Cardiovascular risks and bleeding with non-vitamin K antagonist oral anticoagulant versus warfarin in patients with type 2 diabetes : a tapered matching cohort study

Background: We compared the risk of bleeding and cardiovascular disease (CVD) events between non-vitamin K antagonist oral anticoagulant (NOAC) and warfarin in people with type 2 diabetes (T2DM). Methods: 862 Incident NOAC users and 626 incident warfarin users with T2DM were identified from within 40 UK general practice (1/4/2017-30/9/2018). Outcomes included incident hospitalisation for bleeding, CVD and re-hospitalisation for CVD within 12 months since first anticoagulant prescription, identified from linked hospitalisation data. A tapered matching method was applied to form comparison cohorts: coarsened exact matching restricted the comparison to areas of sufficient overlap in missingness and characteristics: (i) demographic characteristics; (ii) clinical measurements; (iii) prior bleeding and CVD history; (iv) prescriptions with bleeding; (v) anti-hypertensive treatment(s); (vi) anti-diabetes treatment(s). Entropy balancing sequentially balanced NOAC and warfarin users on their distribution of (i-vi). Weighted logistic regression modelling estimated outcome odds ratios (ORs), using entropy balancing weights from steps i-vi. Results: The 12-month ORs of bleeding with NOAC (n = 582) vs matched/balanced warfarin (n = 486) were 1.93 (95% confidence interval 0.97-3.84), 2.14 (1.03-4.44), 2.31 (1.10-4.85), 2.42 (1.14-5.14), 2.41 (1.12-5.18), and 2.51 (1.17-5.38) through steps i-vi. ORs for CVD re-hospitalisation was increased with NOAC treatment through steps i-vi: 2.21 (1.04-4.68), 2.13 (1.01-4.52), 2.47 (1.08-5.62), 2.46 (1.02-5.94), 2.51 (1.01-6.20), and 2.66 (1.02-6.94). Conclusions: Incident NOAC use among T2DM is associated with increased risk of bleeding hospitalisation and CVD re-hospitalisation compared with incident warfarin use. For T2DM, caution is required in prescribing NOACs as first anticoagulant treatment. Further large-scale replication studies in external datasets are warranted

Dialysate glucose response phenotypes during peritoneal equilibration test and their association with cardiovascular death : a cohort study

Different measures of rates of transfer of glucose during the peritoneal equilibrium test (PET), undertaken during peritoneal dialysis (PD) might provide additional information regarding a patient's risk of future cardiovascular mortality. This study aimed to characterize the heterogeneity of dialysate glucose (DG) response phenotypes during the PET and compare the cardiovascular mortality rates associated with the different phenotypes. Our cohort was derived from Henan peritoneal dialysis registry. A total of 3477 patients initiating PD in 2007 to 2014 had the DG measured at 0, 2-hour and 4-hour (D0, D2, and D4 respectively) during the PET for estimation of D2/D0 and D4/D0. Deaths mainly due to CVD within 2 years since the initiation of PD were defined as the outcome. Latent class mixed-effect models were fitted to identify distinct phenotypes of the DG response during the PET. Multivariable unconditional Logistic regression models with adjustment for cardiometabolic risk factors were used to compare the 2-year risk of cardiovascular mortality among patients in the different latent classes. Three distinct DG response phenotypes during the PET were identified. Those with consistently high D2/D0 and D4/D0 ratios had a 1.22 [95% confidence interval: 1.02, 1.35] excess risk of a cardiovascular death within 2 years of commencing PD compared with patients with the lowest D2/D0 ratio and decreased D4/D0 ratio after adjustment for cardiometabolic risk factors. Consistently elevated D2/D0 and D4/D0 ratios during the PET are associated with an increased risk of 2-year cardiovascular mortality independent of other cardiometabolic risk factors. In view of the potential bias due to unmeasured confounders (eg, Family history of cardiovascular diseases, and dietary patterns), this association should be further validated in other external cohorts

Derivation and external validation of a risk prediction algorithm to estimate future risk of cardiovascular death among patients with type 2 diabetes and incident diabetic nephropathy: prospective cohort study

Objective To derive, and externally validate, a risk score for cardiovascular death among patients with type 2 diabetes and newly diagnosed diabetic nephropathy (DN). Research design and methods Two independent prospective cohorts with type 2 diabetes were used to develop and externally validate the risk score. The derivation cohort comprised 2282 patients with an incident, clinical diagnosis of DN. The validation cohort includes 950 patients with incident, biopsy-proven diagnosis of DN. The outcome was cardiovascular death within 2 years of the diagnosis of DN. Logistic regression was applied to derive the risk score for cardiovascular death from the derivation cohort, which was externally validated in the validation cohort. The score was also estimated by applying the United Kingdom Prospective Diabetes Study (UKPDS) risk score in the external validation cohort. Results The 2-year cardiovascular mortality was 12.05% and 11.79% in the derivation cohort and validation cohort, respectively. Traditional predictors including age, gender, body mass index, blood pressures, glucose, lipid profiles alongside novel laboratory test items covering five test panels (liver function, serum electrolytes, thyroid function, blood coagulation and blood count) were included in the final model. C-statistics was 0.736 (95% CI 0.731 to 0.740) and 0.747 (95% CI 0.737 to 0.756) in the derivation cohort and validation cohort, respectively. The calibration slope was 0.993 (95% CI 0.974 to 1.013) and 1.000 (95% CI 0.981 to 1.020) in the derivation cohort and validation cohort, respectively. The UKPDS risk score substantially underestimated cardiovascular mortality. Conclusions A new risk score based on routine clinical measurements that quantified individual risk of cardiovascular death was developed and externally validated. Compared with the UKPDS risk score, which underestimated the cardiovascular disease risk, the new score is a more specific tool for patients with type 2 diabetes and DN. The score could work as a tool to identify individuals at the highest risk of cardiovascular death among those with DN

Effect of onset of type 2 diabetes on risks of cardiovascular disease and heart failure among new Zealanders with impaired glucose tolerance over 25 years: tapered-matched landmark analysis

BackgroundThis study aimed to examine the association between the incident onset of T2DM and 5- and 10-year risks of CVD and HF in people with IGT identified in primary care in South and West Auckland, New Zealand (NZ) between 1994 and 2019.MethodsWe compared CVD and HF risks in patients with IGT and with/without T2D newly diagnosed within the exposure window (1–5 years). Tapered matching and landmark analysis (to account for immortal bias) were used to control for potential effects of known confounders.ResultsAmong 26,794 patients enrolled with IGT, 845 had T2D newly diagnosed within 5 years from enrolment (landmark date) and 15,452 did not have T2D diagnosed. Patients progressing to T2D (vs. those not progressing) had a similar 5-year risk for CVD (hazard ratio 1.19; 95% CI 0.61–2.32) but significantly higher 10-year risk of CVD (2.45(1.40–4.29)), 5-year risk of HF (1.94(1.20–3.12)) and 10-year risk of HF (2.84(1.83–4.39). The association between the onset of T2D and risk of 10-year risk of CVD, 5-year and 10-year risk of HF was more likely among men, the socioeconomically deprived, those currently smoking, patients with higher metabolic measures and/or those with lower renal function. Patients of NZ European ethnicity had a lower 10-year risk of CVD.ConclusionsThe study suggests that the diagnosis of T2D mediates the risk of CVD and HF in people with IGT. The development of risk scores to identify and better manage individuals with IGT at high risk of T2D is warranted

Safety and effectiveness of HSK21542 for hemodialysis patients: a multiple ascending dose study

Background: HSK21542, a novel selective peripherally-restricted κ-opioid receptor agonist has been proven to be a safe and effective analgesic and antipruritic drug in both in vitro and in vivo studies. We aimed to evaluate its safety, pharmacokinetics and efficacy in hemodialysis patients over a 1-week treatment period, and to establish the optimal dosage for a further 12-week stage 2 trial.Methods: In this multiple ascending dose study, hemodialysis patients were randomly assigned to receive HSK21542 (0.05–0.80 μg/kg), or a placebo three times within 2.5 h at the end of each dialysis session for 1 week. Safety evaluations included reports of treatment-emergent adverse events (TEAEs); pharmacokinetics and efficacy outcomes were also assessed.Results: Among the 44 screened patients, 41 were enrolled and completed the trial. The overall incidence of TEAEs was higher in the HSK21542 group compared to the placebo group, with an incidence of 75.0%, 50.0%, 75.0%, and 88.9% in the range of 0.05–0.80 μg/kg. All TEAEs were grade 1 or 2 in severity. HSK21542 exhibited linear pharmacokinetics characteristics within the dose range 0.05–0.80 μg/kg, without drug accumulation after multiple-doses. Compared to the placebo, a significant decrease of the weekly mean Worst Itching Intensity Numerical Rating Scale was found in the HSK21542-0.30 μg/kg group (p = 0.046), but without significant improvement in the Skindex-16 score.Conclusion: HSK21542 was well tolerated in the dose range 0.05–0.80 μg/kg in hemodialysis patients. HSK21542-0.3 μg/kg exhibited promising efficacy in patients with moderate to severe pruritus and warrants a further Stage 2 trial.Clinical Trial Registration:https://clinicaltrials.gov/, identifier NCT04470154

Application of Angiotensin Receptor–Neprilysin Inhibitor in Chronic Kidney Disease Patients: Chinese Expert Consensus

Chronic kidney disease (CKD) is a global public health problem, and cardiovascular disease is the most common cause of death in patients with CKD. The incidence and prevalence of cardiovascular events during the early stages of CKD increases significantly with a decline in renal function. More than 50% of dialysis patients die from cardiovascular disease, including coronary heart disease, heart failure, arrhythmia, and sudden cardiac death. Therefore, developing effective methods to control risk factors and improve prognosis is the primary focus during the diagnosis and treatment of CKD. For example, the SPRINT study demonstrated that CKD drugs are effective in reducing cardiovascular and cerebrovascular events by controlling blood pressure. Uncontrolled blood pressure not only increases the risk of these events but also accelerates the progression of CKD. A co-crystal complex of sacubitril, which is a neprilysin inhibitor, and valsartan, which is an angiotensin receptor blockade, has the potential to be widely used against CKD. Sacubitril inhibits neprilysin, which further reduces the degradation of natriuretic peptides and enhances the beneficial effects of the natriuretic peptide system. In contrast, valsartan alone can block the angiotensin II-1 (AT1) receptor and therefore inhibit the renin–angiotensin–aldosterone system. These two components can act synergistically to relax blood vessels, prevent and reverse cardiovascular remodeling, and promote natriuresis. Recent studies have repeatedly confirmed that the first and so far the only angiotensin receptor–neprilysin inhibitor (ARNI) sacubitril/valsartan can reduce blood pressure more effectively than renin–angiotensin system inhibitors and improve the prognosis of heart failure in patients with CKD. Here, we propose clinical recommendations based on an expert consensus to guide ARNI-based therapeutics and reduce the occurrence of cardiovascular events in patients with CKD