ACE inhibitors and the risk of acute pancreatitis-a population-based case-control study.

PURPOSE: The aim of this study was to examine the association between angiotensin converting enzyme (ACE) inhibitor use and the risk of acute pancreatitis. METHODS: Information on all 4966 cases hospitalized in 2008-2010 for acute pancreatitis was retrieved from the Finnish national registers on hospital discharges and prescriptions. A total of 24 788 age and sex-matched population-based controls were randomly selected using density sampling. ACE inhibitor use between 1 January 2003 and the index date were determined by the date of hospitalization for acute pancreatitis among the cases. The incidence rate ratios of acute pancreatitis not diagnosed as biliary or alcohol-induced were modeled by conditional logistic regression and adjusted for comorbidities. RESULTS: A total of 1276 (26%) cases and 3946 (16%) controls had been exposed to ACE inhibitors. The use of ACE inhibitors was associated with an increased incidence rate of acute pancreatitis (odds ratio [OR] 1.76, 95% confidence interval [CI] 1.59-1.95). The increase was slightly higher among current new users (OR 1.86, 95%CI 1.65-2.09) and somewhat lower among current prevalent (OR 1.54, 95%CI 1.35-1.75) and former users (OR 1.51, 95%CI 1.31-1.74). CONCLUSIONS: Angiotensin converting enzyme inhibitor use seems to be associated with a moderately increased risk of acute pancreatitis. Copyright © 2017 John Wiley & Sons, Ltd.

Use of statins and the risk of acute pancreatitis: a population-based case-control study.

PURPOSE: The aim of this research was to examine the association between statin use and the risk of acute pancreatitis. METHODS: This register-based case-control study with incidence density sampling was based on 4376 patients hospitalized in 2008-2010 for acute pancreatitis and 19 859 randomly selected age and sex-matched controls from the adult population of Finland. The relationship between statin use from 1 January 2004 to the index date and the relative incidence rate of acute pancreatitis was modelled by conditional logistic regression. The rate ratios were adjusted for comorbidities. RESULTS: A total of 826 (19%) cases and 2589 (13%) controls had been exposed to statins. Statin use was associated with an increased incidence rate of acute pancreatitis (odds ratio (OR) 1.25, 95% confidence interval (CI) 1.13-1.39). This increase was seen especially during the first year of use both among current (OR 1.37, 95% CI 0.94-2.00 for at most 3 months of use and OR 1.32, 95% CI 1.07-1.63 for 4-12 months of use) and former users (OR 1.64, 95% CI 1.33-2.03). The overall association remained when restricting analyses to participants with current use only, or with no history of gallstone or alcohol-related diseases, or with no comorbidities or medicines other than statins. CONCLUSIONS: Statin use seems to be associated with an increased risk of acute pancreatitis. The association is more apparent during the first year of statin use and among former users.

Piloting international production of rapid relative effectiveness assessments of pharmaceuticals.

BACKGROUND: This article describes the lessons learned from an international pilot assessment using the first version of the HTA Core Model® and Guidelines for rapid Relative Effectiveness Assessment (REA) of pharmaceuticals based on input from three different perspectives: the assessors, the users (health technology assessment organisations) and the marketing authorisation holder. METHODS: A pilot assessment was performed of pazopanib for the treatment of advanced or metastatic renal cell carcinoma for which 54 individuals from 22 EUnetHTA member organisations from 16 European countries gave their contribution. The work was divided in eight domain teams. Subsequently, results of these domain teams were synthesised in one pilot report. Feedback on the outcomes of the pilot was gathered throughout the project and through structured surveys. RESULTS: The first version of the assessment was produced in six months and consisted of 55 question and answer pairs, 8 domain reports and a synthesis section that combined the results from the different domains. The organisation of the pilot required intense coordination. Main points of criticism on the assessment were the lengthiness of the document and overlap of information throughout the assessment. CONCLUSIONS: A reduction in the number of authoring organisations and individuals participating is necessary to avoid information overlap and increase efficiency in undertaking the assessment. Involving several organisations (e.g. five) in an in-depth review could still ensure the benefit of broad participation from various countries. The focus of a rapid REA should be on the first four domains of the Model.

Inspiratory flows through dry powder inhaler in chronic obstructive pulmonary disease: age and gender rather than severity matters.

BACKGROUND: Dry powder inhalers (DPIs) are inspiratory flow driven and hence flow dependent. Most patients with chronic obstructive pulmonary disease (COPD) are elderly and have poor lung function. The factors affecting their inspiratory flows through inhalers are unclear. OBJECTIVE: To study peak inspiratory flows (PIFs) and their determinants through a DPI in COPD patients of varying age and severity. METHODS: Flow-volume spirometry was performed in 93 COPD patients. Maximum PIF rates were recorded through an empty Easyhaler (PIF(EH); Orion Corporation, Espoo, Finland), a DPI that provides consistent dose delivery at inhalation rates through the inhaler of 28 L/min or higher. RESULTS: The mean PIF(EH) was 54 L/min (range 26-95 L/min) with a coefficient of variation of 7%. All but two patients were able to generate a flow of > or = 28 L/min. In a general linear model, the independent determinants for PIF(EH) were age (P = 0.02) and gender (P = 0.01), and forced expiratory volume in 1 s (FEV(1)) expressed as percent predicted was not a significant factor. The regression model accounted only for 18% of the variation in PIF(EH). CONCLUSION: In patients with COPD, age and gender are more important determinants of inspiratory flow through DPIs than the degree of expiratory airway obstruction. Most COPD patients with varying age and severity are able to generate inspiratory flows through the test inhaler that is sufficient for optimal drug delivery to the lower airways.

Comparison of polyethylene glycol with and without electrolytes in the treatment of constipation in elderly institutionalized patients: a randomized, double-blind, parallel-group study.

BACKGROUND: Polyethylene glycol (PEG) is a commonly used osmotic laxative. PEG with electrolytes is mixed with water, but PEG without electrolytes can also be mixed with, for example, juice, coffee or tea, making it more palatable. Laxatives, including PEG, are commonly used by the elderly, particularly those living in institutions. Few clinical studies, however, have investigated the use of PEG in this population. OBJECTIVE: To test whether PEG 4000 without electrolytes (hypotonic PEG) is at least as effective and safe as PEG 4000 with electrolytes (isotonic PEG) in elderly institutionalized constipated patients. The acceptability of the treatments was also compared. METHODS: This randomized, double-blind, parallel-group study was conducted at ten private assisted-living facilities or communal nursing homes in Finland. Eligible patients were required to have used isotonic PEG at a stable dose without any other treatment for constipation (except for Plantago ovata seeds) for at least 2 weeks prior to a run-in period. After the 1-week run-in, 62 patients (mean age 86 years; range 66-99 years) were randomly either switched to receive hypotonic PEG or continued to receive isotonic PEG, both dissolved in water, 12 g once or twice daily or once every other day, for 4 weeks. Stool frequency, stool consistency, stool straining and gastrointestinal symptoms were recorded. Safety laboratory tests were conducted before and after the treatment period. Acceptability was assessed at the end of the study. RESULTS: At week 4, mean (SD) weekly stool frequencies in the hypotonic and isotonic PEG groups were 8.5 (4.5) and 8.4 (3.6), respectively. The mean stool frequency ratio (95% CI) was 0.90 (0.74, 1.10); thus, the PEG products were considered equally effective. At week 4, the proportion of patients with soft or normal stool consistency was higher in the hypotonic PEG group than in the isotonic PEG group (70% vs 52%), but this difference was not statistically significant. There were no differences between the groups in stool straining or gastrointestinal symptoms. In the safety laboratory tests, no clinically significant differences between the groups were detected, although plasma sodium level was statistically significantly lower in the hypotonic PEG group at the end of the study (137.7 vs 138.9 mmol/L, respectively; p = 0.012). Most patients were willing to continue their study treatment (85% in the hypotonic PEG and 63% in the isotonic PEG group; p = 0.070). Compared with only 12% of the patients receiving hypotonic PEG, however, 31% of the patients in the isotonic PEG group rated the taste of the study treatment as bad or very bad (p = 0.101). CONCLUSION: Hypotonic PEG solution is as effective as isotonic PEG in the treatment of constipation in elderly institutionalized patients. Both treatments appear safe, well tolerated and, when dissolved in water, well accepted by the majority of the patients. When desired, switching from isotonic to hypotonic PEG can safely take place in elderly individuals without compromising efficacy.

Coffee consumption and mortality in a 14-year follow-up of an elderly northern Finnish population.

The present study assessed the relationship between coffee consumption and mortality in a home-dwelling elderly population. A population-based cohort of 817 men and women born in 1920 or earlier and living in northern Finland provided complete data on daily coffee consumption and other variables at the baseline examination in 1991-1992. Deaths were monitored through to the end of 2005 by national death certificates, resulting in 6960 person-years of follow-up. Hazard rate ratios for mortality by daily coffee intake were estimated by Poisson regression models adjusted for some known predictors of mortality. During 14.5 years of follow-up, 623 deaths occurred. The total mortality rate was inversely related to the number of cups (average volume, 125 ml) of coffee consumed daily. After adjustment for age, sub-period of follow-up, sex, marital status, basic educational level, previous occupational group, current smoking, BMI, history of myocardial infarction, self-rated health and presence of diabetes, cognitive impairment or physical disability, the estimated relative risk reduction of total mortality per an increment of one more cup of coffee per d reported at baseline was 4 (95% CI 0, 8) %. The observed associations between coffee consumption and mortality from CVD, cancer, and other or unknown causes, respectively, were qualitatively similar to that of total mortality but the estimates were less precise. The effect of coffee consumption at baseline appeared to attenuate after 10 years since the start of follow-up. The present study provides evidence for daily (caffeine-containing) coffee intake being inversely associated with mortality in the elderly.

Functional COMT Val158Met polymorphism, risk of acute coronary events and serum homocysteine: the Kuopio ischaemic heart disease risk factor study.

BACKGROUND: The role of circulating levels of total homocysteine tHcy in the development of coronary heart disease (CHD) is still under debate. One reason for conflicting results between previous studies on homocysteine and heart diseases could be consequence of different interactions between homocysteine and genes in different study populations. Many genetic factors play a role in folate-homocysteine metabolism, like functional polymorphism (Val108Met) in the Catechol-O-methyltransferase (COMT) gene. METHODOLOGY AND FINDINGS: Our aim was to examine the role of COMT Val158Met polymorphism and interaction of this polymorphism with serum tHcy and folate concentration on the risk of acute coronary and events in middle-aged men from eastern Finland. A population-based prospective cohort of 792 men aged 46-64 years was examined as part of the Kuopio Ischaemic Heart Disease Risk Factor Study. During an average follow-up of 9.3 years, there were 69 acute coronary events in men with no previous history of CHD. When comparing the COMT low activity genotype with the others, we found an age and examination year adjusted hazard rate ratio (HRR) of 1.73 (95% confidence interval (CI), 1.07-2.79), and an age, examination year, serum LDL and HDL cholesterol, and triglyceride concentration, systolic blood pressure and smoking adjusted HRR of 1.77 (95% CI, 1.05-2.77). Although serum tHcy concentration was not statistically significantly associated with acute coronary events (HRR for the highest third versus others 1.52, 95% CI, 0.93-2.49), subjects with both high serum tHcy and the COMT low activity genotype had an additionally increased adjusted risk of HRR 2.94 (95% CI 1.50-5.76) as compared with other men. CONCLUSIONS: This prospective cohort study suggests that the functional COMT Val158Met polymorphism is associated with increased risk of acute coronary events and it may interact with high serum tHcy levels.

High dietary methionine intake increases the risk of acute coronary events in middle-aged men.

BACKGROUND AND AIM: Homocysteine, a methionine metabolite, is suggested to be a risk factor for cardiovascular diseases (CVD). To date, the effects of dietary intake of methionine, the key amino acid in homocysteine metabolism, on CVD have not been studied. Our aim was to examine the effects of dietary methionine intake on the risk of acute coronary events. METHODS AND RESULTS: We examined the effects of dietary methionine intake, assessed with 4-d food record, on acute coronary events in a prospective cohort study consisting of 1981 coronary disease free men from eastern Finland, aged 42-60 years at baseline in 1984-89, in the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study. During an average follow-up time of 14.0 years, 292 subjects experienced an acute coronary event. In a Cox proportional hazards model adjusting for age, examination years, BMI, urinary nicotine metabolites and protein intake (excluding methionine) the relative risks of acute coronary event in the three highest quarters of dietary methionine intake were 1.31 (95% CI: 0.92, 1.86), 1.31 (95% CI: 0.88, 1.96) and 2.08 (95% CI: 1.31, 3.29) as compared with the lowest quarter. Further adjustments did not change the results. However, opposite association was observed with total protein intake, which tended to decrease the risk. CONCLUSIONS: The main finding of this study is that long-term, moderately high dietary methionine intake may increase the risk of acute coronary events in middle-aged Finnish men free of prior CHD. More prospective research is needed to confirm the role of dietary methionine in the development of CVD, and whether its effects are independent of homocysteine.

Catechol-o-methyltransferase gene polymorphism modifies the effect of coffee intake on incidence of acute coronary events.

BACKGROUND: The role of coffee intake as a risk factor for coronary heart disease (CHD) has been debated for decades. We examined whether the relationship between coffee intake and incidence of CHD events is dependent on the metabolism of circulating catecholamines, as determined by functional polymorphism of the catechol-O-methyltransferase (COMT) gene. METHODOLOGY/PRINCIPAL FINDINGS: In a cohort of 773 men who were 42 to 60 years old and free of symptomatic CHD at baseline in 1984-89, 78 participants experienced an acute coronary event during an average follow-up of 13 years. In logistic regression adjusting for age, smoking, family history of CHD, vitamin C deficiency, blood pressure, plasma cholesterol concentration, and diabetes, the odds ratio (90% confidence interval) comparing heavy coffee drinkers with the low activity COMT genotype with those with the high activity or heterozygotic genotypes was 3.2 (1.2-8.4). Urinary adrenaline excretion increased with increasing coffee intake, being over two-fold in heavy drinkers compared with nondrinkers (p = 0.008 for trend). CONCLUSIONS/SIGNIFICANCE: Heavy coffee consumption increases the incidence of acute coronary events in men with low but not high COMT activity. Further studies are required to determine to which extent circulating catecholamines mediate the relationship between coffee intake and CHD.

Serum homocysteine, folate and risk of stroke: Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study.

BACKGROUND: Homocysteine and folate have been suggested to have opposite effects on the risk of stroke, although the results are controversial. DESIGN AND METHODS: The purpose of this study was to assess the effects of serum total homocysteine (tHcy) and serum folate levels on the risk of stroke in a prospective cohort study. The subjects were 1015 men aged 46-64 years and free of prior stroke, examined in 1991-1993 in the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study. RESULTS: At baseline the mean serum tHcy concentration was 10.9 micromol/l (SD 3.4). During an average follow-up time of 9.6 years, 49 men experienced a stroke, of which 34 were ischaemic. In Cox proportional hazards models, men in the highest tHcy third had a risk factor-adjusted hazard rate ratio (RR) of 2.77 [95% confidence interval (CI): 1.23-6.24] for any stroke and 2.61 (95% CI: 1.02-6.71) for ischaemic stroke, compared with men in the lowest third. The mean baseline serum folate concentration was 10.4 nmol/l (SD 4.1). Men in the highest third of serum folate (>11.2 nmol/l) had an adjusted RR for any stroke of 0.35 (95% CI: 0.14-0.87) and for ischaemic stroke of 0.40 (95% CI: 0.15-1.09), compared with men in the lowest third. CONCLUSION: Elevated serum tHcy is associated with increased risk of all strokes and ischaemic strokes in middle-aged eastern Finnish men free of prior stroke. On the other hand, high serum folate concentration may protect against stroke.

The effects of coffee consumption on lipid peroxidation and plasma total homocysteine concentrations: a clinical trial.

Despite extensive research, the cardiovascular effects of coffee consumption in humans remain controversial. Our aim was to investigate the excretion of coffee phenols and the effects of filtered coffee consumption on oxidative stress and plasma homocysteine (tHcy) concentration in humans. The study consisted of a multiple-dose clinical supplementation trial and a single-dose study. In the long-term trial, 43 healthy nonsmoking men optionally consumed daily either no coffee, 3 cups (450 mL), or 6 cups (900 mL) of filtered coffee for 3 weeks, while in the short-term study 35 subjects consumed a single dose of 0, 1 (150 mL), or 2 cups (300 mL) of coffee. Long-term consumption of coffee increased the urinary excretion of caffeic and ferulic acid. The change in the total excretion of phenolic acids in 3 and 6 cups groups represented 3.8 and 2.5% of the amount ingested daily. Plasma tHcy concentrations increased nonsignificantly, but the consumption of coffee had neither short-nor long-term effects on lipid peroxidation or the activity of measured antioxidant enzymes. In conclusion, the consumption of filtered coffee does not have any detectable effects on lipid peroxidation in healthy nonsmoking men. The effect of coffee consumption on tHcy concentrations needs further investigation.

Coffee drinking is dose-dependently related to the risk of acute coronary events in middle-aged men.

Heavy coffee consumption has been associated with increased coronary heart disease (CHD) risk although many studies have not observed any relation. We studied the effect of coffee consumption, assessed with a 4-d food record, on the incidence of nonfatal acute myocardial infarction or coronary death in a cohort of 1971 men who were 42 to 60 y old and free of symptomatic CHD at baseline in 1984-1989. During a mean follow-up of 14 y, 269 participants experienced an acute coronary event. After adjustment for age, smoking, exercise ischemia, diabetes, income, and serum insulin concentration, the rate ratios (95% CIs) in daily nondrinkers and light (375 mL or less), moderate (reference level), and heavy (814 mL or more) drinkers were 0.84 (0.41-1.72), 1.22 (0.90-1.64), 1.00, and 1.43 (1.06-1.94). To address time dependence of the effect, the analysis was repeated for 75 CHD events that occurred during the first 5 y; the respective rate ratios were 0.42 (0.06-3.10), 2.00 (1.16-3.44), 1.00, and 2.07 (1.17-3.65). Further adjustment for serum HDL and LDL cholesterol concentration, diastolic blood pressure, maximal oxygen uptake, and waist-hip ratio slightly increased the rate ratio for heavy coffee intake. Neither the brewing method (boiling vs. filtering) nor the serum LDL cholesterol concentration had any impact on the risk estimates for coffee intake. In conclusion, heavy coffee consumption increases the short-term risk of acute myocardial infarction or coronary death, independent of the brewing method or currently recognized risk factors for CHD.