Cardiovascular outcomes after curative prostate cancer treatment: A population-based cohort study.

Objective: To investigate differences in cardiovascular disease (CVD) morbidity and mortality after radical prostatectomy or definitive radiotherapy with or without androgen deprivation therapy (ADT). Materials and methods: We used population-based data from the Cancer Registry of Norway, the Norwegian Patient Registry and the Norwegian Cause of Death Registry including 19 289 men ≤80 years diagnosed with non-metastatic prostate cancer during 2010-2019. Patients were treated with radical prostatectomy or definitive radiotherapy. We used competing risk models to compare morbidity from overall CVD, acute myocardial infarction (AMI), cerebral infarction, thromboembolism, and CVD-specific mortality for the overall cohort and stratified by prognostic risk groups. Results: After a median follow-up time of 5.4 years (IQR 4.6 years), there were no differences in adjusted rates of AMI, cerebral infarction, and CVD-specific death between radical prostatectomy and definitive radiotherapy in any of the prognostic risk groups. Rates of overall CVD (0.82; 95% CI 0.76-0.89) and thromboembolism (0.30; 95% CI 0.20-0.44) were lower for definitive radiotherapy than radical prostatectomy during the first year of follow-up. After this overall CVD rates (1.19; 95% CI 1.11-1.28) were consistently higher across all risk groups in patients treated with definitive radiotherapy, but there were no differences regarding thromboembolism. Conclusions: During the first years after treatment, no differences were found in rates of AMI, cerebral infarction, and CVD-specific death between radiotherapy and radical prostatectomy in any of the prognostic risk groups. This suggests that ADT use in combination with radiotherapy may not increase the risks of these outcomes in a curative setting. The increased overall CVD rate for definitive radiotherapy after the first year indicates a possible relationship between definitive radiotherapy and other CVDs than AMI and cerebral infarction.

Lower education and immigrant background are associated with lower participation in a diabetes education program - Insights from adult patients in the Outcomes & Multi-morbidity In Type 2 diabetes cohort (OMIT).

OBJECTIVES: Diabetes educational programmes should be offered to patients with type 2 diabetes mellitus (T2DM). We assessed the proportion of diabetes educational program participation among adults with T2DM, and its associations with place of residence in Norway, education, and immigrant background. METHODS: We identified 28,128 diagnosed with T2DM (2008-2019) in the Outcomes & Multi-morbidity In Type 2 diabetes cohort. To examine associations between sociodemographic factors and participation in diabetes start courses (yes/no), we computed adjusted risk ratios (95% CI) using log-binomial regression. RESULTS: Overall, 18% participated on the diabetes start course, but partaking differed by Norwegian counties (range:12-34%). Individuals with an immigrant background were 29% less likely to participate (RR 0.71, CI 0.65-0.79). Similarly, those with a lower educational level were 23% less likely to participate (RR 0.77, CI 0.72-0.83) than those with the highest education. The association between education and start course participation was not significant in the subgroup of immigrant individuals (RR 0.88 CI 0.70-1.12). CONCLUSIONS: We found that diabetes start course participation was overall low, especially in individuals with low education and immigrant background. PRACTICE IMPLICATIONS: More efforts are needed to promote diabetes start courses in patients with T2DM.

Cohort profile: Outcomes & Multi-morbidity In Type 2 diabetes (OMIT) - a national registry-based observational cohort with focus on care and treatment of key high-risk groups in Norway.

PURPOSE: The 'Outcomes & Multi-morbidity in Type 2 Diabetes' (OMIT) is an observational registry-based cohort of Norwegian patients with type 2 diabetes (T2D) established to study high-risk groups often omitted from randomised clinical trials. PARTICIPANTS: The OMIT cohort includes 57 572 patients with T2D identified via linkage of Norwegian Diabetes Register for Adults and the Rogaland-Oslo-Salten-Akershus-Hordaland study, both offering data on clinical patient characteristics and drug prescriptions. Subsequently these data are further linked to the Norwegian Prescription Database for dispensed medications, the Norwegian Population Register for data on death and migration, Statistics Norway for data on socioeconomic factors and ethnicity and the Norwegian Directorate of Health for data on the general practices and clinical procedures involved in the care of cohort patients. OMIT offers large samples for key high-risk patient groups: (1) young-onset diabetes (T2D at age <40 years) (n=6510), (2) elderly (age >75 years) (n=15 540), (3) non-Western ethnic minorities (n=9000) and (4) low socioeconomic status (n=20 500). FINDINGS TO DATE: On average, patient age and diabetes duration is 67.4±13.2 and 12.3±8.3 years, respectively, and mean HbA1c for the whole cohort through the study period is 7.6%±1.5% (59.4±16.3 mmol/mol), mean body mass index (BMI) and blood pressure is 30.2±5.9 kg/m2 and 135±16.1/78±9.8 mm Hg, respectively. Prevalence of retinopathy, coronary heart disease and stroke is 10.1%, 21% and 6.7%, respectively. FUTURE PLANS: The OMIT cohort features 5784 subjects with T2D in 2006, a number that has grown to 57 527 in 2019 and is expected to grow further via repeated linkages performed every third to fifth year. At the next wave of data collection, additional linkages to Norwegian Patient Registry and Norwegian Cause of Death Registry for data on registered diagnoses and causes of death, respectively, will be performed.

Association between medical androgen deprivation therapy and long-term cardiovascular disease and all-cause mortality in nonmetastatic prostate cancer.

Studies have suggested that prostate cancer (PCa) patients receiving androgen deprivation therapy (ADT) are at increased risk of developing or exacerbating cardiovascular disease (CVD). We aimed to explore the association between ADT for PCa and subsequent CVD and all-cause mortality in this nationwide, longitudinal study. We also evaluated the role of cardiovascular risk and ADT duration to determine effect modification. Norwegian registry data were used to identify patients with PCa from 2008-18 and who received primary ADT in the first year after diagnosis. The associations between ADT and composite cardiovascular events, and the individual components of myocardial infarction, stroke and heart failure, in addition to atrial fibrillation and all-cause mortality, were explored using time-varying Cox regression models. We included 30 923 PCa patients, of whom 8449 (27%) received primary ADT. Mean follow-up was 2.9 and 3.8 years for CVD events and mortality, respectively. We found an association between ADT and composite CVD (adjusted HR 1.13: 95% CI 1.05-1.21), myocardial infarction (1.18: 1.05-1.32), stroke (1.21: 1.06-1.38), heart failure (1.23: 1.13-1.35) and all-cause mortality (1.49: 1.39-1.61). These associations persisted in those with low and moderate CVD risk and ADT longer than 7 months. A relationship between ADT and composite CVD and all-cause mortality was observed, especially in those with moderate CVD risk and longer treatment duration. Future studies with more detailed cancer data are needed to verify the clinical relevance of these results, especially when considering all-cause mortality within the context of treatment guidelines and benefits of ADT.

Higher baseline inflammatory marker levels predict greater cognitive decline in older people with type 2 diabetes: year 10 follow-up of the Edinburgh Type 2 Diabetes Study.

AIMS/HYPOTHESIS: We aimed to determine the longitudinal association of circulating markers of systemic inflammation with subsequent long-term cognitive change in older people with type 2 diabetes. METHODS: The Edinburgh Type 2 Diabetes Study is a prospective cohort study of 1066 adults aged 60 to 75 years with type 2 diabetes. Baseline data included C-reactive protein, IL-6, TNF-α fibrinogen and neuropsychological testing on major cognitive domains. Cognitive testing was repeated after 10 years in 581 participants. A general cognitive ability score was derived from the battery of seven individual cognitive tests using principal component analysis. Linear regression was used to determine longitudinal associations between baseline inflammatory markers and cognitive outcomes at follow-up, with baseline cognitive test results included as covariables to model cognitive change over time. RESULTS: Following adjustment for age, sex and baseline general cognitive ability, higher baseline fibrinogen and IL-6 were associated with greater decline in general cognitive ability (standardised ßs = -0.059, p=0.032 and -0.064, p=0.018, respectively). These associations lost statistical significance after adjustment for baseline vascular and diabetes-related covariables. When assessing associations with individual cognitive tests, higher IL-6 was associated with greater decline in tests of executive function and abstract reasoning (standardised ßs = 0.095, p=0.006 and -0.127, p=0.001, respectively). Similarly, raised fibrinogen and C-reactive protein levels were associated with greater decline in processing speed (standardised ßs = -0.115, p=0.001 and -0.111, p=0.001, respectively). These associations remained statistically significant after adjustment for the diabetes- and vascular-related risk factors. CONCLUSIONS/INTERPRETATION: Higher baseline levels of inflammatory markers, including plasma IL-6, fibrinogen and C-reactive protein, were associated with subsequent cognitive decline in older people with type 2 diabetes. At least some of this association appeared to be specific to certain cognitive domains and to be independent of vascular and diabetes-related risk factors.

Cilostazol for intermittent claudication.

BACKGROUND: Peripheral arterial disease (PAD) affects between 4% and 12% of people aged 55 to 70 years, and 20% of people over 70 years. A common complaint is intermittent claudication (exercise-induced lower limb pain relieved by rest). These patients have a three- to six-fold increase in cardiovascular mortality.  Cilostazol is a drug licensed for the use of improving claudication distance and, if shown to reduce cardiovascular risk, could offer additional clinical benefits. This is an update of the review first published in 2007. OBJECTIVES: To determine the effect of cilostazol on initial and absolute claudication distances, mortality and vascular events in patients with stable intermittent claudication. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, and AMED databases, and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registries, on 9 November 2020. SELECTION CRITERIA: We considered double-blind, randomised controlled trials (RCTs) of cilostazol versus placebo, or versus other drugs used to improve claudication distance in patients with stable intermittent claudication. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials for selection and independently extracted data. Disagreements were resolved by discussion. We assessed the risk of bias with the Cochrane risk of bias tool. Certainty of the evidence was evaluated using GRADE. For dichotomous outcomes, we used odds ratios (ORs) with corresponding 95% confidence intervals (CIs) and for continuous outcomes we used mean differences (MDs) and 95% CIs. We pooled data using a fixed-effect model, or a random-effects model when heterogeneity was identified. Primary outcomes were initial claudication distance (ICD) and quality of life (QoL). Secondary outcomes were absolute claudication distance (ACD), revascularisation, amputation, adverse events and cardiovascular events. MAIN RESULTS: We included 16 double-blind, RCTs (3972 participants) comparing cilostazol with placebo, of which five studies also compared cilostazol with pentoxifylline. Treatment duration ranged from six to 26 weeks. All participants had intermittent claudication secondary to PAD. Cilostazol dose ranged from 100 mg to 300 mg; pentoxifylline dose ranged from 800 mg to 1200 mg. The certainty of the evidence was downgraded by one level for all studies because publication bias was strongly suspected. Other reasons for downgrading were imprecision, inconsistency and selective reporting. Cilostazol versus placebo Participants taking cilostazol had a higher ICD compared with those taking placebo (MD 26.49 metres; 95% CI 18.93 to 34.05; 1722 participants; six studies; low-certainty evidence). We reported QoL measures descriptively due to insufficient statistical detail within the studies to combine the results; there was a possible indication in improvement of QoL in the cilostazol treatment groups (low-certainty evidence). Participants taking cilostazol had a higher ACD compared with those taking placebo (39.57 metres; 95% CI 21.80 to 57.33; 2360 participants; eight studies; very-low certainty evidence). The most commonly reported adverse events were headache, diarrhoea, abnormal stools, dizziness, pain and palpitations. Participants taking cilostazol had an increased odds of experiencing headache compared to participants taking placebo (OR 2.83; 95% CI 2.26 to 3.55; 2584 participants; eight studies; moderate-certainty evidence).Very few studies reported on other outcomes so conclusions on revascularisation, amputation, or cardiovascular events could not be made. Cilostazol versus pentoxifylline There was no difference detected between cilostazol and pentoxifylline for improving walking distance, both in terms of ICD (MD 20.0 metres, 95% CI -2.57 to 42.57; 417 participants; one study; low-certainty evidence); and ACD (MD 13.4 metres, 95% CI -43.50 to 70.36; 866 participants; two studies; very low-certainty evidence). One study reported on QoL; the study authors reported no difference in QoL between the treatment groups (very low-certainty evidence). No study reported on revascularisation, amputation or cardiovascular events. Cilostazol participants had an increased odds of experiencing headache compared with participants taking pentoxifylline at 24 weeks (OR 2.20, 95% CI 1.16 to 4.17; 982 participants; two studies; low-certainty evidence). AUTHORS' CONCLUSIONS: Cilostazol has been shown to improve walking distance in people with intermittent claudication. However, participants taking cilostazol had higher odds of experiencing headache. There is insufficient evidence about the effectiveness of cilostazol for serious events such as amputation, revascularisation, and cardiovascular events. Despite the importance of QoL to patients, meta-analysis could not be undertaken because of differences in measures used and reporting. Very limited data indicated no difference between cilostazol and pentoxifylline for improving walking distance and data were too limited for any conclusions on other outcomes.

Retinal venular tortuosity and fractal dimension predict incident retinopathy in adults with type 2 diabetes: the Edinburgh Type 2 Diabetes Study.

AIMS/HYPOTHESIS: Our aim was to determine whether a range of prespecified retinal vessel traits were associated with incident diabetic retinopathy in adults with type 2 diabetes. METHODS: In the prospective observational cohort Edinburgh Type 2 Diabetes Study of 1066 adults with type 2 diabetes, aged 60-75 years at recruitment, 718 were free from diabetic retinopathy at baseline. Baseline retinal traits including vessel widths, tortuosity (curvature) and fractal dimensions (network complexity), were quantified using fundus camera images and semiautomated software, and analysed using logistic regression for their association with incident diabetic retinopathy over 10 years. RESULTS: The incidence of diabetic retinopathy was 11.4% (n = 82) over 10 years. After adjustment for a range of vascular and diabetes-related risk factors, both increased venular tortuosity (OR 1.51; 95% CI 1.15, 1.98; p = 0.003) and decreased fractal dimension (OR 0.75; 95% CI 0.58, 0.96; p = 0.025) were associated with incident retinopathy. There was no evidence of an association with arterial tortuosity, and associations between measurements of vessel widths and retinopathy lost statistical significance after adjustment for diabetes-related factors and vascular disease. Adding venular tortuosity to a model including established risk factors for diabetic retinopathy (HbA1c, BP and kidney function) improved the discriminative ability (C statistic increased from 0.624 to 0.640, p = 0.013), but no such benefit was found with fractal dimension. CONCLUSIONS/INTERPRETATION: Increased retinal venular tortuosity and decreased fractal dimension are associated with incident diabetic retinopathy, independent of classical risk factors. There is some evidence that venular tortuosity may be a useful biomarker to improve the predictive ability of models based on established retinopathy risk factors, and its inclusion in further risk prediction modelling is warranted.

Prioritization of treatments for lower extremity peripheral artery disease in low- and middle-income countries.

INTRODUCTION: Lower extremity peripheral artery disease (PAD) is increasing in prevalence in low- and middle-income countries creating a large health care burden. Clinical management may require substantial resources but little consideration has been given to which treatments are appropriate for less advantaged countries. EVIDENCE ACQUISITION: The aim of this review was to systematically appraise published data on the costs and effectiveness of PAD treatments used commonly in high-income countries, and for an international consensus panel to review that information and propose a hierarchy of treatments relevant to low- and middle-income countries. EVIDENCE SYNTHESIS: Pharmacotherapy for intermittent claudication was found to be expensive and improve walking distance by a modest amount. Exercise and endovascular therapies were more effective and exercise the most cost-effective. For critical limb ischemia, bypass surgery and endovascular therapy, which are both resource intensive, resulted in similar rates of amputation-free survival. Substantial reductions in cardiovascular events occurred with use of low cost drugs (statins, ACE inhibitors, anti-platelets) and smoking cessation. CONCLUSIONS: The panel concluded that, in low- and middle-income countries, cardiovascular prevention is a top priority, whereas a lower priority should be given to pharmacotherapy for leg symptoms and revascularisation, except in countries with established vascular units.