pleiotropy. Egger Mendelian randomisation analysis, which accounts for pleiotropy but has less statistical power, suggests there might be no causal effect. These results might help investigators to determine the priority of trials of urate lowering for the prevention of coronary heart disease compared with other potential interventions.
UK National Institute for Health Research, British Heart Foundation, and UK Medical Research Council.
BACKGROUND The Hospital Readmissions Reduction Program (HRRP) penalizes hospitals for 30-day readmissions and was extended to COPD in October 2014. There is limited evidence available on readmission ...risk factors and reasons for readmission to guide hospitals in initiating programs to reduce COPD readmissions. METHODS Medicare claims data from 2006 to 2010 in seven states were analyzed, with an index admission for COPD defined by discharge International Classification of Diseases, Ninth Revision , codes as stipulated in the HRRP guidelines. Rates of index COPD admission and readmission, patient demographics, readmission diagnoses, and use of post-acute care (PAC) were investigated. RESULTS Over the study period, there were 26,798,404 inpatient admissions, of which 3.5% were index COPD admissions. At 30 days, 20.2% were readmitted to the hospital. Respiratory-related diseases accounted for only one-half of the reasons for readmission, and COPD was the most common diagnosis, explaining 27.6% of all readmissions. Patients discharged home without home care were more likely to be readmitted for COPD than patients discharged to PAC (31.1% vs 18.8%, P < .001). Readmitted beneficiaries were more likely to be dually enrolled in Medicare and Medicaid (30.6% vs 25.4%, P < .001), have a longer median length of stay (5 days vs 4 days, P < .0001), and have more comorbidities ( P < .001). CONCLUSIONS Medicare patients with COPD exacerbations are usually not readmitted for COPD, and these reasons differ depending on PAC use. Readmitted patients are more likely to be dually enrolled in Medicare and Medicaid, suggesting that the addition of COPD to the readmissions penalty may further worsen the disproportionately high penalties seen in safety net hospitals.
Summary Background Although trastuzumab plus chemotherapy is the standard of care for first-line treatment of HER2-positive advanced gastric cancer, there is no established therapy in the second-line ...setting. In GATSBY, we examined the efficacy and tolerability of trastuzumab emtansine in patients previously treated for HER2-positive advanced gastric cancer (unresectable, locally advanced, or metastatic gastric cancer, including adenocarcinoma of the gastro-oesophageal junction). Methods This is the final analysis from GATSBY, a randomised, open-label, adaptive, phase 2/3 study, done at 107 centres (28 countries worldwide). Eligible patients had HER2-positive advanced gastric cancer and progressed during or after first-line therapy. In stage one of the trial, patients were randomly assigned to treatment groups (2:2:1) to receive intravenous trastuzumab emtansine (3·6 mg/kg every 3 weeks or 2·4 mg/kg weekly) or physician's choice of a taxane (intravenous docetaxel 75 mg/m2 every 3 weeks or intravenous paclitaxel 80 mg/m2 weekly). In stage two, patients were randomly assigned to treatment groups (2:1) to receive the independent data monitoring committee (IDMC)-selected dose of trastuzumab emtansine (2·4 mg/kg weekly) or a taxane (same regimen as above). We used permuted block randomisation, stratified by world region, previous HER2-targeted therapy, and previous gastrectomy. The primary endpoint (overall survival) was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov , number NCT01641939. Findings Between Sept 3, 2012, and Oct 14, 2013, 70 patients were assigned to receive trastuzumab emtansine 3·6 mg/kg every 3 weeks, 75 to receive trastuzumab emtansine 2·4 mg/kg weekly, and 37 to receive a taxane in the stage 1 part of the trial. At the pre-planned interim analysis (Oct 14, 2013), the IDMC selected trastuzumab emtansine 2·4 mg/kg weekly as the dose to proceed to stage 2. By Feb 9, 2015, a further 153 patients had been randomly assigned to receive trastuzumab emtansine 2·4 mg/kg weekly and a further 80 to receive a taxane. At data cutoff, median follow-up was 17·5 months (IQR 12·1–23·0) for the trastuzumab emtansine 2·4 mg/kg weekly group and 15·4 months (9·2–18·1) in the taxane group. Median overall survival was 7·9 months (95% CI 6·7–9·5) with trastuzumab emtansine 2·4 mg/kg weekly and 8·6 months (7·1–11·2) with taxane treatment (hazard ratio 1·15, 95% CI 0·87–1·51, one-sided p=0·86). The trastuzumab emtansine 2·4 mg/kg group had lower incidences of grade 3 or more adverse events (134 60% of 224 patients treated with trastuzumab emtansine vs 78 70% of 111 patients treated with a taxane), and similar incidences of adverse events leading to death (eight 4% vs four 4%), serious adverse events (65 29% vs 31 28%), and adverse events leading to treatment discontinuation (31 14% vs 15 14%) than did taxane treatment. The most common grade 3 or more adverse events in the trastuzumab emtansine 2·4 mg/kg weekly group were anaemia (59 26%) and thrombocytopenia (25 11%) compared with neutropenia (43 39%), and anaemia (20 18%), in the taxane group. The most common serious adverse events were anaemia (eight 4%), upper gastrointestinal haemorrhage (eight 4%), pneumonia (seven 3%), gastric haemorrhage (six 3%), and gastrointestinal haemorrhage (five 2%) in the trastuzumab emtansine 2·4 mg/kg weekly group compared with pneumonia (four 4%), febrile neutropenia (four 4%), anaemia (three 3%), and neutropenia (three 3%) in the taxane group. Interpretation Trastuzumab emtansine was not superior to taxane in patients with previously treated, HER2-positive advanced gastric cancer. There is still an unmet need in this patient group and therapeutic options remain limited. Funding F Hoffmann-La Roche.
Studies have shown gender disparities in cholesterol care in patients with cardiovascular disease (CVD), with women less likely than men to have low-density lipoprotein cholesterol levels <100 mg/dl. ...Whether this is related to a lower evidence-based statin or high-intensity statin use is not known. We used a national cohort of 972,532 patients with CVD (coronary heart disease, peripheral artery disease, and ischemic stroke) receiving care in 130 Veterans Health Administration facilities from October 1, 2010, to September 30, 2011, to identify the proportion of male and female patients with CVD receiving any statin and high-intensity statin. Women with CVD (n = 13,371) were less likely than men to receive statins (57.6% vs 64.8%, p <0.0001) or high-intensity statins (21.1% vs 23.6%, p <0.0001). Mean low-density lipoprotein cholesterol levels (99 vs 85 mg/dl) were higher in women compared with men (p <0.0001). In adjusted models, female gender was independently associated with a lower likelihood of receiving statins (odds ratio 0.68, 95% confidence interval 0.66 to 0.71) or high-intensity statins (odds ratio 0.76, 95% confidence interval 0.73 to 0.80). The median facility-level rate of statin and high-intensity statin use among female patients (57.3% interquartile range = 8.93% for statin, 20% interquartile range = 7.7% for high-intensity statin use) showed significant variation. In conclusion, women with CVD are less likely to receive evidence-based statin and high-intensity statins compared with men, although, their use remains low in both genders. There is a significant facility-level variation in evidence-based statin or high-intensity statin use in female patients with CVD. With the “statin dose-based approach” proposed by the recent cholesterol guidelines, these results highlight areas for quality improvement.
Abstract Beta-blocker treatment improves left ventricular function, morbidity, and survival in patients with systolic heart failure (HF). However, there is limited data addressing the safety and ...efficacy of β-blockers in the setting of cocaine use as there is a perceived risk of adverse outcomes. Our aim was to determine if β-blocker treatment was safe in HF patients with history of cocaine use compared to HF patients without history of cocaine use. We also examined whether effects differed between cardioselective versus non-cardioselective β-blockers. Ninety systolic HF patients with cocaine use were compared to 177 patients with non-ischemic, systolic HF and no cocaine use. Outcomes were HF readmissions, major adverse cardiovascular events, and death using multivariable Cox proportional hazard models adjusted for age, black race, hypertension, diabetes, coronary artery disease, renal insufficiency, and ACE inhibitors. β-blocker treatment in systolic HF patients with cocaine use did not have significant differences in HF readmissions (HR 0.66, 95% CI 0.31-0.1.38), major adverse cardiovascular events (HR 0.58, 95% CI 0.27-1.09), death (HR 0.96, 95% CI 0.39-2.34), or all combined outcomes (HR 0.76, 95% CI 0.39-1.47) when compared with β-blocker treatment in HF patients without cocaine use. Within HF patients with cocaine use, mortality rates (HR 1.50, 95% CI 0.28-8.23) were not significantly different between patients treated with non-cardioselective versus cardioselective β-blockers. In conclusion, β-blocker treatment in systolic HF patients with cocaine use was not associated with adverse outcomes.
Abstract
Context
Obesity and diabetes are established risk factors for severe SARS-CoV-2 outcomes, but less is known about their impact on susceptibility to COVID-19 infection and general symptom ...severity.
Objective
We hypothesized that those with obesity or diabetes would be more likely to self-report a positive SARS-CoV-2 test, and, among those with a positive test, have greater symptom severity and duration.
Methods
Among 44 430 COVID-19 Community Research Partnership participants, we evaluated the association of self-reported and electronic health record obesity and diabetes with a self-reported positive COVID-19 test at any time. Among the 2663 participants with a self-reported positive COVID-19 test during the study, we evaluated the association of obesity and diabetes with self-report of symptom severity, duration, and hospitalization. Logistic regression models were adjusted for age, sex, race/ethnicity, socioeconomic status, and health care worker status.
Results
We found a positive graded association between body mass index (BMI) category and positive COVID-19 test (overweight odds ratio OR 1.14 1.05-1.25; obesity I OR 1.29 1.17-2.42; obesity II OR 1.34 1.19-1.50; obesity III OR 1.53 1.35-1.73), and a similar but weaker association with COVID-19 symptoms and severity among those with a positive test. Diabetes was associated with COVID-19 infection but not symptoms after adjustment, with some evidence of an interaction between obesity and diabetes.
Conclusion
While the limitations of this health system convenience sample include generalizability and selection around test seeking, the strong graded association of BMI and diabetes with self-reported COVID-19 infection suggests that obesity and diabetes may play a role in risk for symptomatic SARS-CoV-2 beyond co-occurrence with socioeconomic factors.
Optimal management of patients with chronic myeloid leukaemia in chronic phase with suboptimal cytogenetic response remains undetermined. This study aimed to investigate the safety and efficacy of ...switching to nilotinib vs imatinib dose escalation for patients with suboptimal cytogenetic response on imatinib.
We did a phase 3, open-label, randomised trial in patients with chronic myeloid leukaemia in chronic phase with suboptimal cytogenetic response to imatinib according to the 2009 European LeukemiaNet criteria, in Latin America, Europe, and Asia (59 hospitals and care centres in 12 countries). Eligible patients were aged 18 years or older with Philadelphia chromosome-positive chronic myeloid leukaemia in chronic phase and Eastern Cooperative Oncology Group performance status of 0-2. Before enrolment, all patients had received 3-18 months of imatinib 400 mg once daily and had a suboptimal cytogenetic response according to 2009 ELN recommendations, established through bone marrow cytogenetics. By use of an interactive response technology using fixed blocks, we randomly assigned patients (1:1) to switch to nilotinib 400 mg twice per day or an escalation of imatinib dose to 600 mg once per day (block size of 4). Investigators and participants were not blinded to study treatment. Crossover was allowed for loss of response or intolerance at any time, or for patients with no complete cytogenetic response at 6 months. The primary endpoint was complete cytogenetic response at 6 months in the intention-to-treat population. Efficacy endpoints were based on the intention-to-treat population, with all patients assessed according to the treatment group to which they were randomised (regardless of crossover); the effect of crossover was assessed in post-hoc analyses, in which responses achieved after crossover were excluded. We present the final results at 24 months' follow-up. This study is registered with ClinicalTrials.gov (NCT00802841).
Between July 7, 2009, and Aug 29, 2012, we enrolled 191 patients. 96 patients were randomly assigned to nilotinib and 95 patients were randomly assigned to imatinib. Complete cytogenetic response at 6 months was achieved by 48 of 96 patients in the nilotinib group (50%, 95·18% CI 40-61) and 40 of 95 in the imatinib group (42%, 32-53%; difference 7·9% in favour of nilotinib; 95% CI -6·2 to 22·0, p=0·31). Excluding responses achieved after crossover, 48 (50%) of 96 patients in the nilotinib group and 34 (36%) of 95 patients in the imatinib group achieved complete cytogenic response at 6 months (nominal p=0·058). Grade 3-4 non-haematological adverse events occurring in more than one patient were headache (nilotinib group, n=2 2%, including 1 after crossover to imatinib; imatinib group, n=1 1%), blast cell crisis (nilotinib group, n=1 1%; imatinib group, n=1 1%), and QT prolongation (nilotinib group, n=1 1%; imatinib group, n=1 1%, after crossover to nilotinib). Serious adverse events on assigned treatment were reported in 11 (11%) of 96 patients in the nilotinib group and nine (10%) of 93 patients in the imatinib group. Seven (7%) of 96 patients died in the nilotinib group and five (5%) of 93 patients died in the imatinib group; no deaths were treatment-related.
While longer-term analyses are needed to establish whether the clinical benefits observed with switching to nilotinib are associated with improved long-term survival outcomes, our results suggest that patients with suboptimal cytogenetic response are more likely to achieve improved cytogenetic and molecular responses with switching to nilotinib than with imatinib dose escalation, although the difference was not statistically significant when responses achieved after crossover were included.
Novartis Pharmaceuticals.
For patients undergoing elective percutaneous coronary intervention (PCI), procedural anticoagulation with bivalirudin was previously shown to significantly reduce bleeding complications at the cost ...of a modest increase in ischemic events compared with unfractionated heparin (UFH) and glycoprotein IIb/IIIa inhibitors (GPIs). However, the excess bleeding in patients treated with UFH and GPIs may have been caused by excessively high UFH doses and increased activated clotting times. This study sought to determine the bleeding risk of targeted low-dose UFH with GPIs compared with bivalirudin in patients undergoing elective PCI. Of 1,205 patients undergoing elective PCI, 602 underwent PCI with adjunctive UFH and GPIs with the UFH dose targeted to an activated clotting time of approximately 250 seconds, and 603 patients matched for baseline characteristics underwent PCI with bivalirudin. Outcomes were analyzed for major bleeding (hematocrit decrease >15%, gastrointestinal bleed, or major hematoma) and 6-month major adverse cardiac events (death, myocardial infarction, and target-lesion revascularization). The maximum activated clotting time achieved was 261.7 ± 61.6 seconds in the UFH/GPI group and 355.4 ± 66.6 in the bivalirudin group (p <0.001). In-hospital major bleeding rates were similar between groups (1.8% UFH/GPI vs 1.7% bivalirudin; p = 0.83), as were transfusion requirements (1.2% UFH/GPI vs 0.5% bivalirudin; p = 0.61). The 6-month major adverse cardiac event rate was also similar between groups (9.5% UFH/GPI vs 9.0% bivalirudin; p = 0.81). In conclusion, there were no significant differences in major bleeding and 6-month major adverse cardiac events for patients undergoing elective PCI treated with targeted low-dose UFH and GPIs compared with those treated with bivalirudin.
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