Prognostic Value of Histone Modifying Enzyme EZH2 in RCHOP-Treated Diffuse Large B-Cell Lymphoma and High Grade B-Cell Lymphoma

Background: DLBCL represent a heterogeneous group of aggressive diseases. High grade B-cell lymphomas (HGBCL) were recently individualized from DLBCL as a discrete diagnostic entity due to their worse prognosis. Currently, although most patients are successfully treated with RCHOP regimens, 1/3 will either not respond or ultimately relapse. Alterations in histone modifying enzymes have emerged as the most common alterations in DLBCL, but their role as prognostic biomarkers is controversial. We aimed to ascertain the prognostic value of EZH2 immunoexpression in RCHOP-treated DLBCL and HGBCL. Results: We performed a retrospective cohort study including 125 patients with RCHOP-treated DLBCL or HGBCL. EZH2 expression levels did not differ between diagnostic groups or between DLBCL-NOS molecular groups. We found no associations between EZH2 expression levels and outcome, including in the subgroup analysis (GC versus non-GC). Nonetheless, EZH2/BCL2 co-expression was significantly associated with worse outcome (event free survival and overall survival). Conclusion: Although EZH2 mutations are almost exclusively found in GC-DLBCL, we found similar EZH2 expression levels in both DLBCL-NOS molecular groups, suggesting non-mutational mechanisms of EZH2 deregulation. These findings suggest that the use of EZH2 antagonists might be extended to non-GC DLBCL patients with clinical benefit. EZH2/BCL2 co-expression was associated with a worse outcome.

Risk of atrial fibrillation development of sodium-glucose co-transporter 2 inhibitor and thiazolidinedione treatment among patients with type 2 diabetes

Background Type 2 diabetes is an independent risk factor for the development of atrial fibrillation (AF). Recently, SGLT-2i has been shown to decrease the incidence of AF through several mechanisms including reduction of atrial dilatation via diuresis and lowering body weight. On the other hand, the use of TZD was found to protect diabetic patients from new-onset AF in observational studies. Thus, we aimed to compare the effect of SGLT-2i and TZD on the risk of AF development. Methods Using the Korean National Health Insurance Service database, we included patients with type 2 diabetes who were prescribed SGLT-2i or TZD at least once from January 2014 to December 2018. Patients were followed until the outcome event, death, or 31 December 2018. Sensitivity analysis was performed only including patients who prescribed study drugs ≥90 days. Results A total of 206,986 patients were included (88,227 patients in SGLT-2i group and 118,759 in TZD group). Baseline characteristics were mean age was 57 years and 57.4% were male; mean body mass index was 26.3kg/m2 and 68.3% had hypertension. During follow-up, the incidence rates of AF were 1.36% in SGLT-2i-treated patients and 0.87% TZD-treated patients, respectively (p=0.0002). The hazard ratio (HR) of AF was 0.846 (95% confidence interval [CI]: 0.0.775–0.923) in SGLT-2i-treated patients compared with TZD-treated patients. Conclusions In this study, the risk of AF development was significantly lower in patients treated with SGLT-2i versus TZD. SGLT2 would be a good choice for the patients with high risk of AF development among diabetes mellitus. FUNDunding Acknowledgement Type of funding sources: None.

Comparative effectiveness of combined antiplatelet treatments in acute minor ischaemic stroke

BackgroundNo study has thoroughly compared the effectiveness of combined antiplatelet treatments (other than clopidogrel–aspirin) versus clopidogrel–aspirin or aspirin alone for early secondary prevention in acute ischaemic stroke.MethodsWe identified patients with acute, minor, non-cardiogenic ischaemic stroke treated with aspirin alone, clopidogrel–aspirin or other combination treatment. Propensity scores considering the inverse probability of treatment weighting were used to adjust for baseline imbalances. The primary outcome was the composite of all strokes (ischaemic or haemorrhagic), myocardial infarction and all-cause mortality at 3 months.ResultsAmong 12 234 patients (male: 61.9%; age: 65.5±13 years) who met the eligibility criteria, aspirin, clopidogrel–aspirin and other combination treatments were administered in 52.2%, 42.9% and 4.9% of patients, respectively. In the crude analysis, the primary outcome event at 3 months occurred in 14.5% of the other combination group, 14.4% of the aspirin group and 13.0% of the clopidogrel–aspirin group. In the weighted Cox proportional hazards analysis, the 3-month primary outcome event occurred less frequently in the clopidogrel–aspirin group than in the other combination group (weighted HR: 0.82 (0.59–1.13)), while no association was found between the aspirin group (weighted HR: 1.04 (0.76–1.44)) or other combination group and the 3-month primary outcome.ConclusionOther combined antiplatelet treatment, compared with aspirin alone or clopidogrel–aspirin, was not associated with reduced risks of primary composite vascular events or recurrent stroke during the first 3 months after stroke. Therefore, the results suggest that other combination treatments, particularly the cilostazol-based combination, may not be effective alternatives for clopidogrel–aspirin to prevent early vascular events in patients with acute minor stroke. Further exploration in clinical trials will be needed.

The Association Between Dietary Purine Intake and Mortality: Evidence From the CHNS Cohort Study

Objectives To investigate the association between dietary purine intake and mortality among Chinese adults. Methods Based on data from the 2004–2015 China Health and Nutrition Survey (CHNS) and the corresponding edition of China Food Composition, the average purine intake per day from 2004 to 2011 was calculated and divided into five groups by quintiles. The outcome event and time we concerned were defined as self-reported death and time in 2015 survey. Cox proportional hazards regression was used to estimate hazard ratios (HR) with 95% confidence intervals (CIs) for death. The possibly non-linear relation between purine intake and mortality was examined with restricted cubic splines. Results We included 17,751 subjects and the average purine intake among them was 329.14 ± 142.74 mg/day. Purine intake was inversely associated with mortality (P = 0.002). Compared with the lowest quintiles, the HRs (95% CI) of the highest quintiles were 0.60 (0.46, 0.77) for purine (P < 0.001). Besides, a U-shaped relationship between purine intake and mortality was observed in males; however, there is no dose-response relationship in females. Conclusions Under the low purine intake levels of the Chinese population, purine intake showed a protective effect. We observed a U-shaped relationship between purine intake and mortality in men but not found in women. Funding Sources National Key R&D Program of China (2017YFC0907200,2017YFC0907201).

Aldosterone and Mineralocorticoid Receptor Signaling as Determinants of Cardiovascular and Renal Injury: From Hans Selye to the Present

<b><i>Background:</i></b> A full understanding of the mechanisms of action of aldosterone and its interaction with the mineralocorticoid receptor (MR) allows a theoretical framework to predict the therapeutic potential of MR antagonists (MRAs) in CKD, and heart failure with reduced ejection fraction. <b><i>Summary:</i></b> The initial focus on the mechanisms of action of aldosterone was directed primarily on its role in modulating renal excretory function. In contrast, many recent studies have demonstrated a wider and expanded role for aldosterone in modulating inflammation, collagen formation, fibrosis, and necrosis. Increasing evidence has accrued that implicates the pathophysiological overactivation of the MR as a major determinant of progression of CKD. By promoting inflammation and fibrosis, MR overactivation constitutes a pivotal determinant of CKD progression and its associated morbidity and mortality. In accord with this mechanism of action, blockade of the MR is currently being investigated as a novel treatment regimen to slow the progression of CKD. The recently reported FIDELIO-DKD (FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic Kidney Disease) study demonstrated that patients with CKD and type 2 diabetes who were treated with finerenone (a novel nonsteroidal MRA) manifested a lower risk of a composite primary outcome event compared with patients in the placebo arm (defined as kidney failure, or a sustained decrease of ≥40% in the estimated glomerular filtration rate from baseline, or death from renal causes). In addition, patients in the finerenone group also manifested a lower risk of a key secondary outcome event (defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure). <b><i>Key Messages:</i></b> Based on the success of the FIDELIO-DKD study, future studies should be implemented testing the hypothesis that a wide array of nondiabetic CKD is modulated by overactivation of the MR, and consequently may be amenable to treatment with novel nonsteroidal MRAs. Future studies are encouraged to elucidate the clinical implications of the interplay of nonsteroidal MRAs and the components of the renin-angiotensin cascade. The unique and recently reported interrelationship of fibroblast growth factor (FGF23) and aldosterone may also constitute a propitious subject for future investigation.

Analysis of multicenter clinical trials with very low event rates

Introduction In a five-arm randomized clinical trial (RCT) with stratified randomization across 54 sites, we encountered low primary outcome event proportions, resulting in multiple sites with zero events either overall or in one or more study arms. In this paper, we systematically evaluated different statistical methods of accounting for center in settings with low outcome event proportions. Methods We conducted a simulation study and a reanalysis of a completed RCT to compare five popular methods of estimating an odds ratio for multicenter trials with stratified randomization by center: (i) no center adjustment, (ii) random intercept model, (iii) Mantel–Haenszel model, (iv) generalized estimating equation (GEE) with an exchangeable correlation structure, and (v) GEE with small sample correction (GEE-small sample correction). We varied the number of total participants (200, 500, 1000, 5000), number of centers (5, 50, 100), control group outcome percentage (2%, 5%, 10%), true odds ratio (1, > 1), intra-class correlation coefficient (ICC) (0.025, 0.075), and distribution of participants across the centers (balanced, skewed). Results Mantel–Haenszel methods generally performed poorly in terms of power and bias and led to the exclusion of participants from the analysis because some centers had no events. Failure to account for center in the analysis generally led to lower power and type I error rates than other methods, particularly with ICC = 0.075. GEE had an inflated type I error rate except in some settings with a large number of centers. GEE-small sample correction maintained the type I error rate at the nominal level but suffered from reduced power and convergence issues in some settings when the number of centers was small. Random intercept models generally performed well in most scenarios, except with a low event rate (i.e., 2% scenario) and small total sample size (n ≤ 500), when all methods had issues. Discussion Random intercept models generally performed best across most scenarios. GEE-small sample correction performed well when the number of centers was large. We do not recommend the use of Mantel–Haenszel, GEE, or models that do not account for center. When the expected event rate is low, we suggest that the statistical analysis plan specify an alternative method in the case of non-convergence of the primary method.

The effect of dapagliflozin across the spectrum of baseline risk: a post-hoc analysis of DAPA-HF

Background In DAPA-HF, compared to placebo, the sodium-glucose cotransporter 2 (SGLT-2) inhibitor, dapagliflozin, reduced the risk of cardiovascular death or worsening heart failure in patients with heart failure with reduced ejection fraction (HFrEF). The majority of patients in DAPA-HF reported mild functional limitation, however there is significant heterogeneity in prognosis among these patients. Purpose To examine the effect of dapagliflozin compared with placebo across the spectrum of baseline risk in DAPA-HF. Methods The primary composite outcome of DAPA-HF was time-to-first cardiovascular death or worsening heart failure event (hospitalization for heart failure or outpatient visit requiring intravenous therapy). We examined whether the effect of dapagliflozin was modified by baseline risk, as determined by the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure) risk score based upon 13 predictive variables giving a potential maximum score of 57. The number needed to treat (NNT) to over a median follow-up of 18.2 months was calculated by applying the overall relative risk reduction in DAPA-HF (26%, 95% CI 15–35) to the proportion of patients with a primary outcome event in the placebo group of each MAGGIC risk score category (defined by quintiles of score). Results The MAGGIC risk score was calculable for 4740 of 4744 patients in DAPA-HF. The median score was 22 (range 3–43). The event rate for the primary outcome was 7.2 per 100 patient-years in the lowest risk score quintile and 25.7 in the highest. A 1-point increase in score was associated with an 8% increase in the risk of a primary outcome event (p&lt;0.001). Dapagliflozin, compared to placebo, reduced the risk of the primary outcome across quintiles of the MAGGIC risk score (Figure - Interaction p value=0.69) and when the score was analysed as a continuous variable (Interaction p value=0.56). The NNT to prevent one primary event was 39 (95% CI 29–68) in the lowest quintile of risk scores, compared with 14 (11–25) in the highest quintile (Figure). Similar results were found for the individual components of the primary composite outcome and for all-cause mortality. Conclusions DAPA-HF included patients with a wide spectrum of risk. Treatment with dapagliflozin, compared to placebo, reduced the risk of cardiovascular death or worsening heart failure, irrespective of baseline risk as measured by the MAGGIC risk score. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): DAPA-HF was funded by AstraZeneca

Are current NEWS2 clinical response thresholds optimised for a general in-patient population?

Background: The National Early Warning Score 2 (NEWS2) is mandated in acute hospital trusts in England. Assessment of the implications of this policy across an unselected in-patient population has been limited. Objective: Evaluate NEWS2 performance in an acute, in-patient, population by relating potential costs and benefits of specific alerting thresholds 24 hours prior to a composite outcome event (unplanned intensive care admission or death). Methods: All in-patient spells between Nov 2018 to Jul 2019 in a single acute hospital in the UK were analysed. Standardised Early Warning Score(SEWS) and NEWS2 data acquisition was from the electronic health record (EHR). Existing SEWS alert thresholds were maintained. The performance of NEWS2 and SEWS threshold score against the composite outcome was assessed. A single clinical review cost (Euros129.50) was used to model the whole system cost of triggered responses at different NEWS2 thresholds. Results: In patients more than or equal to 24 hours post-admission, a mean daily rate of progression to the outcome event was 1.95/1000. An increase in alert threshold from NEWS2 equal or greater than 5, to equal to or greater than 6, reduced the proportion that would trigger a clinical review from 10.0% to 5.3% per day. This was associated with the false negative rate at threshold increasing from 1.13/1000 patients to 1.36/1000. A simple resource model allowing one triggered clinical response every 24 hours defined an incremental cost per patient benefiting of Euros26,463, equating to 18 additional healthcare professionals per 1000 patients to deliver clinical response to an additional 0.23 patients/day benefitting. Conclusion: The low event rate across the whole in-patient population, moderate performance of a single NEWS2 score and associated resource requirements mean that in any resource limited setting, rules-based unmodified NEWS2 response thresholds may divert clinical resource and focus.