A historical cohort study on predictors for successful weaning from prolonged mechanical ventilation and up to 3-year survival follow-up in a rehabilitation center.

BACKGROUND: We followed prolonged mechanically ventilated (PMV) patients for weaning attempts and explored factors associated with successful weaning and long-term survival. METHODS: This historical cohort study included all adult PMV patients admitted to a single rehabilitation hospital during 2015-2018 and followed for survival according to weaning success up to 3 years or the end of 2021. RESULTS: The study included 223 PMV patients. Of them, 124 (55.6 %) underwent weaning attempts, with 69 (55.6 %) successfully weaned, 55 (44.4 %) unsuccessfully weaned, and 99 patients with no weaning attempts. The mean age was 67 ± 20 years, with 39 % female patients. Age, sex distributions and albumin levels at admission were not significantly different among the groups. The successful weaning group had a 6 % higher proportion of conscious patients than the failed weaning group (55 % vs. 49 %, respectively, p = 0.45). Patients successfully weaned were less frequently treated with antibiotics for 5 days or more than those unsuccessfully weaned (74 % vs 80 %, respectively, p = 0.07). They also had a lower proportion of time from intubation to tracheostomy greater than 14 days (45 % vs 66 %, p = 0.02). The age, sex, antibiotic treatment, time to tracheostomy exceeding 14 days and time from admission to first weaning attempt adjusted one-year mortality risk of successful vs. failed weaning was somewhat lower, HR = 0.75, 95%CI: 0.33-1.60, p = 0.45, with the same trend by the end of 3 years, HR = 0.77, 95%CI: 0.42-1.39, p = 0.38. CONCLUSION: Successful weaning from PMV may be associated with better survival and allows chronically ventilated patients to become independent on a ventilator. A larger study is needed to further validate our findings.

Emulated Trial for Discharge Prescription of Guideline-Directed Medical Therapy and 15-Year Survival After Coronary Artery Bypass Graft Surgery.

OBJECTIVES: To explore admission and discharge prescription rates of guideline-directed medical therapy (GDMT), defined as aggregate antiplatelet agents, statins, and ß-blockers, after coronary artery bypass graft (CABG) surgery and to reveal its association with long-term survival. PATIENTS AND METHODS: This is a prospective cohort study-based emulated trial of patients undergoing elective or semi-elective isolated CABG surgery in 7 cardiothoracic units in Israel from January 1, 2004, to December 31, 2007, and followed up until December 31, 2020, for all-cause mortality. RESULTS: Only 59.2% of 968 patients (n=573) were discharged on GDMT after CABG surgery. Admission GDMT use conferred a 7 times greater likelihood of discharge GDMT prescription (odds ratio, 7.07; 95% CI, 5.04 to 9.91; P<.001), with no sex differences observed. After applying inverse probability of treatment weighting, baseline characteristics were well balanced between groups. During a median follow-up of 13.7 years, a Cox regression model with propensity score-adjusted inverse probability of treatment weighting revealed lower mortality in patients with discharge GDMT prescription who underwent CABG surgery than in their counterparts (hazard ratio, 0.75; 95% CI, 0.60 to 0.93; P=.008). CONCLUSION: The use of aggregate GDMT before surgery conferred a greater likelihood of GDMT prescription upon discharge, which, in turn, is associated with better long-term survival. Educational efforts of pertinent medical professionals are needed to minimize preventive treatment gaps. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00356863.

Glucagon-Like Peptide-1 Receptor Agonists and Pancreatic Cancer Risk in Patients With Type 2 Diabetes.

Importance: Concerns have been raised that glucagon-like peptide-1 receptor agonists (GLP-1RA) may increase the risk of pancreatic cancer. Objective: To investigate the association of GLP-1RA treatment with pancreatic cancer incidence over 9 years of follow-up. Design, Setting, and Participants: In this population-based historical cohort study, adult patients (aged 21 to 89 years) with type 2 diabetes insured by Clalit Healthcare Services, the largest state-mandated health organization in Israel, were followed up from 2009, when GLP-1RA became available in Israel, until pancreatic cancer diagnosis, death, reaching age 90 years, or end of follow-up (December 2017). Data were analyzed from June 2022 to November 2023. Exposures: Treatment with GLP-1RA was compared with basal insulin. Main Outcome and Measures: Pancreatic cancer incidence was compared according to weighted cumulative exposures to GLP-1RA and to basal insulin in a Cox model implemented in discrete time, with time origin at 2 years after diabetes diagnosis, adjusting for confounding. In sensitivity analyses, propensity score-matched pair new-user design and prevalent new-user design were used for the comparison. Because of risk for reverse-causation bias, results in the fifth to seventh year after medication were emphasized. Results: During a cumulative follow-up of 3 290 439 person-years of 543 595 adults with a mean (SD) age of 59.9 (12.8) years (277 502 women [51%]) with incident diabetes, 1665 patients received pancreatic cancer diagnoses. In total, 33 377 patients (6.1%) used GLP-1RA and 106 849 (19.7%) used basal insulin. The estimated hazard ratio (HR) for pancreatic cancer associated with incremental use of 1 defined daily dose per day of GLP-1RA compared with basal insulin in the fifth to seventh year previously (all other characteristics, including age, sex, ethnic background, sociodemographic status, baseline body mass index, smoking history, history of pancreatitis, other glucose-lowering medications treatment history, and length of diabetes, being equal) was 0.50 (95% CI, 0.15-1.71). The new-user and prevalent new-user designs showed HRs from the fifth year onwards following initiation of GLP-1RA vs basal insulin of 0.52 (95 % CI, 0.19-1.41) and 0.75 (95 % CI, 0.37-1.53), respectively. Conclusions and Relevance: In this historical cohort study of adults with type 2 diabetes, no support for an increased pancreatic cancer incidence over 7 years following start of GLP-1RA treatment was found. However, monitoring for pancreatic cancer risk beyond 7 years following initiation of therapy is still required. Trial Registration: ClinicalTrials.gov Identifier: NCT02072902.

Reverse causation biases weighted cumulative exposure model estimates, but can be investigated in sensitivity analyses.

OBJECTIVES: To examine the effects of reverse causation on estimates from the weighted cumulative exposure (WCE) model that is used in pharmacoepidemiology to explore drug-health outcome associations, and to identify sensitivity analyses for revealing such effects. STUDY DESIGN AND SETTING: 314,099 patients with diabetes under Clalit Health Services, Israel, were followed over 2002-2012. The association between metformin and pancreatic cancer (PC) was explored using a WCE model within the framework of discrete-time Cox regression. We used computer simulations to explore the effects of reverse causation on estimates of a WCE model and to examine sensitivity analyses for revealing and adjusting for reverse causation. We then applied those sensitivity analyses to our data. RESULTS: Simulation demonstrated bias in the weighted cumulative exposure model and showed that sensitivity analysis could reveal and adjust for these biases. In our data, a positive association was observed (hazard ratio (HR) = 3.24, 95% confidence interval (CI): 2.24-4.73) with metformin exposure in the previous 2 years. After applying sensitivity analysis, assuming reverse causation operated up to 4 years before cancer diagnosis, the association between metformin and PC was no longer apparent. CONCLUSION: Reverse causation can cause substantial bias in the WCE model. When suspected, sensitivity analyses based on causal analysis are advocated.

Sex specific serum uric acid levels are associated with ischemic changes on ECG and with 20-year all-cause mortality among older adults.

BACKGROUND: Uric acid is an emerging biomarker for cardiovascular morbidity and mortality, but its association with all-cause mortality and ECG findings remains unestablished, specifically among older adults. We aimed to evaluate the association between serum uric acid (SUA) with incidental findings of ECG abnormalities and with long-term all-cause mortality. METHODS: We conducted a prospective cohort study of 851 community dwelling men and women, who were examined between 1999 and 2008, and followed over 20 years until December 2019 for all-cause mortality. Subjects free of Gout or diuretics treatment at baseline were included. SUA was categorized according to sex-specific tertiles and evaluated against baseline ECG findings and all-cause mortality. RESULTS: Mean baseline age was 72±7 years and 416 (49%) were females. Ischemic changes on ECG were observed in 85 (10.0%) participants, of them 36 (13.5%) belonged to the upper SUA tertile and 49 (8.4%) to the lower ones (p = 0.02). Multivariable logistic regression showed 80% higher odds for ischemic changes on ECG among participants in the high SUA tertile (adjusted-OR = 1.8, 95%CI 1.1-2.9, p = 0.03) compared with the lower SUA two-tertiles. During a median follow-up of 14 years, 380 (44.7%) participants died. SUA ≥5.3 mg/dl for women and ≥ 6.2 mg/dl for men, was associated with a 30% greater risk for all-cause mortality in a multivariable Cox regression model (HR = 1.3, 95%CI: 1.0-1.6, p = 0.03). CONCLUSIONS: High SUA level was associated with ischemic changes on ECG and with an increased risk for all-cause mortality over 20 years of follow-up among community dwelling older adults free of Gout. Even lower sex-specific thresholds of SUA were associated with all-cause mortality than previously proposed. SUA should be considered as a biomarker for cardiovascular risk and all-cause mortality.

The efficacy of calorimetry-based nutritional support versus recommended dietary intake-based nutritional support in the successful weaning of chronically ventilated patients: A study protocol for a double blind randomized controlled trial.

BACKGROUND & AIMS: Mechanically ventilated patients are weaned during acute care hospitalization when it is determined that they are ready for withdrawal. If weaning fails, patients are admitted to a rehabilitation medical center for continued supportive care and additional weaning attempts. This study's objective is to increase the success rate of weaning from prolonged mechanical ventilation (PMV), and to shorten the overall weaning period by tailoring the patient's caloric intake according to their individually measured energy needs. METHODS: We designed a randomized, controlled, double-blinded trial to be conducted among PMV patients undergoing routine ventilation-weaning attempts. Patients in the intervention arm will be fed according to energy needs determined by calorimetry. Patients in the control arm will be fed according to the standard of care, namely the Recommended Dietary Allowance (RDA) guidelines. Each patient will undergo up to five weaning attempts. Study outcomes will include successful weaning rate, time to successful weaning, and 3-12 months survival rate. DISCUSSION: This trial aims to examine the safety and efficacy of a nutritional diet based on an individual's measured caloric needs in terms of weaning rates and weaning time. We hypothesize that calorimetry-based nutrition plan will prove to be superior in both success rate and time to successful weaning compared to the standard nutrition plan based on the resting energy expenditure (REE) formula during the weaning process. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04825717.

Polypharmacy is differentially associated with 20-year mortality among community-dwelling elderly women and men: The Israel Glucose Intolerance, Obesity and Hypertension cohort study.

BACKGROUND: Elderly individuals are characterized by multimorbidity and high medication intake, entailing risks for adverse events. We examined the overall and sex-specific association of polypharmacy (≥5 drugs concurrently) with 20-year mortality among community-dwelling older adults. METHODS: Survivors of the longitudinal Israel Study of Glucose Intolerance, Obesity, and Hypertension underwent extensive evaluation during 1999-2004, and were followed-up for all-cause mortality until 2019. Cox regression examined association of polypharmacy with all-cause mortality. RESULTS: Data included 1210 participants (mean baseline age 72.9 ± 7.4 years, 53% females), 50.7% of them died over a median follow-up of 12.8 years. Women received a higher mean number of drugs (4.3 vs 3.5; p < 0.0001), were twice more likely to take vitamins, and had higher comorbidity. Polypharmacy prevalence was 38.3%, and more frequent with age, female sex, European-American origin, sedentary lifestyle and poor self-rated health. Polypharmacy was independently associated with mortality in women only (HR=1.41, 95%CI:1.05-1.89). An interaction was found with sex (p = 0.045). CONCLUSIONS: Polypharmacy was more prevalent in older women than men and associated with increased 20-year mortality in women only. Sex-specific adaptation of guidelines for appropriate drug use among community-dwelling older adults is warranted.

The real-world safety profile of sodium-glucose co-transporter-2 inhibitors among older adults (≥ 75 years): a retrospective, pharmacovigilance study.

BACKGROUND: As indications for sodium-glucose co-transporter-2 inhibitors (SGLT2i) are expanding, a growing number of older adults have become candidates for treatment. We studied the safety profile of SGLT2i among older adults. METHODS: A retrospective, pharmacovigilance study of the FDA's global database of safety reports. To assess reporting of pre-specified adverse events following SGLT2i among adults (< 75 years) and older adults (≥ 75), we performed a disproportionality analysis using the sex-adjusted reporting odds ratio (adj.ROR). RESULTS: We identified safety reports of 129,795 patients who received non-insulin anti-diabetic drugs (NIAD), including 24,253 who were treated with SGLT2i (median age 60 [IQR: 51-68] years, 2,339 [9.6%] aged ≥ 75 years). Compared to other NIAD, SGLT2i were significantly associated with amputations (adj.ROR = 355.1 [95%CI: 258.8 - 487.3] vs adj.ROR = 250.2 [79.3 - 789.5]), Fournier gangrene (adj.ROR = 45.0 [34.5 - 58.8] vs adj.ROR = 88.0 [27.0 - 286.6]), diabetic ketoacidosis (adj.ROR = 32.3 [30.0 - 34.8] vs adj.ROR = 23.3 [19.2 - 28.3]), genitourinary infections (adj.ROR = 10.3 [9.4 - 11.2] vs adj.ROR = 8.6 [7.2 - 10.3]), nocturia (adj.ROR = 5.5 [3.7 - 8.2] vs adj.ROR = 6.7 [2.8 - 15.7]), dehydration (adj.ROR = 2.5 [2.3 - 2.8] vs adj.ROR = 2.6 [2.1 - 3.3]), and fractures (adj.ROR = 1.7 [1.4 - 2.1] vs adj.ROR = 1.5 [1.02 - 2.1]) in both adults and older adults, respectively. None of these safety signals was significantly greater in older adults (Pinteraction threshold of 0.05). Acute kidney injury was associated with SGLT2i in adults (adj.ROR = 1.97 [1.85 - 2.09]) but not in older adults (adj.ROR = 0.71 [0.59 - 0.84]). Falls, hypotension, and syncope were not associated with SGLT2i among either adults or older adults. CONCLUSION: In this global post-marketing study, none of the adverse events was reported more frequently among older adults. Our findings provide reassurance regarding SGLT2i treatment in older adults, although careful monitoring is warranted.

High variation between healthcare professionals in nutrition therapy plans of patients with feeding tubes admitted to a long-term rehabilitation center from an acute-care hospital.

BACKGROUND: Nutrition therapy plans (NTPs) in discharge summaries of tube-fed patients transferred from acute-care hospitals to rehabilitation centers are fundamental for continuity of care. This study examined the presence and quality of NTPs in discharge summaries of tube-fed patients. METHODS: This cross-sectional study was based on data retrieved from electronic medical records. The outcome measures were the presence of NTPs in discharge summaries, the presence of key elements of the NTPs, and the level of compatibility between multiple NTPs per discharge summary prepared by different health professionals. Descriptive statistics were used to assess the number of NTPs, the presence of key elements, and the degree of compatibility between NTPs for the same patient. RESULTS: A total of 100 discharge summaries of tube-fed patients admitted to a rehabilitation hospital during 2015-2017 were identified. The majority (91%) of discharge summaries included at least one NTP; 57 included more than one. Variance in the presence of key elements was observed in 165 NTPs prepared by physicians, nurses, and dietitians. Water amount and nutrition route were least reported by dietitians (6.3% and 9.4%, respectively), compared with physicians (77.6% and 81%) and nurses (77.3% and 62.7%). However, nutrition details were reported more frequently by dietitians (65.6%) than physicians (20.7%) and nurses (32%). Low compatibility was observed between dietitians and both nurses and physicians, in the range of 0%-26%. CONCLUSION: Large discrepancies were found between NTPs for the same patient prepared by dietitians, physicians, and/or nurses, and a portion of patients arrived without any NTP.

Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses.

BACKGROUND: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. METHODS: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. RESULTS: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min-1·1.73 m-2, compared with those with eGFR between 60 and 105 mL·min-1·1.73 m-2. Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min-1·1.73 m-2, with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min-1·1.73 m-2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min-1·1.73 m-2. Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. CONCLUSIONS: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

The insulin sensitivity Mcauley index (MCAi) is associated with 40-year cancer mortality in a cohort of men and women free of diabetes at baseline.

BACKGROUND: The association between insulin resistance and cancer-mortality is not fully explored. We investigated the association between several insulin sensitivity indices (ISIs) and cancer-mortality over 3.5 decades in a cohort of adult men and women. We hypothesized that higher insulin resistance will be associated with greater cancer-mortality risk. METHODS: A cohort of 1,612 men and women free of diabetes during baseline were followed since 1979 through 2016 according to level of insulin resistance (IR) for cause specific mortality, as part of the Israel study on Glucose Intolerance, Obesity and Hypertension (GOH). IR was defined according to the Mcauley index (MCAi), calculated by fasting insulin and triglycerides, the Homeostatic Model Assessment (HOMA), the Matsuda Insulin Sensitivity Index (MISI), and the Quantitative Insulin Sensitivity Check Index (QUICKI), calculated by plasma glucose and insulin. RESULTS: Mean age at baseline was 51.5 ± 8.0 years, 804 (49.9%) were males and 871 (54.0%) had prediabetes. Mean follow-up was 36.7±0.2 years and 47,191 person years were accrued. Cox proportional hazard model and competing risks analysis adjusted for age, sex, country of origin, BMI, blood pressure, total cholesterol, smoking and glycemic status, revealed an increased risk for cancer-mortality, HR = 1.5 (95% CI: 1.1-2.0, p = 0.005) for the MCAi Q1 compared with Q2-4. No statistically significant associations were observed between the other ISIs and cancer-mortality. CONCLUSION: The MCAi was independently associated with an increased risk for cancer-mortality in adult men and women free of diabetes and should be further studied as an early biomarker for cancer risk.

[PREDICTION MODEL FOR ASSESSING PHYSICAL FITNESS IN CARDIAC PATIENTS].

AIMS: To develop and validate a readily-available tool for the evaluation of the fitness of cardiac patients. BACKGROUND: Physical fitness is an important factor in the tertiary prevention for cardiac patients. METHODS: In this cross-sectional study, 154 cardiac patients: 119 men and 35 women, mean age 63.1±11.2 years, entering the cardiac-rehabilitation program at the Sheba Medical Center, gave informed consent and completed a 24-hour recall physical activity questionnaire. Information on BMI, medication use and on their performance on a symptom-free limited treadmill test, i.e. measured estimated VO2 (ml/kg/min) and resting heart rate (bpm), were obtained from the medical chart. RESULTS: A linear-regression equation for predicting the measured estimated VO2 includes the overall physical activity index calculated from the physical activity questionnaire, sex, age, BMI, type of coronary heart disease (acute myocardial infarction, coronary artery bypass graft, percutaneous coronary intervention), duration of illness, resting heart rate, use of beta-blockers and level of education. The correlation coefficient between measured VO2 values and calculated values is r=0.6. Upon categorizing patients to high and low physical fitness according to the VO2 median value, the validity of the equation was found to be good: sensitivity=61.2%, specificity=65.2%, positive predictive value=68.4%, negative predictive value=57.7%. CONCLUSIONS: The prediction equation for assessing VO2 in cardiac patients is a simple, inexpensive tool, which may be used for monitoring changes in the patients' physical fitness. It may assist the physician in following a cardiac patient's response to physical activity recommendations and improving fitness when the ergometric stress-test availability is low.

Association between Self-Classification of COVID-19 Risk Levels and Adverse Lifestyle Changes among Physically Active Older Adults Following the Coronavirus Outbreak.

The COVID-19 pandemic has imposed barriers to a healthy lifestyle, especially for older adults who are considered to be at a high-risk of infection. This study examined the associations between negative changes and the self-classification to COVID-19 risk level among physically active older adults who are members of a nationwide health club chain. A cross-sectional digital survey was sent to 19,160 older adults (age ≥ 65). The data collected included information on the subjects' self-classification to the COVID-19 high-risk group (HRG) and changes in physical activity (PA), body weight, and smoking habits since the outbreak. Logistic regression models were used to investigate the associations between the dependent variables of 'experienced a negative change' and the independent variables. Of the 1670 survey respondents, 78.3% classified themselves as COVID-19 HRG. Over half of the respondents reported a reduction in PA hours, 26.6% reported weight gain, and 17.7% of smokers increased their amount of smoking. A self-classification to the HRG was associated with 1.46 (95%CI 1.10−1.93, p < 0.009) and 1.67 (95%CI 1.21−2.31, p < 0.002) greater odds for reduced hours of exercise and weight gain compared to the not high-risk group, respectively. Decision makers should consider how policies may cause barriers to a healthy lifestyle and develop risk communication strategies to encourage positive health-related behaviors, even during a pandemic.

Is health-related quality of life 1-year after coronary artery bypass graft surgery associated with living in a greener environment?

INTRODUCTION: Greenery in the residential environment and in the hospital has been associated with improved surgical outcomes and recovery. We investigated the association between the level of residential greenness of patients with coronary disease and their heart disease-related Quality of Life (HRQoL) 1-year after a coronary artery bypass grafting (CABG) surgery. METHODS: Participants in a prospective cohort study who underwent CABG surgery at seven cardiothoracic units throughout Israel during the years 2004-2007 filled in the MacNew HRQoL one day before and one year after surgery. Successful recovery was defined as ≥0.5 increase in the MacNew score between baseline and follow-up. Exposure to residential greenness in 90 m and 300 m buffers around the patient's home was assessed with Linear Spectral Unmixing analysis of Landsat 30 m imagery. RESULTS: The cohort comprised of 861 patients (22% female) with a mean age of 65.5 years, and 59.2% classified as low-income. In the total cohort, higher residential greenness was associated with an improvement in emotional HRQoL (OR = 1.33 (95%CI: 0.99-1.79)), adjusting for demographic and socio-economic factors, living in the periphery/center, presence of diabetes, attending cardiac rehabilitation following surgery, BMI, and change in physical fitness and depression over the 1-year follow-up. Although no association was found between greenness and change in the physical or social subscales, a positive association was specifically observed among the low-income patients for the global HRQoL score, OR = 1.42 (95%CI: 0.97-2.10), as compared to the higher-income patients, p for interaction = 0.03. CONCLUSIONS: Residential greenness is associated with improvement in HRQoL 1-year after CABG surgery, but not the physical and social scales, only in low-income patients. Ensuring greenery in the living environment may act as a social intervention that supports human health and disease recovery.

Hyperglycaemic disorders associated with PCSK9 inhibitors: a real-world, pharmacovigilance study.

AIMS: While genetic and biological studies indicated a potential association between proprotein-convertase subtilisin/kexin type 9 inhibitors (PCSK9i) and hyperglycaemia, real-world data are limited. Therefore, we sought to investigate this association using the FDA adverse event reporting system (FAERS). METHODS AND RESULTS: The FAERS database (2015-2020) was retrospectively queried to characterize reporting of hyperglycaemic adverse events (AEs) with PCSK9i. Disproportionality analyses were performed using the adjusted reporting odds ratio (adj.ROR), and the lower bound of the information component (IC) 95% credibility interval (IC025 > 0 is deemed significant). Among 7 295 624 eligible patients, 71 748 reports of evolocumab and 15 976 of alirocumab were identified. Compared to the full database, PCSK9i treatment was associated with increased reporting of hyperglycaemic AEs [n = 1841, adj.ROR = 1.14 (1.07-1.22), IC025 = 0.13]. Hyperglycaemic AEs were primarily mild hyperglycaemia [n = 1469, adj. ROR = 1.48 (1.36-1.62), IC025 = 0.51] rather than diabetes [n = 372, adj. ROR = 0.67 (0.60-0.74), IC025 = -0.90]. Among PCSK9i agents, evolocumab, but not alirocumab, was associated with hyperglycaemic AEs [n = 1587, adj. ROR = 1.24 (1.15-1.32), IC025 = 0.20; n = 254, adj. ROR = 0.73 (0.60-0.88), IC025 = -0.38, respectively]. Hyperglycaemic AEs were reported more often with PCSK9i compared to ezetimibe [adj.ROR = 1.99 (1.35-2.94)], and less often compared to statins [adj.ROR = 0.26 (0.25-0.28)]. Notably, hyperglycaemic AEs were reported more frequently by diabetic than by non-diabetic patients (P < 0.001), mostly occurred within 6 months of treatment and were reversible upon drug discontinuation. CONCLUSION: In a real-world setting, PCSK9i treatment was associated with increased reporting of mild hyperglycaemia, but not diabetes. While initial monitoring is warranted, the favourable glycaemic safety profile compared to statins supports their essential role in the management of lipid disorders.

Metformin Treatment Among Men With Diabetes and the Risk of Prostate Cancer: A Population-Based Historical Cohort Study.

There is conflicting evidence regarding the association between metformin treatment and prostate cancer risk in diabetic men. We investigated this association in a population-based Israeli cohort of 145,617 men aged 21-89 years with incident diabetes who were followed over the period 2002-2012. We implemented a time-dependent covariate Cox model, using weighted cumulative exposure to relate metformin history to prostate cancer risk, adjusting for use of other glucose-lowering medications, age, ethnicity, and socioeconomic status. To adjust for time-varying glucose control variables, we used inverse probability weighting of a marginal structural model. With 666,553 person-years of follow-up, 1,592 men were diagnosed with prostate cancer. Metformin exposure in the previous year was positively associated with prostate cancer risk (per defined daily dose; without adjustment for glucose control, hazard ratio (HR) = 1.53 (95% confidence interval (CI): 1.19, 1.96); with adjustment, HR = 1.42 (95% CI: 1.04, 1.94)). However, exposure during the previous 2-7 years was negatively associated with risk (without adjustment for glucose control, HR = 0.58 (95% CI: 0.37, 0.93); with adjustment, HR = 0.60 (95% CI: 0.33, 1.09)). These positive and negative associations with previous-year and earlier metformin exposure, respectively, need to be confirmed and better understood.

Residential greenness and increased physical activity in patients after coronary artery bypass graft surgery.

AIMS: Physical activity is a fundamental component of rehabilitation following coronary artery bypass (CABG) surgery. Proximity to neighbourhood green spaces may encourage physical activity. We investigated the association between residential greenness and exercise-related physical activity post-CABG surgery. METHODS: Participants in a prospective cohort study of 846 patients (78% men) who underwent CABG surgery at seven cardiothoracic units during the time period 2004-2007 were interviewed regarding their physical activity habits one day before and one year after surgery. Exposure to residential neighbourhood greenness (within a 300 m buffer around their place of residence) was measured using the Normalized Difference Vegetative Index. Participation in exercise-related physical activity (yes/no), weekly duration of exercise-related physical activity and the change in exercise-related physical activity between baseline and follow-up were examined for associations with residential greenness, adjusting for socio-demographic factors, propensity score adjusted participation in cardiac rehabilitation and health-related covariates after multiple imputation for missing variables. RESULTS: Living in a higher quartile of residential greenness was associated with a 52% greater odds of being physically active (OR 1.52, 95% CI 1.22-1.90). This association persisted only (OR 1.75, 95% CI 1.35-2.27) among patients who did not participate in cardiac rehabilitation following surgery and was stronger in women (OR 2.38, 95% CI 1.40-4.07) than in men (OR 1.37, 95% CI 1.07-1.75). Participants who lived in greener areas were more likely to increase their post-surgical physical activity than those who lived in less green areas (OR 1.59, 95% CI 1.25-2.01). CONCLUSIONS: Residential greenness appears to be beneficial in increasing exercise-related physical activity in cardiac patients, especially those not particpating in cardiac rehabilitation after CABG surgery.

The association between insulin sensitivity indices, ECG findings and mortality: a 40-year cohort study.

BACKGROUND: Type 2 Diabetes is a major risk factor for cardiovascular (CV) mortality. Insulin resistance can be evaluated non-invasively by insulin sensitivity indices (ISI) such as the Mcauley index (MCAi), which is a function of the fasting insulin and triglycerides. Currently, the association between ISIs and ECG findings and all-cause and CV mortality is still not established in a large scale and heterogeneous population. METHOD: In a prospective study of the Israel cohort on Glucose Intolerance, Obesity and Hypertension (GOH) second phase (1979-1982) 1830 men and women were followed until December-2016 for CV-mortality and December-2019 for all-cause mortality. ECGs were recorded and OGTTs performed during baseline. ISIs were categorized into quartiles and evaluated against ECG findings and all-cause and CV-mortality. RESULTS: Mean age at baseline was 52.0 ± 8.1 years, and 75 (15.2%) and 47 (25.3%) participants in the upper quartiles (Q2-4) and the lower quartile (Q1) of the MCAi, presented with Ischemic changes on ECG respectively (p = 0.02). Multivariable analysis showed higher odds for ECG ischemic changes, for individuals in Q1-MCAi (adjusted-OR = 1.7, 95% CI 1.02-2.8), compared with Q2-4-MCAi, which attenuated when excluding individuals with diabetes (adjusted-OR = 1.6, 95% CI 0.9-2.7, p = 0.09). Median follow up for all-cause and for cardiovascular mortality was 31 years and 37 years, respectively. Cox proportional-hazards regression showed an increased risk for all-cause mortality for individuals in Q1-MCAi (HR = 1.2, 95% CI 1.02-1.3) as well as an increased risk for CV-mortality (HR = 1.4, 95%CI 1.1-1.8) compared with Q2-4-MCAi. Individuals in Q4-Ln Homeostatic model assessment- Insulin Resistance (HOMA-IR) and Q1- Quantitative Insulin Sensitivity Check Index (QUICKI) also presented with increased risk for all-cause-mortality (HR = 1.2, 95%CI 1.04-1.4; and HR = 1.2, 95% CI 1.04-1.4, respectively). Other ISIs did not show significant associations with CV-mortality. CONCLUSION: Higher insulin-resistance, according to the MCAi, associated with ECG-changes, and with greater risk for all-cause and CV-mortality over a 40-year follow-up. The MCAi may be considered as an early predictive and prognostic biomarker for CV-morbidity and mortality in adults.

Cardiovascular Toxicities of Antiangiogenic Tyrosine Kinase Inhibitors: A Retrospective, Pharmacovigilance Study.

BACKGROUND: Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) are an essential therapeutic option in the management of various solid tumors, particularly renal cell carcinoma (RCC). However, post-marketing data regarding their potential cardiovascular toxicities are scant. OBJECTIVE: To identify and characterize cardiovascular adverse events (CVAEs) of VEGFR-TKIs indicated for RCC. PATIENTS AND METHODS: Disproportionality analysis of the US Food and Drug Administration adverse event reporting system (July 2014-December 2019) using the reporting odds ratio (ROR) and the lower bound of the Information component (IC) 95% credibility interval (IC025 > 0 is significant). RESULTS: We identified 51,836 adverse event reports of sunitinib, pazopanib, axitinib, cabozantinib, and lenvatinib in the full database [36% women; median age 65 years (range 57-73)]. CVAEs accounted for 11,784 (23%) of the reports, with hypertension [n = 5548 (11%), ROR = 6.55 (95% CI 6.37-6.74), IC025 = 2.48] and hemorrhages [n = 3710 (7.2%), ROR = 1.28 (1.24-1.32), IC025 = 0.28] being the most frequent types. Additional CVAEs were over-reported with VEGFR-TKIs treatment, including aortic dissection [n = 61 (0.1%), ROR = 3.50 (2.71-4.51)], pericardial diseases [n = 173 (0.3%), ROR = 1.98 (1.70-2.30)], cardiomyopathy [n = 61 (0.1%), ROR = 1.89 (1.47-2.43)], heart failure [n = 868 (1.7%), ROR = 1.35 (1.26-1.44)], and venous thromboembolism [n = 604 (1.2%), ROR = 1.33 (1.23-1.45), all IC025 > 0]. The major pericardial disorder was non-malignant pericardial effusion [n = 134 (77%)]. Aortic dissections were also over-reported in patients without concomitant elevated blood pressure [ROR = 2.68 (1.97-3.63), IC025 = 0.91]. Finally, CVAEs were reported more often following lenvatinib and sunitinib treatment compared to other VEGFR-TKIs. CONCLUSIONS: In post-marketing surveillance data, VEGFR-TKIs are associated with increased reporting of various CVAEs, including pericardial diseases, particularly non-malignant pericardial effusion, and aortic dissections. Moreover, VEGFR-TKIs differ in their CVAE reporting patterns. Clinicians should be conscious of these findings in the care of VEGFR-TKIs recipients.