Renin-angiotensin System Inhibitor Therapy Research Articles

#762 Hyperkalemia and discontinuation of RAS blockade after initiating SGLT-2i vs. DPP-4i in patients with type 2 diabetes; a population-based cohort study

Abstract Rate of hyperkalemia and discontinuation of renin-angiotensin system blockade after initiating SGLT-2 inhibitors vs. DPP-4 inhibitors in patients with type 2 diabetes; a population-based cohort study Background and Aims Post-hoc analyses of clinical trials have suggested that sodium-glucose cotransporter-2 inhibitors (SGLT-2i) lower the rate of hyperkalemia and facilitate the use of renin-angiotensin system inhibitors (RASi) in people with type 2 diabetes and CKD. Whether these effects are generalizable to patients treated in routine clinical practice is unclear. Here, we evaluated the comparative effects of SGLT-2i and dipeptidyl peptidase-4 inhibitors (DPP-4i) on the rate of hyperkalemia and RASi discontinuation. Method We conducted a population-based active-comparator, new-user cohort study using data from the Stockholm CREAtinine Measurements (SCREAM) project of people with type 2 diabetes who newly initiated SGLT-2i or DPP-4i between January 2014 and December 2021. The primary outcomes were time to first outpatient hyperkalemia (plasma potassium >5.0 mmol/L) occurrence and recurrent hyperkalemia. The secondary outcomes were mild (potassium >5-≤5.5 mmol/L) and moderate-severe (potassium >5.5 mmol/L) hyperkalemias. Among RASi users, we also studied time to RASi discontinuation through evaluation of pharmacy fills. Cox regression with inverse probability of treatment weighting was used to estimate hazard ratios (HRs) and rate differences for time to first hyperkalemia. Weighted Poisson regression was used to estimate incidence rate ratios (IRRs) for hyperkalemia recurrence. Results We included 24 417 individuals (of which 14 470 initiated SGLT-2i and 9, 947 DPP-4i therapy), followed for median 2.0 (Q1-Q3 0.8-3.7) years. Mean age was 67 years and 37% were women. Compared with DPP-4i, initiation of SGLT-2i was associated with a lower rate of first hyperkalemia (adjusted hazard ratio [HR] 0.83; 95% CI 0.72-0.96) and recurrent hyperkalemia (incidence rate ratio [IRR] 0.75; 0.64-0.85). Similar findings were observed among people with eGFR ≥60 (HR 0.73; 95% CI 0.63-0.86) and <60 (HR 0.87; 95% CI 0.63-1.16) ml/min/1.73 m2, as well as for mild (HR 0.82; 95% CI 0.71-0.95) and moderate-severe (HR 0.67; 95% CI 0.52-0.84) hyperkalemias. Out of 15 746 participants that were prevalent RASi users, 17% discontinued RASi therapy during 2.0 (IQR 0.8-3.7) years of follow-up. Initiation of SGLT-2i vs. DPP-4i was not associated with the rate of RASi discontinuation (HR: 1.00; 0.91-1.11). Conclusion In patients with type 2 diabetes managed in routine clinical care, the use of SGLT-2i was associated with a lower rate of first and recurrent hyperkalemia compared with DPP-4i. However, this was not accompanied by higher persistence on RASi therapy.

#853 Kidney-protective medication and risk of adverse clinical outcomes in patients with chronic kidney disease: preliminary findings from DISCOVER CKD

Abstract Background and Aims Renin-angiotensin-system inhibitors (RASi) have been a foundational therapy in chronic kidney disease (CKD) for several decades. Sodium-glucose co-transporter-2 inhibitors (SGLT2i) have also emerged as a critical disease-modifying therapy in CKD, with contemporary data from trials showing SGLT2i to significantly improve kidney and cardiovascular (CV) outcomes in patients with or without diabetes. Nonetheless, several studies have revealed sub-optimal prescribing of RASi and/or SGLT2i therapy (both herein referred to as kidney-protective medication) in patients with CKD. Using prospective data from the DISCOVER CKD study, we conducted an exploratory analysis to assess the association of kidney-protective medication real-world use with mortality risk, CV events (fatal and non-fatal), and hospitalisation in patients with CKD. Method DISCOVER CKD (NCT04034992) is a multi-country, non-interventional cohort study designed to characterise the epidemiology of CKD, including describing patient characteristics, disease progression, clinical outcomes, patient journey, practice patterns, and clinical management. In the prospective phase, patients with CKD were recruited from the UK, USA, Spain, Italy, Sweden and Japan between September 2019 and June 2022. Clinical data were extracted manually from patients’ health records into a standardised case report form. The current analysis includes 12 months’ follow-up data. A Cox proportional hazards model was used to compare the risk of all-cause mortality and CV events and a negative binomial regression model was used to compare the risk of all-cause hospitalisation between patients receiving and not receiving kidney-protective medication at baseline, with adjustments for age, sex, CKD stage, diabetes mellitus, hyperkalaemia, and heart failure. DISCOVER CKD received research ethics board approval, and informed consent was obtained from all patients. Results Of the 1052 patients enrolled in DISCOVER CKD, 643 (61.1%) were receiving kidney-protective medication in the form of RASi (n = 618) and SGLT2i (n = 147) at baseline. The mean age of participants receiving and not receiving kidney-protective medication was 62.4 years and 62.7 years, respectively; 34.4% and 40.8%, respectively, were female. Most patients had CKD stage 3A (n = 332, 31.6%) or 3B (n = 308, 29.3%), and 8.4% (n = 88) had ongoing dialysis. Body mass index (30.4 vs 29.4 kg/m2) and blood pressure were similar for those receiving kidney-protective medication versus those who were not. Laboratory assessments were also generally similar, although estimated glomerular filtration rate (eGFR; 40.9 vs 33.7 mL/min/1.73 m2) and haemoglobin (132.0 g/L vs 124.0 g/L) were higher in patients receiving kidney-protective medication versus those not. During the follow-up, patients receiving kidney-protective medication had a 67% lower risk of all-cause mortality (hazard ratio [HR] 0.33; 95% confidence interval [CI] 0.12–0.80, p = 0.019), and a 20% lower risk of all-cause hospitalisation (HR, 0.80; 95% CI 0.64–0.99, p = 0.042) compared with patients not receiving kidney-protective medication. In the population without pre-existing CV disease, a trend towards a lower rate of CV events was observed in patients with kidney-protective medication (CV events rates: 2.2 vs 3.2 per 100 person-years; HR, 0.38; 95% CI 0.12–1.08, p = 0.074 (Figure). Conclusion In this multinational CKD cohort, preliminary analysis indicates that using kidney-protective medication was associated with lower risks of adverse outcomes including death. Further analysis to mitigate potential confounding will be performed to confirm these preliminary findings.

#1021 A phase 3 randomized controlled trial of ravulizumab in adult patients with IgA nephropathy

Abstract Background and Aims The pathogenesis of IgA nephropathy (IgAN) includes the deposition of immune complexes in the kidney and activation of the complement system. Complement components, including C5a (anaphylatoxin) and C5b-9 (membrane attack complex), are generated leading to mesangial inflammation and glomerular injury [1]. Ravulizumab, a humanized monoclonal antibody, is a long-acting complement C5 inhibitor that provides immediate, complete, and sustained inhibition of the terminal complement pathway, thereby targeting a key component of the pathophysiology of IgAN. A phase 2 study of ravulizumab (NCT04564339) demonstrated a rapid effect and significant reduction in proteinuria compared with placebo at week 26 (change from baseline in 24-hour urine protein to creatinine ratio [UPCR] –40.3% vs –10.9%), and treatment was well-tolerated [2]. This abstract describes the study design of the planned phase 3 trial of ravulizumab in adult patients with IgAN. Method This phase 3, randomized, double-blind, placebo-controlled trial (I CAN) will evaluate the efficacy and safety of ravulizumab (IV; weight-based dosing Q8W) in adults with IgAN. Eligibility criteria include a diagnosis of primary IgAN based on kidney biopsy at any point, estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 at screening, and UPCR ≥0.75 g/g or urine protein ≥1.0 g/day (Table 1). The study consists of a 6-week screening period, followed by randomization (1:1) of participants to ravulizumab or placebo and a 2-year blinded treatment period (Fig. 1); all patients receive a stable and maximally tolerated dose of renin-angiotensin system inhibitor therapy. Approximately 450 patients will be randomized, stratified by proteinuria (<2 g/g vs ≥2 g/g), eGFR (<45 vs ≥45 mL/min/1.73 m2), and SGLT2i use (yes/no). The co-primary endpoints are change from baseline to week 34 in 24-hour UPCR evaluated on the log scale and the annualized total eGFR slope over 106 weeks. The sample size for the proteinuria endpoint of n = 204 will provide ∼90% power to detect a 35% relative treatment effect in UPCR at week 34 at a one-sided significance level of 0.005. The total sample size of n = 450 for the eGFR endpoint will provide ∼90% power to detect a difference in total annualized eGFR slope of 2.2 mL/min/1.73 m2 at week 106 at a one-sided significance level of 0.025. An open-label exploratory cohort (n = 20) with eGFR 20-29 mL/min/1.73 m2 and with kidney biopsy within 6 months of or during screening will be enrolled and analyzed separately from the main cohort. At completion of the blinded treatment period, all study participants will have the option to enter an open-label ravulizumab access period for up to 2 years. Results The co-primary endpoints are the change in 24-hour UPCR at week 34 and the annualized total eGFR slope over 106 wks. Secondary and exploratory endpoints include change in 24-hour UPCR at weeks 10, 26, 50, and 106, a composite kidney failure endpoint over 106 weeks, reduction in 24-hour UPCR ≥50% from baseline, time to UPCR <1 g/g and <0.3 g/g, and patient reported outcomes on fatigue, quality of life, and work-related productivity. Safety, tolerability, immunogenicity, pharmacokinetics, and pharmacodynamics will be evaluated. Conclusion Through immediate, complete, and sustained inhibition of C5, ravulizumab targets the pathophysiology of IgAN and has the potential to provide a disease modifying treatment option. This pivotal phase 3 study (I CAN) will evaluate the efficacy of ravulizumab in patients with IgAN who are at high risk of disease progression. The trial will evaluate effects on proteinuria and eGFR that may translate to long term kidney function preservation and provide a rapidly acting treatment option for patients living with IgAN.

Impact of Insurance Status and Region on Angiotensin Receptor–Neprilysin Inhibitor Prescription During Heart Failure Hospitalizations

BackgroundAn angiotensin receptor–neprilysin inhibitor (ARNI) is the preferred renin-angiotensin system (RAS) inhibitor for heart failure with reduced ejection fraction (HFrEF). Among eligible patients, insurance status and prescriber concern regarding out-of-pocket costs may constrain early initiation of ARNI and other new therapies. ObjectivesIn this study, the authors sought to evaluate the association of insurance and other social determinants of health with ARNI initiation at discharge from HFrEF hospitalization. MethodsThe authors analyzed ARNI initiation from January 2017 to June 2020 among patients with HFrEF eligible to receive RAS inhibitor at discharge from hospitals in the Get With The Guidelines–Heart Failure registry. The primary outcome was the proportion of ARNI prescription at discharge among those prescribed RAS inhibitor who were not on ARNI on admission. A logistic regression model was used to determine the association of insurance status, U.S. region, and their interaction, as well as self-reported race, with ARNI initiation at discharge. ResultsFrom 42,766 admissions, 24,904 were excluded for absolute or relative contraindications to RAS inhibitors. RAS inhibitors were prescribed for 16,817 (94.2%) of remaining discharges, for which ARNI was prescribed in 1,640 (9.8%). Self-reported Black patients were less likely to be initiated on ARNI compared to self-reported White patients (OR: 0.64; 95% CI: 0.50-0.81). Compared to Medicare beneficiaries, patients with third-party insurance, Medicaid, or no insurance were less likely to be initiated on ARNI (OR: 0.47 [95% CI: 0.31-0.72], OR: 0.41 [95% CI: 0.25-0.67], and OR: 0.20 [95% CI: 0.08-0.47], respectively). ARNI therapy varied by hospital region, with lowest utilization in the Mountain region. An interaction was demonstrated between the impact of insurance disparities and hospital region. ConclusionsAmong patients hospitalized between 2017 and 2020 for HFrEF who were prescribed RAS inhibitor therapy at discharge, insurance status, geographic region, and self-reported race were associated with ARNI initiation.

Comparative Outcomes of Sacubitril/Valsartan Use After Hospitalization for Heart Failure Among Medicare Beneficiaries Naïve to Renin-Angiotensin System Inhibitors

Sacubitril/valsartan improves outcomes in patients with heart failure with reduced ejection fraction (HFrEF) compared with angiotensin-converting enzyme inhibitors (ACEis). However, data on postdischarge outcomes in renin-angiotensin system inhibitor (RASi)-naïve patients are limited. We included Medicare beneficiaries aged ≥65years who were hospitalized for HFrEF in the Get With The Guidelines-Heart Failure registry between October 2015 and June 2019, had part D prescription coverage, and were not on RASi therapy during the 6months before hospital admission. We examined the associations between sacubitril/valsartan prescription at hospital discharge and outcomes at 30days and 1year after discharge using overlap-weighted median regression and Cox proportional hazards models. The end points included "home time" (defined as days alive and out of any health care institution), mortality, and rehospitalization. Among 3,572 patients with HFrEF and who are naïve to RASi therapy, at discharge, 290 (8.1%) were prescribed sacubitril/valsartan and 1,390 (38.9%) were prescribed ACEis and angiotensin receptor blockers. After adjusting for baseline characteristics, patients prescribed sacubitril/valsartan had a longer median home time (parameter estimate 27.0days, 95% confidence interval [CI] 12.40 to 41.6, p <0.001) and lower all-cause mortality (hazard ratio [HR] 0.74, 95% CI 0.61 to 0.91, p=0.004) at 1year than patients not prescribed sacubitril/valsartan. The prescription of sacubitril/valsartan was not significantly associated with all-cause rehospitalization (HR 0.87, 95% CI 0.74 to 1.03, p=0.10) or heart failure rehospitalization (HR 0.87, 95% CI 0.70 to 1.07, p=0.19). In a restricted comparison of patients discharged on sacubitril/valsartan versus ACEis and angiotensin receptor blockers, there were no significant differences in the outcomes. In conclusion, in this contemporary population of RASi-naïve patients with HFrEF from routine clinical practice, compared with not initiating, the initiation of sacubitril/valsartan at discharge was associated with longer home time and improvements in overall survival.

Renin-Angiotensin System Inhibitors in Patients With COVID-19: A Meta-Analysis of Randomized Controlled Trials Led by the International Society of Hypertension.

BackgroundPublished randomized controlled trials are underpowered for binary clinical end points to assess the safety and efficacy of renin‐angiotensin system inhibitors (RASi) in adults with COVID‐19. We therefore performed a meta‐analysis to assess the safety and efficacy of RASi in adults with COVID‐19.Methods and ResultsMEDLINE, EMBASE, ClinicalTrials.gov, and the Cochrane Controlled Trial Register were searched for randomized controlled trials that randomly assigned patients with COVID‐19 to RASi continuation/commencement versus no RASi therapy. The primary outcome was all‐cause mortality at ≤30 days. A total of 14 randomized controlled trials met the inclusion criteria and enrolled 1838 participants (aged 59 years, 58% men, mean follow‐up 26 days). Of the trials, 11 contributed data. We found no effect of RASi versus control on all‐cause mortality (7.2% versus 7.5%; relative risk [RR], 0.95; [95% CI, 0.69–1.30]) either overall or in subgroups defined by COVID‐19 severity or trial type. Network meta‐analysis identified no difference between angiotensin‐converting enzyme inhibitors versus angiotensin II receptor blockers. RASi users had a nonsignificant reduction in acute myocardial infarction (2.1% versus 3.6%; RR, 0.59; [95% CI, 0.33–1.06]), but increased risk of acute kidney injury (7.0% versus 3.6%; RR, 1.82; [95% CI, 1.05–3.16]), in trials that initiated and continued RASi. There was no increase in need for dialysis or differences in congestive cardiac failure, cerebrovascular events, venous thromboembolism, hospitalization, intensive care admission, inotropes, or mechanical ventilation.ConclusionsThis meta‐analysis of randomized controlled trials evaluating angiotensin‐converting enzyme inhibitors/angiotensin II receptor blockers versus control in patients with COVID‐19 found no difference in all‐cause mortality, a borderline decrease in myocardial infarction, and an increased risk of acute kidney injury with RASi. Our findings provide strong evidence that RASi can be used safely in patients with COVID‐19.

Renin-Angiotensin-System Inhibitors Are Associated With Lower In-hospital Mortality in COVID-19 Patients Aged 80 and Older.

BackgroundOlder adults are at higher risk of morbidity and mortality for coronavirus disease 2019 (COVID-19). Renin-angiotensin-system inhibitors (RASi) were found to have a neutral or protective effect against mortality in COVID-19 adult patients.AimsWe investigated whether this association was confirmed also in COVID-19 older patients.MethodsThis is a prospective observational study on 337 hospitalized older adults (aged 80 years and older). We classified the study population according to usage of RASi before and during hospitalization. A propensity score analysis was also performed to confirm the findings.ResultsThe mean age was 87.4 ± 6.1 years. Patients taking RASi at home were 147 (43.6%). During hospitalization, 38 patients (11.3% of the entire study population) discontinued RASi, while 57 patients (16.9% of the entire study population) started RASi. In-hospital mortality was 43.9%. Patients taking RASi during hospitalization (patients who maintained their home RASi therapy + patients who started RASi during hospitalization) had a significantly lower in-hospital mortality than untreated patients [HR 0.48 (95% CI: 0.34–0.67)], even after adjustment for required respiratory support, functional status, albumin, inflammation, and cardiac biomarkers. The analysis of the groups derived from the “propensity score matching” (58 patients in each group) confirmed these results [HR 0.46 (95% CI: 0.23–0.91)].DiscussionDespite the high risk of death in older COVID-19 patients, RASi therapy during hospitalization was associated with a clinically relevant lower in-hospital mortality, likely due to the benefit of RAS modulation on the cardiopulmonary system during the acute phase of the disease.ConclusionOur findings confirm the protective role of RASi even in COVID-19 patients aged 80 years and older.

Chronic Hyperkaliemia in Chronic Kidney Disease: An Old Concern with New Answers.

Increasing potassium intake ameliorates blood pressure (BP) and cardiovascular (CV) prognoses in the general population; therefore the World Health Organization recommends a high-potassium diet (90–120 mEq/day). Hyperkalaemia is a rare condition in healthy individuals due to the ability of the kidneys to effectively excrete dietary potassium load in urine, while an increase in serum K+ is prevalent in patients with chronic kidney disease (CKD). Hyperkalaemia prevalence increases in more advanced CKD stages, and is associated with a poor prognosis. This scenario generates controversy on the correct nutritional approach to hyperkalaemia in CKD patients, considering the unproven link between potassium intake and serum K+ levels. Another concern is that drug-induced hyperkalaemia leads to the down-titration or withdrawal of renin-angiotensin system inhibitors (RASI) and mineralocorticoids receptors antagonists (MRA) in patients with CKD, depriving these patients of central therapeutic interventions aimed at delaying CKD progression and decreasing CV mortality. The new K+-binder drugs (Patiromer and Sodium-Zirconium Cyclosilicate) have proven to be adequate and safe therapeutic options to control serum K+ in CKD patients, enabling RASI and MRA therapy, and possibly, a more liberal intake of fruit and vegetables.

Effects of renin-angiotensin system inhibitor type and dosage on survival after transcatheter aortic valve implantation.

The objective of the study was to determine the effect of renin-angiotensin system inhibitors (RASI) on the survival of subgroups of patients with aortic stenosis after transcatheter aortic valve implantation (TAVI) and to assess the impact of types and dosages of RASI on outcomes. This single-centre, retrospective analysis included 2862 patients (n=2227 with RASI and n=635 without RASI) after successful TAVI. Propensity score matching established comparable patient populations (n=625 per group). Survival was analysed by Kaplan-Meier curves and Cox regression and was corrected for baseline, procedural, and medical parameters. Self-reported adherence to RASI therapy 3 months after hospital discharge was 94%. Three-year all-cause mortality rates were 12.3% and 20.2% for patients with or without RASI, respectively (log-rank<0.001).In the matched study populations, mortality rates were 14.2%vs. 20.0% (log-rank<0.03).RASI was particularly beneficial in patients with ejection fraction<40%[adjusted hazard ratio (HR) and 95% confidence interval 0.50 (0.29-0.87)], EuroScore II≥4% [HR 0.47 (0.35-0.65)], or low-flow, low-gradient aortic stenosis [HR 0.53 (0.31-0.93)] who were also on beta-blockers and statins. An association between discharge dosage and survival was observed, with HR 0.75 (0.58-0.96) and 0.57 (0.44-0.72) for patients on<50%and≥50% target dose, respectively. Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) reduced mortality rates similarly (13.9%vs. 9.8%, log-rank 0.103). The beneficial association between RASI after TAVI and improved survival during follow-up is particularly evident in high-risk patients and may be dose dependent. No superiority was noted in the effectiveness of ACEI or ARB.

Continuation Versus Interruption of Renin-Angiotensin System Inhibitors in Acute Decompensated Heart Failure: A Brief Report.

This article is temporarily under embargo.

Abstract 10738: Comparative Outcomes of Sacubitril/Valsartan Use Among Medicare Beneficiaries NaïVe to Renin-angiotensin System Inhibitors and Hospitalized with Heart Failure

Introduction: Sacubitril/valsartan improves outcomes in patients with heart failure with reduced ejection fraction (HFrEF) compared to ACE inhibitors; however, comparative effectiveness data on post-discharge outcomes in renin-angiotensin system inhibitor (RASi)-naïve patients are limited. Methods: We analyzed Medicare beneficiaries age ≥65 years who were hospitalized for HFrEF in the Get With The Guidelines Heart Failure registry between 10/2015 and 6/2019, had Part D prescription coverage, and were not on RASi therapy 6 months prior to hospital admission. We examined associations between sacubitril/valsartan prescription at hospital discharge and outcomes at 30 days and 1 year after discharge using overlap weighted Cox proportional hazards models. The primary endpoint was “home-time”, defined as days alive and out of any healthcare institution. Secondary endpoints included mortality and rehospitalization. Results: Among 3,572 patients with HFrEF and naïve to RASi therapy, 290 (8.1%) were prescribed sacubitril/valsartan at hospital discharge. After adjusting for baseline patient characteristics, patients prescribed sacubitril/valsartan had greater home-time (parameter estimate [PEs] 27.0, 95%CI 12.4-41.6, p&lt;0.001) and lower all-cause mortality (HR 0.74, 95%CI 0.6-0.9, p=0.004) compared with patients not on sacubitril/valsartan. Prescription of sacubitril/valsartan was not significantly associated with all-cause (HR 0.87, 95%CI 0.7-1.0, p=0.10) or HF rehospitalization (HR 0.87, 95%CI 0.7-1.1, p=0.19) (Figure) Conclusions: In this contemporary, real-world population of RASi-naïve patients with HFrEF, initiation of sacubitril/valsartan at discharge was associated with greater home-time and improvements in overall survival similar to that seen in randomized trials. These findings support recent expert consensus recommendations endorsing a direct-to-sacubitril/valsartan therapeutic approach among RASi-naïve patients.

Association of beta-blockers or inhibitors of renin-angiotensin system with clinical outcomes in patients with mid-range left ventricular ejection fraction after acute myocardial infarction

Abstract Background In the era of the initial optimal interventional and medical therapy for acute myocardial infarction (AMI), a number of patients with mid-range left ventricular ejection fraction (EF) (&amp;gt;40%, &amp;lt;50%) becomes increasing. Purpose This observational study aimed to investigate the association between oral beta-blockers or inhibitors of renin-angiotensin system (RAS) and 2-year clinical outcomes in patients with mid-range EF after AMI. Methods Among 13,624 patients enrolled in the Korea Acute Myocardial Infarction Registry-National Institute of Health (KAMIR-NIH), propensity-score matched patients who survived the initial attack and had mid-range EF were selected according to beta-blocker or RAS inhibitor therapy at discharge. Results Beta-blocker therapy at discharge was associated with lower 2-year major adverse cardiac events (MACE) of cardiac death, MI, revascularization or re-hospitalization due to heart failure (8.7 vs. 12.8/100 person-year; hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.50–0.93; P=0.015), and no significant interaction between EF ≤45% and &amp;gt;45% was observed (P for interaction=0.354). This association was mainly driven by lower MI in patients with beta-blockers (1.6 vs. 3.1/100 person-year; HR 0.50; 95% CI 0.26–0.95; P=0.035). Inhibitors of RAS at discharge were not associated with lower 2-year MACE, but with lower re-hospitalization due to heart failure (1.8 vs. 3.5/100 person-year; HR 0.53; 95% CI 0.33–0.86; P=0.010) without significant interaction between EF ≤45% and &amp;gt;45% (P for interaction=0.333). Conclusions Beta-blockers or RAS inhibitors at discharge were associated with better 2-year clinical outcomes without significant interaction between ≤45% and &amp;gt;45% in patients with mid-range EF after AMI.&amp;lt;/ef&amp;lt;50%)&amp;gt; Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Korea Centers for Disease Control and Prevention. 2-year clinical outcomes

Stopping renin-angiotensin system inhibitors after hyperkalemia and risk of adverse outcomes

Stopping renin-angiotensin system inhibitors (RASi) after an episode of hyperkalemia is common but may involve therapeutic compromises, in that the cessation of RASi deprives patients of their beneficial cardiovascular effects. Observational study from the Stockholm Creatinine Measurements (SCREAM) project including patients initiating RASi in routine care and surviving a first-detected episode of hyperkalemia (potassium >5.0 mmol/L). We used target trial emulation techniques based on cloning, censoring and weighting to compare stopping vs. continuing RASi within 6 months after hyperkalemia. Outcomes were 3-year risks of mortality, major adverse cardiovascular events (MACE, composite of cardiovascular death, myocardial infarction and stroke hospitalization) and recurrent hyperkalemia. Of 5669 new users of RASi who developed hyperkalemia (median age 72 years, 44% women), 1425 (25%) stopped RASi therapy within 6 months. Compared with continuing RASi, stopping therapy was associated with a higher 3-year risk of death (absolute risk difference 10.8%; HR 1.49, 95% CI 1.34-1.64) and MACE (risk difference 4.7%; HR 1.29, 1.14-1.45), but a lower risk of recurrent hyperkalemia (risk difference -9.5%; HR 0.76, 0.69-0.84). Results were consistent for events following potassium of >5.0 or >5.5 mmol/L, after censoring when the treatment decision was changed, across prespecified subgroups, and after adjusting for albuminuria. These findings suggest that stopping RASi after hyperkalemia may be associated with a lower risk of recurrence of hyperkalemia, but higher risk of death and cardiovascular events.

Renin-angiotensin system inhibitors and mortality among diabetic patients with STEMI undergoing mechanical reperfusion during the COVID-19 pandemic

BackgroundDuring the coronavirus disease 2019 (COVID-19) pandemic, concerns have been arisen on the use of renin-angiotensin system inhibitors (RASI) due to the potentially increased expression of Angiotensin-converting-enzyme (ACE)2 and patient's susceptibility to SARS-CoV2 infection. Diabetes mellitus have been recognized favoring the coronavirus infection with consequent increase mortality in COVID-19. No data have been so far reported in diabetic patients suffering from ST-elevation myocardial infarction (STEMI), a very high-risk population deserving of RASI treatment. MethodsThe ISACS-STEMI COVID-19 registry retrospectively assessed STEMI patients treated with primary percutaneous coronary intervention (PPCI) in March/June 2019 and 2020 in 109 European high-volume primary PCI centers. This subanalysis assessed the prognostic impact of chronic RASI therapy at admission on mortality and SARS-CoV2 infection among diabetic patients. ResultsOur population is represented by 3812 diabetic STEMI patients undergoing mechanical reperfusion, 2038 in 2019 and 1774 in 2020. Among 3761 patients with available data on chronic RASI therapy, between those ones with and without treatment there were several differences in baseline characteristics, (similar in both periods) but no difference in the prevalence of SARS-CoV2 infection (1.6% vs 1.3%, respectively, p = 0.786). Considering in-hospital medication, RASI therapy was overall associated with a significantly lower in-hospital mortality (3.3% vs 15.8%, p < 0.0001), consistently both in 2019 and in 2010. ConclusionsThis is first study to investigate the impact of RASI therapy on prognosis and SARS-CoV2 infection of diabetic patients experiencing STEMI and undergoing PPCI during the COVID-19 pandemic. Both pre-admission chronic RASI therapy and in-hospital RASI did not negatively affected patients’ survival during the hospitalization, neither increased the risk of SARS-CoV2 infection. Trial registration numberNCT 04412655

Association between early worsening of kidney function and poor outcomes in patients treated with renin angiotensin system inhibitors: A meta‐analysis

As renin angiotensin system inhibitors (RASi) are widely used in the clinic, early worsening of kidney function (EWKF) after RASi therapy deserves attention, as its clinical significance is unknown. The aim was to evaluate the relationship between EWKF and long-term outcomes including all-cause mortality, kidney and cardiovascular events, in all the patients treated with RASi. We searched PubMed, Embase, and the Cochrane databases for controlled trials that compared the outcomes of patients with and without EWKF after RASi treatment. Our primary outcome was all-cause mortality, and secondary outcomes were kidney and cardiovascular events. We pooled data using a random effects model. A total of ten studies were enrolled, of which eight were randomized trials (including 33 454 patients) and two were observational studies (including 148 144 patients). Of the eight randomized trials, 4996 patients with type 2 diabetes, 19 118 with heart failure (HF), and 9340 with atherosclerotic vascular disease and diabetes with end-organ damage. Both observational studies investigated all kinds of patients with initial RASi treatment. In patients with RASi, the EWKF group had a higher risk of all-cause mortality than the no-EWKF group in the randomized studies (n= 13 581; RR, 1.22; 95% CI, 1.04-1.42; P=.02) and in observational studies (n=148 144; OR, 1.70; 95% CI, 1.43-2.01; P < .00001). In patients who experienced EWKF, no statistically significant difference was found between the efficacy of RASi and placebo in all-cause mortality (n=1762; RR, 0.85; 95% CI, 0.68-1.06; P=.14). RASi treatment led to an increased incidence of EWKF which was associated with poorer long-term outcomes. As the benefit of RAS blockade to patients with EWKF was limited, we suggest clinicians use RASi with caution when EWKF occurs.

Impact of renin-angiotensin system inhibitors on mortality during the COVID Pandemic among STEMI patients undergoing mechanical reperfusion: Insight from an international STEMI registry

BackgroundConcerns have been raised on a potential interaction between renin-angiotensin system inhibitors (RASI) and the susceptibility to coronavirus disease 2019 (COVID-19). No data have been so far reported on the prognostic impact of RASI in patients suffering from ST-elevation myocardial infarction (STEMI) during COVID-19 pandemic, which was the aim of the present study. MethodsSTEMI patients treated with primary percutaneous coronary intervention (PPCI) and enrolled in the ISACS-STEMI COVID-19 registry were included in the present sub-analysis and divided according to RASI therapy at admission. ResultsOur population is represented by 6095 patients, of whom 3654 admitted in 2019 and 2441 in 2020. No difference in the prevalence of SARSCoV2 infection was observed according to RASI therapy at admission (2.5% vs 2.1%, p = 0.5), which was associated with a significantly lower mortality (adjusted OR [95% CI]=0.68 [0.51–0.90], P = 0.006), confirmed in the analysis restricted to 2020 (adjusted OR [95% CI]=0.5[0.33–0.74], P = 0.001). Among the 5388 patients in whom data on in-hospital medication were available, in-hospital RASI therapy was associated with a significantly lower mortality (2.1% vs 16.7%, OR [95% CI]=0.11 [0.084–0.14], p < 0.0001), confirmed after adjustment in both periods. Among the 62 SARSCoV-2 positive patients, RASI therapy, both at admission or in-hospital, showed no prognostic effect. ConclusionsThis is the first study to investigate the impact of RASI therapy on the prognosis and SARSCoV2 infection of STEMI patients undergoing PPCI during the COVID-19 pandemic. Both pre-admission and in-hospital RASI were associated with lower mortality. Among SARSCoV2-positive patients, both chronic and in-hospital RASI therapy showed no impact on survival.

Continuation versus discontinuation of renin–angiotensin system inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label trial

BackgroundBiological considerations suggest that renin–angiotensin system inhibitors might influence the severity of COVID-19. We aimed to evaluate whether continuing versus discontinuing renin–angiotensin system inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) affects outcomes in patients admitted to hospital with COVID-19.MethodsThe REPLACE COVID trial was a prospective, randomised, open-label trial done at 20 large referral hospitals in seven countries worldwide. Eligible participants were aged 18 years and older who were admitted to hospital with COVID-19 and were receiving a renin–angiotensin system inhibitor before admission. Individuals with contraindications to continuation or discontinuation of renin–angiotensin system inhibitor therapy were excluded. Participants were randomly assigned (1:1) to continuation or discontinuation of their renin–angiotensin system inhibitor using permuted block randomisation, with allocation concealed using a secure web-based randomisation system. The primary outcome was a global rank score in which participants were ranked across four hierarchical tiers incorporating time to death, duration of mechanical ventilation, time on renal replacement or vasopressor therapy, and multiorgan dysfunction during the hospitalisation. Primary analyses were done in the intention-to-treat population. The REPLACE COVID trial is registered with ClinicalTrials.gov, NCT04338009.FindingsBetween March 31 and Aug 20, 2020, 152 participants were enrolled and randomly assigned to either continue or discontinue renin–angiotensin system inhibitor therapy (continuation group n=75; discontinuation group n=77). Mean age of participants was 62 years (SD 12), 68 (45%) were female, mean body-mass index was 33 kg/m2 (SD 8), and 79 (52%) had diabetes. Compared with discontinuation of renin–angiotensin system inhibitors, continuation had no effect on the global rank score (median rank 73 [IQR 40–110] for continuation vs 81 [38–117] for discontinuation; β-coefficient 8 [95% CI −13 to 29]). There were 16 (21%) of 75 participants in the continuation arm versus 14 (18%) of 77 in the discontinuation arm who required intensive care unit admission or invasive mechanical ventilation, and 11 (15%) of 75 participants in the continuation group versus ten (13%) of 77 in the discontinuation group died. 29 (39%) participants in the continuation group and 28 (36%) participants in the discontinuation group had at least one adverse event (χ2 test of adverse events between treatment groups p=0·77). There was no difference in blood pressure, serum potassium, or creatinine during follow-up across the two groups.InterpretationConsistent with international society recommendations, renin–angiotensin system inhibitors can be safely continued in patients admitted to hospital with COVID-19.FundingREPLACE COVID Investigators, REPLACE COVID Trial Social Fundraising Campaign, and FastGrants.

Stopping Renin-Angiotensin System Inhibitors in Patients with Advanced CKD and Risk of Adverse Outcomes: A Nationwide Study.

It is unknown whether stopping renin-angiotensin system (RAS) inhibitor therapy in patients with advanced CKD affects outcomes. We studied patients referred to nephrologist care, listed on the Swedish Renal Registry during 2007-2017, who developed advanced CKD (eGFR<30 ml/min per 1.73 m2) while on RAS inhibitor therapy. Using target trial emulation techniques on the basis of cloning, censoring, and weighting, we compared the risks of stopping within 6 months and remaining off treatment versus continuing RAS inhibitor therapy. These included risks of subsequent 5-year all-cause mortality, major adverse cardiovascular events, and initiation of kidney replacement therapy (KRT). Of 10,254 prevalent RAS inhibitor users (median age 72 years, 36% female) with new-onset eGFR <30 ml/min per 1.73 m2, 1553 (15%) stopped RAS inhibitor therapy within 6 months. Median eGFR was 23 ml/min per 1.73 m2. Compared with continuing RAS inhibition, stopping this therapy was associated with a higher absolute 5-year risk of death (40.9% versus 54.5%) and major adverse cardiovascular events (47.6% versus 59.5%), but with a lower risk of KRT (36.1% versus 27.9%); these corresponded to absolute risk differences of 13.6 events per 100 patients, 11.9 events per 100 patients, and -8.3 events per 100 patients, respectively. Results were consistent whether patients stopped RAS inhibition at higher or lower eGFR, across prespecified subgroups, after adjustment and stratification for albuminuria and potassium, and when modeling RAS inhibition as a time-dependent exposure using a marginal structural model. In this nationwide observational study of people with advanced CKD, stopping RAS inhibition was associated with higher absolute risks of mortality and major adverse cardiovascular events, but also with a lower absolute risk of initiating KRT.

Comparative Effectiveness of Renin-Angiotensin System Inhibitors and Calcium Channel Blockers in Individuals With Advanced CKD: A Nationwide Observational Cohort Study

It is unknown whether initiating renin-angiotensin system (RAS) inhibitor therapy in patients with advanced chronic kidney disease (CKD) is superior to alternative antihypertensive agents such as calcium channel blockers (CCBs). We compared the risks for kidney replacement therapy (KRT), mortality, and major adverse cardiovascular events (MACE) in patients with advanced CKD in routine nephrology practice who were initiating either RAS inhibitor or CCB therapy. Observational study in the Swedish Renal Registry, 2007 to2017. 2,458 new users of RAS inhibitors and 2,345 CCB users with estimated glomerular filtration rates<30mL/min/1.73m2 (CKD G4-G5 without KRT) who were being followed up by a nephrologist. As a positive control cohort, new users of the same drugs with CKD G3 (estimated glomerular filtration rate, 30-60mL/min/1.73m2) were evaluated. RAS inhibitor versus CCB therapy initiation. Initiation of KRT (maintenance dialysis or transplantation), all-cause mortality, and MACE (composite of cardiovascular death, myocardial infarction, or stroke). HRs with 95% CIs were estimated using propensity score-weighted Cox proportional hazards regression adjusting for demographic, clinical, and laboratory covariates. Median age was 74 years, 38% were women, and median follow-up was 4.1 years. After propensity score weighting, there was significantly lower risk for KRT after new use of RAS inhibitors compared with new use of CCBs (adjusted HR, 0.79 [95% CI, 0.69-0.89]) but similar risks for mortality (adjusted HR, 0.97 [95% CI, 0.88-1.07]) and MACE (adjusted HR, 1.00 [95% CI, 0.88-1.15]). Results were consistent across subgroups and in as-treated analyses. The positive control cohort of patients with CKD G3 showed similar KRT risk reduction (adjusted HR, 0.67 [95% CI, 0.56-0.80]) with RAS inhibitor therapy compared with CCBs. Potential confounding by indication. Our findings provide evidence from real-world clinical practice that initiation of RAS inhibitor therapy compared with CCBs may confer kidney benefits among patients with advanced CKD, with similar cardiovascular protection.

Abstract 12691: Long-term Optimal Medical Therapy for Patients With Mid-range Left Ventricular Ejection Fraction After Acute Myocardial Infarction

Introduction: In the era of the initial optimal interventional and medical therapy for acute myocardial infarction (AMI), a number of patients with mid-range left ventricular ejection fraction (40% &lt;EF&lt;50%) becomes increasing. However, the long-term optimal medical therapy for these patients has been rarely studied. Aims: This observational study aimed to investigate the association between the medical therapy with beta-blockers or inhibitors of renin-angiotensin system (RAS) and clinical outcomes in patients with mid-range EF after AMI. Methods: Among 13,624 patients enrolled in the Korea Acute Myocardial Infarction Registry-National Institute of Health (KAMIR-NIH), propensity-score matched patients who survived the initial attack and had mid-range EF were selected according to beta-blocker or RAS inhibitor therapy at discharge. Results: Patients with beta-blockers showed significantly lower 1-year cardiac death (2.4 vs. 5.2/100 patient-year; hazard ratio [HR] 0.46; 95% confidence interval [CI] 0.22-0.98; P =0.045) and MI (1.7 vs. 4.0/100 patient-year; HR 0.41; 95% CI 0.18-0.95; P =0.037). On the other hand, RAS inhibitors were associated with lower 1-year re-hospitalization due to heart failure (2.8 vs. 5.5/100 patient-year; HR 0.54; 95% CI 0.31-0.92; P =0.024), and no significant interaction with classes of RAS inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) was observed ( P for interaction=0.332). Conclusions: Beta-blockers or RAS inhibitors at discharge were associated with better 1-year clinical outcomes in patients with mid-range EF after AMI.