Estimated Lifetime Benefit of Combined RAAS and SGLT2 Inhibitor Therapy in Patients with Albuminuric CKD without Diabetes

Background and objectives: Despite high rates of complications in patients with CKD without diabetes, the implementation of proven therapies in this group remains low. Expressing the clinical benefitofatherapyin terms of extra years free from the disease or death may facilitate implementation. We estimated lifetime survival free of kidney failure for patients with albuminuric CKD without diabetes treated with the combination therapy of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and sodium-glucose cotransporter-2 (SGLT2) inhibitors relative to patients not treated. Design, setting, participants, & measurements: We used trial-level estimates of the effect of treatment with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ramipril/benazepril; n=690) and SGLT2 inhibitors (dapagliflozin; n=1398) compared with placebo to derive the effect of combination therapy versus no treatment. Using this effect, we estimated treatment effect of combination therapy to the active treatment group of patients with albuminuric CKD without diabetes participating in the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial (n=697) and projected eventfree and overall survival for those treated and not treated with combination therapy. We also performed our calculations anticipating lower adherence and less pronounced benefits than were observed in the clinical trials. The primary outcome was a composite of doubling of serum creatinine, kidney failure, or death. Results: The aggregate estimated hazard ratio comparing combination therapy with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and SGLT2 inhibitor versus no treatment for the primary end point was 0.35 (95% confidence interval, 0.30 to 0.41). For a 50-year-old patient until the age of 75 years, the estimated survival free from the primary composite end point was 17.0 (95% confidence interval, 12.4 to 19.6) years with the combination therapy and 9.6 years (95% confidence interval, 8.4 to 10.7) with no treatment with any of these agents, corresponding to a gain in eventfree survival of 7.4 (95% confidence interval, 6.4 to 8.7) years. When assuming lower adherence and less pronounced efficacy of combination therapy, the gain in eventfree survival ranged from 5.3 years (95% confidence interval, 4.4 to 6.1) to 5.8 years (95% confidence interval, 4.8 to 6.8). Conclusions: Treatment with the combination of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and SGLT2 inhibitor in patients with albuminuric CKD without diabetes is expected to substantially increase kidney failure–free survival. Clinical Trial registry name and registration number: Benazepril for Advanced Chronic Renal Insufficiency, NCT00270426, and a Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients with Chronic Kidney Disease (Dapa-CKD), NCT03036150

Systematic assessment of fluid responsiveness during early septic shock resuscitation: secondary analysis of the ANDROMEDA-SHOCK trial

BACKGROUND: Fluid boluses are administered to septic shock patients with the purpose of increasing cardiac output as a means to restore tissue perfusion. Unfortunately, fluid therapy has a narrow therapeutic index, and therefore, several approaches to increase safety have been proposed. Fluid responsiveness (FR) assessment might predict which patients will effectively increase cardiac output after a fluid bolus (FR+), thus preventing potentially harmful fluid administration in non-fluid responsive (FR-) patients. However, there are scarce data on the impact of assessing FR on major outcomes. The recent ANDROMEDA-SHOCK trial included systematic per-protocol assessment of FR. We performed a post hoc analysis of the study dataset with the aim of exploring the relationship between FR status at baseline, attainment of specific targets, and clinically relevant outcomes. METHODS: ANDROMEDA-SHOCK compared the effect of peripheral perfusion- vs. lactate-targeted resuscitation on 28-day mortality. FR was assessed before each fluid bolus and periodically thereafter. FR+ and FR- subgroups, independent of the original randomization, were compared for fluid administration, achievement of resuscitation targets, vasoactive agents use, and major outcomes such as organ dysfunction and support, length of stay, and 28-day mortality. RESULTS: FR could be determined in 348 patients at baseline. Two hundred and forty-two patients (70%) were categorized as fluid responders

Effects of newer kidney protective agents on kidney endpoints provide implications for future clinical trials

Doubling of serum creatinine (equivalent to a 57% decline in the estimated glomerular filtration rate (eGFR)) is an accepted component of a composite kidney endpoint in clinical trials. Smaller declines in eGFR (40%, 50%) have been applied in several recently conducted clinical trials. Here, we assessed the effects of newer kidney protective agents on endpoints including smaller proportional declines in eGFR to compare relative event rates and the magnitude of observed treatment effects. We performed a post hoc analysis of 4401 patients in the CREDENCE, 4304 in the DAPA-CKD, 5734 in the FIDELIO-DKD, and 3668 in the SONAR trials, which assessed the effects of canagliflozin, dapagliflozin, finerenone and atrasentan in patients with chronic kidney disease. Effects of active therapies versus placebo on alternative composite kidney endpoints incorporating different eGFR decline thresholds (40%, 50%, or 57% eGFR reductions from baseline) with kidney failure or death due to kidney failure were compared. Cox-proportional hazards regression models were used to assess and compare treatment effects. During follow-up, event rates were higher for endpoints incorporating smaller versus larger eGFR decline thresholds. Compared to the treatment effects on kidney failure or death due to kidney failure, the magnitude of relative treatment effects was generally similar when considering composite endpoints incorporating smaller declines in eGFR. Hazard ratios for the four interventions ranged from 0.63 to 0.82 for the endpoint incorporating 40% eGFR decline and 0.59 to 0.76 for the endpoint incorporating 57% eGFR decline. Clinical trials incorporating a 40% eGFR decline in a composite endpoint would require approximately half the number of participants compared to a 57% eGFR decline with equivalent statistical power. Thus, in populations at high risk of CKD progression, the relative effects of newer kidney protective therapies appear generally similar across endpoints based on varying eGFR decline thresholds.</p

AGS tune jump system to cross horizontal depolarization resonances overview

Two partial snakes overcome the vertical depolarizing resonances in the AGS. But a new type of depolarizing intrinsic resonance from horizontal motion appeared. We reduce these using horizontal tune jumps timed to these resonances. We gain a factor of six in crossing rate with a tune jump of 0.05 in 100 {micro}s. Two quadrapoles, we described in 2009, pulse 42 times, the current matching beam energy. The power supplies for these quads are described in detail elsewhere in this conference. The controls for the Jump Quad system is based on a BNL designed Quad Function Generator. Two modules are used; one for timing, and one to supply reference voltages. Synchronization is provided by a proprietary serial bus, the Event Link. The AgsTuneJump application predicts the times of the resonances during the AGS cycle and calculates the power supply trigger times from externally collected tune and energy versus time data and the Low and High PS voltage functions from a voltage to current model of the power supply. The system was commissioned during runs 09 & 10 and is operational. Many beam effects are described elsewhere. The TuneJump system has worked well and has caused little trouble save for the perturbations in the lattice having such a large effect due to our need to run with the vertical tune within a few thousandths of the integer tune. As these problems were mostly sorted out by correcting the 6th harmonic orbit distortions which caused a large 18 theta beta wave. Also running with minimal chromaticity reduces emittance growth. There are still small beta waves which are being addressed. The timing of the pulses is still being investigated, but as each crossing causes minimal polarization loss, this is a lengthy process

Diastolic shock index and clinical outcomes in patients with septic shock

Background: Loss of vascular tone is a key pathophysiological feature of septic shock. Combination of gradual diastolic hypotension and tachycardia could reflect more serious vasodilatory conditions. We sought to evaluate the relationships between heart rate (HR) to diastolic arterial pressure (DAP) ratios and clinical outcomes during early phases of septic shock. Methods: Diastolic shock index (DSI) was defined as the ratio between HR and DAP. DSI calculated just before starting vasopressors (Pre-VPs/DSI) in a preliminary cohort of 337 patients with septic shock (January 2015 to February 2017) and at vasopressor start (VPs/DSI) in 424 patients with septic shock included in a recent randomized controlled trial (ANDROMEDA-SHOCK; March 2017 to April 2018) was partitioned into five quantiles to estimate the relative risks (RR) of death with respect to the mean risk of each population (assumed to be 1). Matched HR and DAP subsamples were created to evaluate the effect of the individual components of the DSI on RRs. In addition, time-course of DSI and interaction between DSI and vasopressor dose (DSI*NE.dose) were compared between survivors and non-survivors from both populations, while ROC curves were used to identify variables predicting mortality. Finally, as exploratory observation, effect of early start of vasopressors was evaluated at each Pre-VPs/DSI quintile from the preliminary cohort. Results: Risk of death progressively increased at gradual increments of Pre-VPs/DSI or VPs/DSI (One-way ANOVA, p < 0.001). Progressive DAP decrease or HR increase was associated with higher mortality risks only when DSI concomitantly increased. Areas under the ROC curve for Pre-VPs/DSI, SOFA and initial lactate were similar, while mean arterial pressure and systolic shock index showed poor performances to predict mortality. Time-course of DSI and DSI*NE.dose was significantly higher in non-survivors from both populations (repeated-measures ANOVA, p < 0.001). Very early start of vasopressors exhibited an apparent benefit at higher Pre-VPs/DSI quintile. Conclusions: DSI at pre-vasopressor and vasopressor start points might represent a very early identifier of patients at high risk of death. Isolated DAP or HR values do not clearly identify such risk. Usefulness of DSI to trigger or to direct therapeutic interventions in early resuscitation of septic shock need to be addressed in future studies