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  • Effects of Sacubitril/Valsartan Versus Irbesartan in Patients with Chronic Kidney Disease: A Randomised Double-Blind Trial.

    16 October 2018

    Background -Sacubitril/valsartan reduces the risk of cardiovascular mortality among patients with heart failure with reduced ejection fraction, but its effects on kidney function and cardiac biomarkers in people with moderate-to-severe chronic kidney disease are unknown. Methods -UK HARP-III was a randomised double-blind trial which included 414 participants with an estimated glomerular filtration rate (GFR) 20-60 mL/min/1.73m2 who were randomly assigned to sacubitril/valsartan 97/103 mg twice daily versus irbesartan 300 mg once daily. The primary outcome was measured GFR (mGFR) at 12 months using analysis of covariance with adjustment for each individual's baseline mGFR. All analyses were by intention to treat. This trial is registered at ISRCTN11958993 Results -207 participants were assigned to sacubitril/valsartan and 207 to irbesartan. Baseline mGFR was 34.0 (0.8) and 34.7 (0.8) mL/min/1.73m2 respectively. At 12 months there was no difference in measured GFR: 29.8 (SE 0.5) among those assigned sacubitril/valsartan versus 29.9 (0.5) mL/min/1.73m2 among those assigned irbesartan; difference -0.1 (0.7) mL/min/1.73m2 Effects were similar in all pre-specified subgroups. There was also no significant difference in estimated GFR at 3, 6, 9 or 12 months and no clear difference in urinary albumin:creatinine ratio between treatment arms (study average difference -9%, 95% CI -18% to 1%). However, compared to irbesartan, allocation to sacubitril/valsartan reduced study average systolic and diastolic blood pressure by 5.4 (95% CI 3.4-7.4) and 2.1 (95% CI 1.0-3.3) mmHg, and levels of troponin I and N-terminal of pro-hormone brain natriuretic peptide (tertiary endpoints) by 16% (95% CI 8-23) and 18% (95% CI 11-25), respectively. The incidence of serious adverse events (29.5% vs 28.5%; rate ratio [RR] 1.07, 95% CI 0.75-1.53), non-serious adverse reactions (36.7% vs 28.0%; RR 1.35, 95% CI 0.96-1.90) and potassium ≥ 5.5 mmol/L (32% vs 24%; p=0.10) were not significantly different between randomized groups. Conclusions -Over 12 months, sacubitril/valsartan has similar effects on kidney function and albuminuria to irbesartan, but has the additional effect of lowering blood pressure and cardiac biomarkers in people with chronic kidney disease. Clinical Trial Registration -URL: www.isrctn.com Unique Identifier: ISRCTN11958993.

  • Metabolic and lifestyle risk factors for acute pancreatitis in Chinese adults: A prospective cohort study of 0.5 million people.

    16 October 2018

    Little prospective evidence exists about risk factors and prognosis of acute pancreatitis in China. We examined the associations of certain metabolic and lifestyle factors with risk of acute pancreatitis in Chinese adults.The prospective China Kadoorie Biobank (CKB) recruited 512,891 adults aged 30 to 79 years from 5 urban and 5 rural areas between 25 June 2004 and 15 July 2008. During 9.2 years of follow-up (to 1 January 2015), 1,079 cases of acute pancreatitis were recorded. Cox regression was used to estimate adjusted hazard ratios (HRs) for acute pancreatitis associated with various metabolic and lifestyle factors among all or male (for smoking and alcohol drinking) participants. Overall, the mean waist circumference (WC) was 82.1 cm (SD 9.8) cm in men and 79.0 cm (SD 9.5) cm in women, 6% had diabetes, and 6% had gallbladder disease at baseline. WC was positively associated with risk of acute pancreatitis, with an adjusted HR of 1.35 (95% CI 1.27-1.43; p < 0.001) per 1-SD-higher WC. Individuals with diabetes or gallbladder disease had HRs of 1.34 (1.07-1.69; p = 0.01) and 2.42 (2.03-2.88; p < 0.001), respectively. Physical activity was inversely associated with risk of acute pancreatitis, with each 4 metabolic equivalent of task (MET) hours per day (MET-h/day) higher physical activity associated with an adjusted HR of 0.95 (0.91-0.99; p = 0.03). Compared with those without any metabolic risk factors (i.e., obesity, diabetes, gallbladder disease, and physical inactivity), the HRs of acute pancreatitis for those with 1, 2, or ≥3 risk factors were 1.61 (1.47-1.76), 2.36 (2.01-2.78), and 3.41 (2.46-4.72), respectively (p < 0.001). Among men, heavy alcohol drinkers (≥420 g/week) had an HR of 1.52 (1.11-2.09; p = 0.04, compared with abstainers), and current regular smokers had an HR of 1.45 (1.28-1.64; p = 0.02, compared with never smokers). Following a diagnosis of acute pancreatitis, there were higher risks of pancreatic cancer (HR = 8.26 [3.42-19.98]; p < 0.001; 13 pancreatic cancer cases) and death (1.53 [1.17-2.01]; p = 0.002; 89 deaths). Other diseases of the pancreas had similar risk factor profiles and prognosis to acute pancreatitis. The main study limitations are ascertainment of pancreatitis using hospital records and residual confounding.In this relatively lean Chinese population, several modifiable metabolic and lifestyle factors were associated with higher risks of acute pancreatitis, and individuals with acute pancreatitis had higher risks of pancreatic cancer and death.

  • FLT-PET for early response evaluation of colorectal cancer patients with liver metastases: a prospective study.

    16 October 2018

    BACKGROUND: Fluoro-L-thymidine (FLT) is a positron emission tomography/computed tomography (PET/CT) tracer which reflects proliferative activity in a cancer lesion. The main objective of this prospective explorative study was to evaluate whether FLT-PET can be used for the early evaluation of treatment response in colorectal cancer patients (CRC) with liver metastases. Patients with metastatic CRC having at least one measurable (>1 cm) liver metastasis receiving first-line chemotherapy were included. A FLT-PET/CT scan was performed at baseline and after the first treatment. The maximum and mean standardised uptake values (SUVmax, SUVmean) were measured. After three cycles of chemotherapy, treatment response was assessed by CT scan based on RECIST 1.1. RESULTS: Thirty-nine consecutive patients were included of which 27 were evaluable. Dropout was mainly due to disease complications. Nineteen patients (70%) had a partial response, seven (26%) had stable disease and one (4%) had progressive disease. A total of 23 patients (85%) had a decrease in FLT uptake following the first treatment. The patient with progressive disease had the highest increase in FLT uptake in SUVmax. There was no correlation between the response according to RECIST and the early changes in FLT uptake measured as SUVmax (p = 0.24). CONCLUSIONS: No correlation was found between early changes in FLT uptake after the first cycle of treatment and the response evaluated from subsequent CT scans. It seems unlikely that FLT-PET can be used on its own for the early response evaluation of metastatic CRC.

  • Reproductive hormone analyses and effects of adjuvant zoledronic acid in early breast cancer - An AZURE (BIG 01/04) sub-study.

    16 October 2018

    Purpose: Adjuvant bisphosphonates have been shown to improve disease outcomes in early breast cancer in women who are postmenopausal at the start of treatment. We explored the influence of pretreatment serum levels of reproductive hormones in the hypothalamic-pituitary-gonadal (HPG) axis from a subset of patients included in the AZURE trial to investigate their impact on disease recurrence and whether reproductive hormone measurements are of value in selecting patients for treatment with adjuvant zoledronic acid.Patients and methods; The AZURE trial is an academic, multi-centre, international phase III trial that randomised patients to standard adjuvant therapy (chemotherapy and/or endocrine therapy)±intravenous zoledronic acid, 4 mg for 5 years. Serum from 865 patients taken at randomisation was stored at -80 °C prior to central batch analysis for inhibin A, oestradiol and follicle stimulating hormone (FSH). We assessed the clinical value of pretreatment hormone levels for predicting invasive disease free survival (IDFS), skeletal recurrence and distant recurrence and response to treatment with zoledronic acid. Results: Oestradiol in the postmenopausal range (<50 pmol/l) was associated with a significantly shorter IDFS (HR 1.36 95%CI: 1.05-1.78 p=0.022), predominantly due to distant recurrence (HR 1.33 95%CI: 0.98-1.81 p=0.065), compared to oestradiol ≥50pmol/l. In contrast, FSH in the postmenopausal range (>26 IU/l) was associated with a longer time to bone as first recurrence (HR 0.66 95%CI: 0.41-1.04 p=0.072) compared to an FSH ≤26 IU/l. When all 3 hormone levels were within the assay specified postmenopausal range, a trend to improved IDFS was seen with addition of zoledronic acid in biochemically postmenopausal women only (postmenopausal HR=0.81; 95%CI: 0.54-1.22, non-postmenopausal HR=0.99; 95%CI: 0.69-1.39) with risk reductions that mirrored the results of the main AZURE study, although the interaction between menopausal status and treatment effect was not statistically significant (p=0.47). Conclusion: Oestradiol and FSH may influence the pattern of disease recurrence with postmenopausal levels possibly creating a less conducive environment for the formation of bone metastases, therefore disseminated tumour cells could seek alternative niches outside of bone. Biochemical evaluation of a panel of reproductive hormones may be helpful to assist selection of patients for adjuvant zoledronic acid when menopausal status is unknown.