Opium tincture has anti-propulsive effects in patients with chronic diarrhea: a randomized, placebo-controlled, and cross-over trial.

OBJECTIVE: Chronic diarrhea affects approximately 5% of the population. Opioids inhibit gastrointestinal motility, and opium tincture has shown anti-propulsive effects in healthy, but no controlled studies of its clinical efficacy exist. We aimed to investigate the anti-propulsive and central nervous system (CNS) effects of opium tincture in patients with chronic diarrhea. MATERIALS AND METHODS: The study was a randomized, double-blinded, placebo-controlled, cross-over trial in subjects with chronic diarrhea refractory to standard treatment. Participants received opium tincture or placebo during two intervention periods, each lasting seven days. Bowel movements were recorded daily, and gastrointestinal transit time was investigated with the wireless motility capsule system. Gastrointestinal symptoms, health-related quality of life, and CNS effects (pupil size, reaction time, memory, and general cognition) were also investigated, along with signs of addiction. RESULTS: Eleven subjects (mean age: 45 ± 17 years, 46% males) with a median of 4.7 daily bowel movements were included. The number of daily bowel movements was reduced during opium tincture treatment to 2.3 (p = 0.045), but not placebo (3.0, p = 0.09). Opium tincture prolonged the colonic transit time compared to placebo (17 h vs. 12 h, p < 0.001). In both treatment arms, there were no changes in self-reported gastrointestinal symptoms, health-related quality of life, or CNS effects, and no indication of addiction was present. CONCLUSION: Opium tincture induced anti-propulsive effects in patients with chronic diarrhea refractory to standard treatment. This indicates that opium tincture is a relevant treatment strategy for selected patients with chronic diarrhea. Moreover, no evidence of opioid-induced sedation or addiction was found.Trial Registration Number: NCT05690321 (registered 2023-01-10).

Metabolic Sequelae and All-Cause Mortality in Chronic Pancreatitis With and Without Prior Acute Pancreatitis: A Nationwide Population-Based Cohort Study.

INTRODUCTION: The purpose of this study was to investigate the risk of metabolic sequelae and all-cause mortality in a population-based cohort of chronic pancreatitis (CP) patients with and without prior acute pancreatitis (AP). METHODS: We used nationwide health registries to identify all Danish residents (18 years and older) with incident CP from 2000 to 2018. Information on AP/CP diagnoses, metabolic sequelae (post-pancreatitis diabetes mellitus [PPDM], exocrine pancreatic dysfunction, and osteoporosis), and all-cause mortality were obtained from Danish national health registries. CP cases were stratified based on the presence of AP before CP diagnosis. The risk of metabolic sequelae and all-cause mortality was expressed as hazard ratios (HRs) with 95% confidence intervals (CIs), calculated using multivariate Cox proportional hazards models. RESULTS: A total of 9,655 patients with CP were included. Among patients with CP, 3,913 (40.5%) had a prior AP diagnosis. Compared with patients without a history of AP, patients with prior AP had a decreased risk of death (HR 0.79, 95% CI 0.74-0.84), which was largely confined to the initial period after CP diagnosis. Patients with prior AP had an increased risk of PPDM (HR 1.53, 95% CI 1.38-1.69), which persisted for up to a decade after CP diagnosis. No overall differences in risk were observed for exocrine pancreatic dysfunction (HR 0.97, 95% CI 0.87-1.07) and osteoporosis (HR 0.87, 95% CI 0.74-1.02). DISCUSSION: This nationwide study revealed that most of the patients with CP have no prior episode(s) of AP, indicating that an attack of AP sensitizing the pancreas is not essential for CP development. CP patients with and without prior AP have different risk profiles of PPDM and all-cause mortality.

Metformin treatment is associated with reduced risk of hypoglycaemia, major adverse cardiovascular events, and all-cause mortality in patients with post-pancreatitis diabetes mellitus: a nationwide cohort study.

OBJECTIVE: Post-pancreatitis diabetes mellitus (PPDM) is a frequent complication of pancreatitis and is associated with an increased risk of adverse outcomes. Metformin is recommended for the treatment of PPDM, but evidence of its risk-benefit profile is limited. In a pharmaco-epidemiologic study, we investigated the association between metformin treatment and adverse outcomes in patients with PPDM. DESIGN AND METHODS: In a Danish nationwide population-based cohort study, we included adults (≥18 years) with incident PPDM or type 2 diabetes between 2009 and 2018. Post-pancreatitis diabetes mellitus was categorised into acute and chronic subtypes (PPDM-A and PPDM-C). Associations between metformin treatment and severe hypoglycaemia, major adverse cardiovascular events (MACE), and all-cause mortality were examined across the diabetes subgroups using Cox regression analysis. Treatments with metformin, insulin, and other glucose-lowering therapies were handled as time-varying exposures. RESULTS: We included 222 337 individuals with new-onset type 2 diabetes and 3781 with PPDM, of whom 2305 (61%) were classified as PPDM-A and 1476 (39%) as PPDM-C. Treatment with metformin was associated with a lower risk of severe hypoglycaemia (adjusted hazard ratio [HR] 0.41, 95% CI 0.27-0.62, P < .0001), MACE (HR 0.74, 95% CI 0.60-0.92, P = .0071), and all-cause mortality (HR 0.56, 95% CI 0.49-0.64, P < .0001) in patients with PPDM. In sensitivity analyses and among individuals with type 2 diabetes, metformin treatment exhibited comparable trends of risk reduction. CONCLUSIONS: Metformin is associated with a lower risk of adverse outcomes, including all-cause mortality in patients with PPDM, supporting the use of metformin as a glucose-lowering therapy for these patients.

Multistate Model of the Natural History of Inflammatory Pancreatic Diseases: A Nationwide Population-based Cohort Study.

BACKGROUND & AIMS: Understanding the nature of inflammatory pancreatic diseases is essential for planning health care system requirements and interventions. The aim of this study was to quantify the trajectories of inflammatory pancreatic diseases and their association with pancreatic cancer in a population-based setting. METHODS: National health registries were used to identify all Danish residents (18 years or older) in the period from 2000 through 2018 with incident cases of acute pancreatitis (AP), recurrent acute pancreatitis (RAP), chronic pancreatitis (CP), and pancreatic cancer. We used a multistate model to examine transitions from a healthy state to intermediate states of acute pancreatic inflammation (AP and RAP) to chronic states (CP and pancreatic cancer) and, ultimately, death. Results were reported as transition incidence rates per 1000 person-years with 95% CIs. RESULTS: There were 4,663,864 individuals included (mean age, 46 years; 51% were women). During a mean follow-up of 16.8 years, 31,396 individuals were diagnosed with incident AP, 5546 with RAP, 8898 with CP, and 18,182 with pancreatic cancer. The cumulative incidence of pancreatitis (acute and chronic) during the study period was 0.80% (95% CI, 0.79%-0.80%). The transition incidence rates to CP were 12.1 (95% CI, 8.1-18.1) from AP, 46.8 (95% CI, 31.6-69.3) from RAP, and 0.07 (95% CI, 0.04-0.13) from a healthy state. Similar patterns were observed for transitions to pancreatic cancer. Most patients diagnosed with CP (64.2%) and pancreatic cancer (96.4%) transitioned directly from a healthy state. Among patients with pancreatitis, 41.0% (95% CI, 40.5%-41.5%) died during follow-up. CONCLUSIONS: The study findings revealed an increased risk of CP and pancreatic cancer in patients with a history of AP. However, most patients with CP and pancreatic cancer transitioned directly from a healthy state.

Short-term prognosis of normalising serum potassium following an episode of hypokalaemia in patients with chronic heart failure.

BACKGROUND/ AIM: It is well known that patients with chronic heart failure and hypokalaemia have increased mortality risk. We investigated the impact of normalising serum potassium following an episode of hypokalaemia on short-term mortality among patients with chronic heart failure. METHODS AND RESULTS: We identified 1673 patients diagnosed with chronic heart failure who had a serum potassium measurement under 3.5 mmol/l within 14 days and one year after initiated medical treatment with both loop diuretics and angiotensin-converting enzyme inhibitors or angiotensin-II receptor blockers. A second serum potassium measurement was required 8-30 days after the episode of hypokalaemia. All-cause mortality and cardiovascular mortality was examined within 90 days from the second serum potassium measurement. Mortality was examined according to six predefined potassium groups derived from the second measurement:<3.5 mmol/l (n = 302), 3.5-3.7 mmol/l (n = 271), 3.8-4.1 mmol/l (n = 464), 4.2-4.4 mmol/l (n = 270), 4.5-5.0 mmol/l (n = 272), and 5.1-8.0 mmol/l (n = 94). We used Cox regression to estimate both all-cause mortality risk and cardiovascular mortality, with serum potassium at 3.8-4.1 mmol/l as reference. After 90 days, the all-cause mortality in the six groups was 29.5%, 22.1%, 20.3%, 24.8%, 23.5% and 43.6%, respectively. In multivariable adjusted analysis, patients with serum potassium <3.5 mmol/l (hazard ratio: 1.51; 95% confidence interval: 1.13-2.02) and serum potassium 5.1-8.0 mmol/l (hazard ratio: 2.18; 95% confidence interval: 1.50-3.17) had an increased risk of all-cause mortality compared to the reference. After 90 days, the cardiovascular mortality in the six groups was 19.2%, 17.7%, 14.4%, 18.9%, 18.8% and 34.0%, respectively. In multivariable adjusted analysis, patients with serum potassium 5.1-8.0 mmol/l (hazard ratio: 2.32; 95% confidence interval: 1.51-3.56) had an increased risk of cardiovascular mortality compared to the reference, while serum potassium <3.5 mmol/l (hazard ratio: 1.37; 95% confidence interval: 0.97-1.95) had a trend toward increased risk of cardiovascular mortality compared to the reference. CONCLUSION: Patients with chronic heart failure and hypokalaemia, who after 8-30 days remained hypokalaemic, had a significantly higher 90-day all-cause mortality risk compared to patients in the reference group (3.8-4.1 mmol/l). Patients with chronic heart failure and hypokalaemia, who after 8-30 days had the serum potassium level increased to a level within 5.1-8.0 mmol/l, had both a significantly higher 90-day all-cause mortality risk and cardiovascular mortality risk compared to patients in the reference group (3.8-4.1 mmol/l).

Long-term impact of baseline anaemia on clinical outcomes following percutaneous coronary intervention in stable angina.

BACKGROUND: In patients with stable angina (SA), the clinical benefits of percutaneous coronary intervention (PCI) reside almost exclusively within the realm of symptomatic improvement rather than improvement in hard clinical endpoints. The benefits of PCI should always be balanced against its potential short-term and long-term risks. Common among these risks is the presence of anaemia and its interaction with poor clinical outcomes and increased morbidity; this study aims to elucidate the impact of anaemia on long-term clinical outcomes of this patient group. METHODS: From Danish national registries, we identified patients with SA treated with PCI who had a haemoglobin measurement maximum of 90 days prior to PCI procedure. Anaemia was defined as haemoglobin <130 and <120 g/L in men and women, respectively. Follow-up was up to 3 years after PCI, and Cox regression was used to estimate HRs with 95% CIs of hospitalisation due to bleeding, acute coronary syndrome (ACS) and all-cause mortality in patients with anaemia compared with patients without anaemia. RESULTS: Of 2837 included patients, 14.6% had anaemia prior to PCI. During follow-up, 93 patients (3.3%) had a bleeding episode, which was higher in patients with anaemia (5.8%) compared with patients without anaemia (2.8%). A total of 213 patients (7.5%) developed ACS, which was higher in patients with anaemia (10.6%) compared with patients without anaemia (7.0%). Furthermore, 185 patients (6.5%) died, with a mortality rate of 18.1% in patients with anaemia compared with 4.5% in patients without anaemia. In multivariable analyses, anaemia was associated with a significantly increased risk of bleeding (HR 1.69; 95% CI 1.04 to 2.73; P 0.033), ACS (HR 1.47; 95% CI 1.04 to 2.10; P 0.031) and all-cause mortality (HR 2.41; 95% CI 1.73 to 3.30; P <0.001). CONCLUSION: Anaemia in patients with SA was significantly associated with bleeding, ACS and all-cause mortality following PCI.

The Association Between Serum Calcium Levels and Short-Term Mortality in Patients with Chronic Heart Failure.

BACKGROUND: Patients with chronic heart failure have vulnerable myocardial function and are susceptible to electrolyte disturbances. In these patients, diuretic treatment is frequently prescribed, though it is known to cause electrolyte disturbances. Therefore, we investigated the association between altered calcium homeostasis and the risk of all-cause mortality in chronic heart failure patients. METHODS: From Danish national registries, we identified patients with chronic heart failure with a serum calcium measurement within a minimum 90 days after initiated treatment with both loop diuretics and angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. Patients were divided into 3 groups according to serum calcium levels, and Cox regression was used to assess the mortality risk of <1.18 mmol/L (hypocalcemia) and >1.32 mmol/L (hypercalcemia) compared with 1.18 mmol/L-1.32 mmol/L (normocalcemia) as reference. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. RESULTS: Of 2729 patients meeting the inclusion criteria, 32.6% had hypocalcemia, 63.1% normocalcemia, and 4.3% hypercalcemia. The highest mortality risk was present in early deaths (≤30 days), with a HR of 2.22 (95% CI; 1.74-2.82) in hypocalcemic patients and 1.67 (95% CI; 0.96-2.90) in hypercalcemic patients compared with normocalcemic patients. As for late deaths (>30 days), a HR of 1.52 (95% CI; 1.12-2.05) was found for hypocalcemic patients and a HR of 1.87 (95% CI; 1.03-3.41) for hypercalcemic patients compared with normocalcemic patients. In adjusted analyses, hypocalcemia and hypercalcemia remained associated with an increased mortality risk in both the short term (≤30 days) and longer term (>30 days). CONCLUSION: Altered calcium homeostasis was associated with an increased short-term mortality risk. Almost one-third of all the heart failure patients suffered from hypocalcemia, having a poor prognosis.

Associations of serum potassium levels with mortality in chronic heart failure patients.

AIMS: Medication prescribed to patients suffering from chronic heart failure carries an increased risk of impaired potassium homeostasis. We examined the relation between different levels of serum potassium and mortality among patients with chronic heart failure. METHODS AND RESULTS: From Danish National registries, we identified 19 549 patients with a chronic heart failure diagnosis who had a measurement of potassium within minimum 90 days after initiated medical treatment with loop diuretics and angiotensin converting enzyme inhibitors or angiotensin-II receptor blockers. All-cause mortality was examined according to eight predefined potassium levels: 2.8-3.4 mmol/L, 3.5-3.8 mmol/L, 3.9-4.1 mmol/L, 4.2-4.4 mmol/L, 4.5-4.7 mmol/L, 4.8-5.0 mmol/L, 5.1-5.5 mmol/L, and 5.6-7.4 mmol/L. Follow-up was 90 days from potassium measurement. We estimated the risk of all-cause mortality using multivariable adjusted Cox proportional hazard model, with normal serum potassium level at 4.2-4.4 mmol/L as reference. After 90 days, the mortality in the eight strata was 14.4, 8.0, 6.3, 5.0, 5.8, 7.9, 10.3, and 21.1% respectively. In multivariable adjusted analysis, patients with potassium levels of 2.8-3.4 mmol/L [hazard ratio (HR): 3.16; confidence interval (CI): 2.43-4.11], 3.5-3.8 mmol/L (HR: 1.62; CI: 1.31-1.99), 3.9-4.1 mmol/L (HR: 1.29; CI: 1.08-1.55), 4.8-5.0 mmol/L (HR: 1.34; CI: 1.10-1.63), 5.1-5.5 mmol/L (HR: 1.60; CI: 1.29-1.97), and 5.6-7.4 mmol/L (HR: 3.31; CI: 2.61-4.20) had an increased risk of all-cause mortality. CONCLUSION: Levels within the lower and upper levels of the normal serum potassium range (3.5-4.1 mmol/L and 4.8-5.0 mmol/L, respectively) were associated with a significant increased short-term risk of death in chronic heart failure patients. Likewise, potassium below 3.5 mmol/L and above 5.0 mmol/L was also associated with increased mortality.