Risk Of Hyperkalemia Research Articles

Molecular pharmacology of mineralocorticoid receptor antagonists: The role of co-regulators

Mineralocorticoid receptor (MR) antagonists have shown remarkable benefits in the treatment of cardiovascular disease. However, their underutilization in clinical practice may be attributed to concerns regarding the risk of hyperkalemia. An ideal selective MR modulator would inhibit the detrimental effects of MR in non-epithelial cells of the cardiovascular system while sparing its physiological function in kidney epithelial cells, thereby reducing the risk of adverse events. To address this issue, a new generation of non-steroidal MR antagonists, including esaxereneone, balcinrenone, ocedurenone, and finerenone, has been developed with distinct molecular structures and pharmacology. They share a mechanism of action that is different from the previously developed steroidal MR antagonists, leading to altered co-regulator interaction, potentially involving conformational changes of the receptor. Interfering with MR co-regulator interaction or the co-regulator itself may enable selective targeting of downstream signaling cascades and – in the long term – lead to more personalized medicine.In this review article, we summarize what is currently known about the mechanisms of action of the different MR antagonists with a focus on MR co-factor interaction and what may be inferred from this for future developments.

Liver Disease Is a Risk Factor for Recurrent Hyperkalemia: A Retrospective Cohort Study.

Liver disease is often associated with dysfunctional potassium homeostasis but is not a well-established risk factor for hyperkalemia. This retrospective cohort study examined the potential relationship between liver disease and recurrent hyperkalemia. Patients with ≥1 serum potassium measurement between January 2004 and December 2018 who experienced hyperkalemia (serum potassium >5.0 mmol/L) were identified from the United States Veterans Affairs database. A competing risk regression model was used to analyze the relationship between patient characteristics and recurrent hyperkalemia. Of 1,493,539 patients with incident hyperkalemia, 71,790 (4.8%) had liver disease (one inpatient or two outpatient records) within 1 year before the index hyperkalemia event. Recurrent hyperkalemia within 1 year after the index event occurred in 234,807 patients (15.7%) overall, 19,518 (27.2%) with liver disease, and 215,289 (15.1%) without liver disease. The risk of recurrent hyperkalemia was significantly increased in patients with liver disease versus those without (subhazard ratio, 1.34; 95% confidence interval, 1.32-1.37; p < 0.0001). Aside from vasodilator therapy, the risk of recurrent hyperkalemia was not increased with concomitant medication. In this cohort study, liver disease was an independent risk factor strongly associated with recurrent hyperkalemia within 1 year, independent of concomitant renin-angiotensin-aldosterone system inhibitor or potassium-sparing diuretic use.

Outcomes of primary total joint arthroplasty in patients with a history of solid organ transplantation, a single institution analysis

Background: An increasing number of patients with a history of solid organ transplantation (SOT) are presenting for total joint arthroplasty (TJA). The primary aim of this study is to evaluate clinical outcomes after primary total joint arthroplasty in patients with a history of SOT compared to matched controls. Methods: We performed a review of prospectively collected data on consecutive adult patients with a history of SOT undergoing TJA from January 2014 to January 2021. Pearson-Chi square tests were used to compare differences in baseline demographics and clinical characteristics between SOT and matched controls. Multi-variate logistic regression analyses were used to assess whether patients who had a prior SOT were at higher risk of experiencing post-operative complications, readmissions, reoperations, longer length of stay and non-home discharges after primary TJA. Results: A total of 81 operations met inclusion criteria which were compared to 82 age matched controls without a history of SOT. Patients with a history of SOT were more likely to require a hospitalization greater than 2 days compared to the control group (n=63, 77.8% vs. n=16, 19.5%; P=0.011), had an increased risk of hyperkalemia (n=15, 18.5% vs. n=1, 1.2%; P=0.049), and any post-operative complication (n=55, 67.9% vs. n=21, 25.6%; P=0.025). Conclusions: Despite the increased risk of acute post-operative complications and longer hospital stays, primary TJA has been shown to be a safe and effective option for treatment of DJD or AVN in patients with a history of SOT when completed via a multi-disciplinary approach. Level of Evidence: Retrospective Analysis, Level IV.

MRAs may have lost their cornerstone position for heart failure treatment in the age of SGLT-2 inhibitors: A meta-analysis of randomized controlled trials.

Mineralocorticoid receptor antagonists (MRAs) are a cornerstone drug class for heart failure therapy. Several clinical studies have demonstrated its role in heart failure therapy. However, due to the recommendation of sodium-glucose cotransporter-2 (SGLT-2) inhibitors for the treatment of heart failure, there is a lack of sufficient evidence regarding whether MRAs can continue to play a cornerstone role in heart failure treatment. A meta-analysis was performed on subgroups of the DAPA-HF and EMPEROR-Reduced trials. Using trial-level data, we performed a meta-analysis to assess the effects of SGLT-2 inhibitors and MRAs on various clinical endpoints of heart failure. The incidence of cardiovascular-related death or heart failure hospitalization was the primary outcome. In addition, we assessed cardiovascular death, all-cause death, heart failure hospitalization, renal outcomes, and hyperkalemia. This study has already been registered with PROSPERO, CRD42022385023. Compared with SGLT-2 inhibitor monotherapy, combined treatment did not demonstrate more significant advantages in terms of heart failure or cardiovascular death (RR = 1.00; 95% CI: 0.78-1.28), cardiovascular death (RR = 0.96; 95% CI: 0.61-1.52), heart failure hospitalization (RR = 0.92; 95% CI: 0.79-1.07), all-cause death (RR = 1.00; 95% CI: 0.63-1.59) and composite kidney endpoint (RR = 0.85; 95% CI: 0.49-1.46). Moreover, in comparison to SGLT-2 inhibitors, combined therapy increased the risk of moderate-severe hyperkalemia (blood potassium > 6.0mmol/l) (RR = 4.13; 95% CI: 2.23-7.65). In patients with HFrEF who have started MRAs treatment, the addition of an SGLT-2 inhibitor provides significant clinical benefit. However, the addition of MRAs to SGLT-2 inhibitors to treat heart failure is not essential.

Response to "Plant-based diets and postprandial hyperkalemia".

Diet therapy for hyperkalemia in people with chronic kidney disease (CKD) has shifted considerably in recent years with the observations that reported potassium intake is weakly, or not at all, associated with plasma potassium levels in this population. One of the lingering debates is whether dietary potassium presents a risk of hyperkalemia in the postprandial state. Although there is general agreement about the need for additional research, the commentary by Varshney et al contends that the available research sufficiently demonstrates that high-potassium plant foods do not pose a risk of postprandial hyperkalemia. Others argue that this remains unsettled science. Although the traditional approach of providing people with CKD lists of high-potassium foods to limit or avoid may be unnecessary, those at high risk of hyperkalemia should be encouraged to consume balanced meals and control portions, at least until some of the key research gaps in this area are resolved. This editorial critiques the analyses offered by Varshney et al and explains the rationale for a more cautious approach to care.

Plant-based diets and postprandial hyperkalemia.

This Letter to the Editor is a response to St-Jules and Fouque and their interpretation of postprandial hyperkalemia, especially regarding plant-based diets. Based on the reviewed literature review, potassium kinetic studies cited by the authors include only 1 study with a food-based intervention that actually showed reduced postprandial hyperkalemia with plant-based diets. The remainder of the studies used potassium salts or supplements that behave differently compared with whole plant foods. As such, we recommend avoiding restriction of whole plant foods in patients with chronic kidney disease when solely based on the theoretical risk of postprandial hyperkalemia.

Mineralocorticoid receptor antagonist use in chronic kidney disease with type 2 diabetes: a clinical practice document by the European Renal Best Practice (ERBP) board of the European Renal Association (ERA).

Chronic kidney disease (CKD) in individuals with type 2 diabetes (T2D) represents a major public health issue; it develops in about 30%-40% of patients with diabetes mellitus and is the most common cause of CKD worldwide. Patients with CKD and T2D are at high risk of both developing kidney failure and of cardiovascular events. Renin-angiotensin system (RAS) blockers were considered the cornerstone of treatment of albuminuric CKD in T2D for more than 20 years. However, the residual risk of progression to more advanced CKD stages under RAS blockade remains high, while in major studies with these agents in patients with CKD and T2D no significant reductions in cardiovascular events and mortality were evident. Steroidal mineralocorticoid receptor antagonists (MRAs) are known to reduce albuminuria in individuals on RAS monotherapy, but their wide clinical use has been curtailed by the significant risk of hyperkalemia and absence of trials with hard renal outcomes. In recent years, non-steroidal MRAs have received increasing interest due to their better pharmacologic profile. Finerenone, the first compound of this class, was shown to effectively reduce the progression of kidney disease and of cardiovascular outcomes in participants with T2D in phase 3 trials. This clinical practice document prepared from a task force of the European Renal Best Practice board summarizes current knowledge on the role of MRAs in the treatment of CKD in T2D aiming to support clinicians in decision-making and everyday management of patients with this condition.

#3068 POTASSIUM LEVELS AND EGFR DO NOT PREDICT SEVERE HYPERKALEMIA FOLLOWING SPIRONOLACTONE INTRODUCTION IN PATIENTS WITH CKD AT HIGH RISK OF HYPERKALEMIA

Abstract Background and Aims Mineralocorticoid receptor antagonists (MRA) reduce blood pressure, albuminuria and the rate of disease progression in patients with chronic kidney disease (CKD) and albuminuria. Despite these apparent benefits, only a very small fraction of patients with CKD are treated with an MRA. This may in part be due to the fear of hyperkalemia (HK), which in the most severe cases can cause life-threatening arrythmias. Indeed, international guidelines and previous studies have excluded patients believed to be at high risk of severe HK from treatment with MRA including patients with pre-existing high serum potassium. To examine if the risk of HK can in fact be predicted by baseline potassium levels or eGFR, we performed a clinical study testing the effect of introducing spironolactone on plasma potassium (P-K) levels in closely monitored, high-risk patients excluded from other studies. Secondly, we analyzed the effect of spironolactone on eGFR and albuminuria. Method We included patients with eGFR 25-60 ml/min/1.73 m2 on maximal tolerated RAAS-blockade (ACEi or ARB) and a history of at least two HK-episodes (P-K &amp;gt; 4.5mmol/l) within 24 months prior to inclusion. Following dietary counselling on avoidance of potassium-rich foods, spironolactone was initiated at 25 mg daily. If tolerated as defined by a decline in eGFR &amp;lt; 30%, a P-K ≤ 5.5mmol/l and the absence of severe hypotension, the dose was increased to 50 mg after two weeks. Total follow-up was four weeks measuring P-K, eGFR, blood pressure and spot urine albumin creatinine ratio. Results from maximal tolerated dose were compared to baseline using paired t-test. In a post-hoc analysis, patients were grouped based on the occurrence of severe HK (P-K &amp;gt; 5.5mmol/l) or not, and baseline characteristics and the change from baseline to maximal dose were compared using unpaired t-test. Linear regression model was used to test the association between baseline P-K vs. P-K at maximal dose of spironolactone and the change in P-K from baseline to maximal dose of spironolactone vs. baseline eGFR. Results Fifty-eight patients were included with a mean age of 65 years. Forty-seven were males and 23 had diabetes. Forty-eight patients reached a spironolactone dose of 50 mg. Following spironolactone introduction, mean eGFR declined from 39 at baseline to 34ml/min/1.73 m2 (p&amp;lt;0.001) and albuminuria was reduced from a median of 1276mg/g to 654 mg/g (49%; 95%CI: 44 – 54%) with no significant change in blood pressure. Mean P-K increased 0.5mmol/l (95% CI 0.3 - 0.7mmol/l) from 4.7mmol/l to 5.2mmol/l. Seventeen patients developed severe HK with a P-K &amp;gt; 5.5mmol/l and four were briefly admitted with a P-K &amp;gt; 6.2mmol/l. Importantly, there was no difference in baseline P-K nor eGFR in patients that developed severe HK when compared with those that did not (4.70 vs 4.67 mmol/L, p = 0.83 and 36.2 vs. 40.1 ml/min/1.73 m2, p = 0,13). Furthermore, baseline P-K did not correlate with P-K at maximum spironolactone dose (Figure 1) and the change in P-K did not significantly correlate with baseline eGFR (Figure 2). Conclusion Short-term treatment with spironolactone in patients with CKD at high risk of HK leads to similar reductions in albuminuria and eGFR when compared with low-risk cohorts. With dietary counseling, 30% of patients will develop severe HK within 4 weeks. Importantly and contrary to common belief, neither baseline P-K levels nor baseline eGFR were associated with the development of severe HK. Thus, excluding patients from MRA treatment based solely on eGFR and P-K levels is not appropriate. Instead, we believe an empirical approach based on dietary counseling and close monitoring of P-K should be used.

#5603 HYPERKALAEMIA MAY LIMIT POTENTIAL RENAL INTERVENTIONS IN PATIENTS WITH LOW GFR AND SIGNIFICANT PROTEINURIA

Abstract Background and Aims Evidence-based therapies including ACE inhibitors, ARBs and mineralocorticoid receptor antagonists (MRA) can significantly delay progression of CKD, yet their use is potentially limited by hyperkalaemia risk. In this study, we describe hyperkalaemia events among CKD patients to provide a better understanding of the current unmet need. Method This was a retrospective secondary data analysis from electronic medical records (EMR) in the US TriNetX analytics data CKD subset from Jan 2015-Dec 2019. Patients with ≥1 uACR measure were included, whereby the first date of the uACR measure was considered the index date. The study cohort included patients aged &amp;gt; 18 years with a) two consecutive estimated glomerular filtration rate (eGFR) values between 20 and 90 mL/min/1.73m2 recorded 91–730 days apart prior to the index date, or, b) at least one CKD diagnosis code before the index date. Patient demographics, ACE/ARB, MRA and SGLT2i treatments on index were described. The frequency of HK (defined as serum potassium &amp;gt;5.5 mmol/L or a diagnosis code) during a 1-year baseline period and 1-year follow-up period was described by uACR (&amp;gt;700mg/g, 300–700mg/g, &amp;lt;300mg/g) and eGFR (&amp;lt;20mL/min/1.73m2, 20–45mL/min/1.73m2, 45–60mL/min/1.73m2, 60–90mL/min/1.73m2 and &amp;gt;90mL/min/1.73m2) categories. Results Baseline characteristics of the included patients are described in the table below. During the 1-year follow-up period, HK events were more frequently recorded for patients with uACR&amp;gt;700mg/g (15.3%), eGFR&amp;lt;60ml/min/1.73m2 (9.3%) and combined uACR&amp;gt;700mg/g and eGFR&amp;lt;60ml/min/&amp;lt;1.73m2 (18.3%). Conclusion The preliminary results of this analysis shows that HK occurs more frequently among patients with low eGFR and/or high uACR. Despite guidelines, uACR testing is not done frequently in clinical practice and likely performed more frequently among patients with high uACR. Further analyses and more conservative study definitions will be applied to more comprehensively clarify the unmet need among patients at risk of HK. Of particular interest are the patients who discontinued RAASi treatment after a hyperkalemia event during baseline and were not on renoprotective treatment, yet who had recurrent hyperkalemia. Adequate treatment options for these patients are currently limited, and there is a need for more renoprotective treatments with limited hyperkalemia risk.

#5214 RENAL TOLERABILITY OF SGLT-2 INHIBITORS COMBINING WITH RENIN-ANGIOTENSIN SYSTEM BLOCKERS AND MINERALOCORTICOID RECEPTOR ANTAGONISTS IN CKD

Abstract Background and aims Recently the sodium glucose cotransporter-2 (SGLT-2) inhibitors combining with angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor II blocker (ARBs) or angiotensin-receptor neprilysin inhibitor (ARNI)) and mineralocorticoid receptor antagonist (MRA) ((triple therapy (TT)), would help prevent further progression of renal and cardiovascular (CV) endpoints including progression of end-stage kidney disease (ESKD). The degree to which data on TT initiation and discontinuation in cronic kidney disease (CKD) patients can be generalized to patients in real-world practice is unclear. Aims to evaluate renal tolerability to the TT at target doses as well as clinical incidents and dosage adjustments. To analyze the risk factors for TT discontinuation. Method A retrospective cohort study was carried out in patients ≥18 years old with chronic kidney disease (CKD) treated with TT in Rey Juan Carlos Hospital between January 2019 to December 2022. The collected clinical data included age, gender, associated morbidities, serum creatinine (Scr), estimated glomerular filtration rate (eGFR), potassium, sodium levels, dose adjustments before administration of TT and in the first year of follow up. Multivariate logistic models were performed to evaluate the risk factors to dosage adjusted and discontinuation of TT. Results Among 104 patients treated with TT were included. Medium age was 69 years old (range, 37-91). Most of them were men, 78% (81). The main cause to initiate TT was cardiorenal syndrome 59% (61). Before to initiate TT, in 35% patients the treatment was adjusted. The main modification was reduced or discontinuation of diuretics (loop or thiazide) therapy 23% (24/104). In the first year of follow up, in 69 patients (66%) it was necessary dosage adjustments, being the reduced of MRA (spironolactone and eplerenone) the main modification treatment 38% (26/69). The major cause of dose adjustment was developed of acute kidney injury (AKI) in 43 patients (41%). According to KDIGO criteria, 38 patients (88%) reached stage 1; 4 patients (9%) stage 2 and 1 case (2%) stage 3. The independent risk factor associated with dosage adjustment were AKI development (OR: 28.57; 95% CI 6.04-134.4; P = 0.0001) adjusted by sex and age. Despite the dosage adjustment and titers, in 29 patients (28%) TT was discontinued in a median time of 4 months (IQR 2–11) after its initiation. The risk factor associated with TT discontinuation were AKI developed (P = 0,003) and eGFR at the 12 months of follow up (P = 0,01). There were no significant excess risks of symptomatic hypotension, volume depletion, and hyperkalemia after a year of follow up. Conclusions The renal tolerability of use to triple therapy in chronic kidney disease appears to be low. The AKI development was the main risk factor of dosage adjustment and discontinuation of TT. Its necessary to clarify which is the best way to maximizing renal tolerability in this complex groups of patients. The use of early combination therapy requires careful assessment. Its important to find strategies to guide clinicians about the steps and challenges to improving overall use of triple therapy tolerability and dosage adjustment.

#3318 PHASE II DOSE-SELECTION, RANDOMISED DOUBLE-BLIND TRIAL OF THE ASI, BI 690517, ALONE AND IN COMBINATION WITH EMPA IN PEOPLE WITH CKD

Abstract Background and Aims Elevated aldosterone levels are associated with chronic kidney disease (CKD) progression and adverse kidney and cardiovascular disease outcomes. Therapy with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) improves clinical outcomes, yet elevated aldosterone levels often persist. BI 690517 is a first-in-class, selective aldosterone synthase inhibitor (ASi) that may reduce deleterious mineralocorticoid receptor-dependent and -independent actions of aldosterone. Coadministration of BI 690517 with a sodium–glucose cotransporter-2 inhibitor could mitigate the risk of hyperkalaemia. This study is investigating the efficacy and safety of three doses of BI 690517, alone and in combination with empagliflozin (EMPA), on top of an ACEi or ARB, for treatment of CKD with or without type 2 diabetes. Method A randomised, double-blind, placebo-controlled, parallel-dose Phase II trial (NCT05182840) in adults with or without type 2 diabetes who had an estimated glomerular filtration rate (eGFR) ≥30 and &amp;lt;90 mL/min/1.73 m2, urine albumin:creatinine ratio (UACR) ≥200 and &amp;lt;5000 mg/g, and serum potassium ≤4.8 mmol/L on stable background therapy with an ACEi or ARB. After an 8-week run-in period to assigned background therapy (EMPA 10 mg or matched placebo randomised 1:1), participants were randomised 1:1:1:1 to BI 690517 (low, medium or high dose) or matched placebo for 14 weeks. Primary outcome was the change in UACR measured in a first morning void (UACRFMV) from baseline to Week 14. Secondary outcomes were the proportion of participants with ≥15 and 30% decreases in UACRFMV. Safety outcomes and changes in eGFR and serum potassium were also evaluated. Results Recruitment is complete, with 1719 participants from 168 sites in 29 countries screened. In total, 714 were randomised and entered the run-in period (last randomisation on 30 December 2022). The trial is currently ongoing; data on baseline characteristics will become available and shared. Conclusion This study will provide key data on the potential synergistic kidney-protective effects and safety of combination therapy with BI 690517 plus EMPA, as well as data on monotherapy, for CKD with or without type 2 diabetes. Findings will inform BI 690517 dose selection for further clinical trial development.

The association between dual RAAS inhibition and risk of acute kidney injury and hyperkalemia in patients with diabetic kidney disease: a systematic review and meta-analysis.

Dual renin-angiotensin-aldosterone system (RAAS) blockade involves dual therapy with a combination of angiotensin-converting enzyme inhibitors (ACEis), angiotensin receptor blockers (ARBs), direct renin inhibitors (DRIs) or mineralocorticoid receptor antagonists (MRAs). It is hypothesized that dual RAAS blockade would result in a more complete inhibition of the RAAS cascade. However, large clinical trials on dual RAAS inhibition have shown increased risk of acute kidney injury (AKI) and hyperkalemia without additional benefit on mortality, cardiovascular events, or CKD progression compared to RAAS inhibitor monotherapy in patients with diabetic kidney disease (DKD). The development of newer, more selective non-steroidal MRAs as cardiorenal protective therapies has created a new opportunity for dual RAAS inhibition. We conducted a systematic review and meta-analysis of the risks of AKI and hyperkalemia with dual RAAS blockade in patients with DKD. This is a systematic review and meta-analysis of the randomized controlled trials (RCT) published from 2006 to May 30, 2022. Study population included adult patients with DKD receiving dual RAAS blockade. A total of 31 RCTs and 33048 patients were included in the systematic review. Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using random effects. There were 208 AKI events in 2690 patients on ACEi+ARB versus 170 in 4264 patients with ACEi or ARB monotherapy (pooled RR 1.48, 95% CI: 1.23-1.39). There were 304 hyperkalemia events in 2818 patients on ACEi+ARB versus 208 in 4396 patients with ACEi or ARB monotherapy (pooled RR 1.97, 95% CI: 1.32-2.94). A non-steroidal MRA+ACEi or ARB showed no increase in the risk of AKI (pooled RR 0.97, 95% CI: 0.81-1.16) compared to ACEi or ARB monotherapy but had a 2-fold higher risk of hyperkalemia with 953 events in 7837 patients in dual therapy versus 454 events in 6895 patients in monotherapy (pooled RR 2.05, 95% CI: 1.84-2.28). A steroidal MRA+ACEi or ARB had a 5-fold higher risk of hyperkalemia with 28 events in 245 at risk in dual therapy versus 5 events in 248 at risk in monotherapy (pooled RR 5.42 95% CI: 2.15-13.67). Dual therapy with RAASi is associated with an increased risk of AKI and hyperkalemia compared to RAASi monotherapy. Conversely, dual therapy with RAAS inhibitors and non-steroidal MRAs have no additional risk of AKI but a similar risk of hyperkalemia, which is lower than dual therapy with RAAS inhibitors and steroidal MRAs.

The Efficacy and Safety of Patiromer for Heart Failure Patients: A Systematic Review and Meta-Analysis.

To evaluate the efficacy and safety of patiromer, a novel potassium binder, in reducing the risk of hyperkalemia in patients with heart failure and optimizing their RAASi therapy. Systematic review and meta-analyses. The authors conducted a systematic search in Pubmed, Embase, Web of Science, and Cochrane Library for randomized controlled trials investigating the efficacy and safety of patiromer in heart failure patients from inception to 31 January 2023 and updated on 25 March 2023. The primary outcome was the association between the reduction of hyperkalemia and patiromer compared with placebo, and the secondary outcome was the association between optimization of RAASi therapy and patiromer. A total of four randomized controlled trials (n = 1163) were included in the study. Patiromer was able to reduce the risk of hyperkalemia in heart failure patients by 44% (RR 0.56, 95% CI 0.36 to 0.87; I2 = 61.9%), improve tolerance to target doses of MRA in patients with heart failure (RR 1.15, 95% CI 1.02 to 1.30; I2 = 49.4%), and decrease the proportion of all-cause discontinuation of RAASi (RR 0.49, 95% CI 0.25 to 0.98; I2 = 48.4%). However, patiromer therapy was associated with an increased risk of hypokalemia (RR 1.51, 95% CI 1.07 to 2.12; I2 = 0%), while no other statistically significant adverse events were observed. Patiromer appears to have a considerable effect on reducing the incidence of hyperkalemia in heart failure patients and on optimizing the therapy of RAASi in those patients.

Amlodipine: risk of hyperkalaemia

Amlodipine: risk of hyperkalaemia

EPH43 Potential Association of Remdesivir and Hyperkalemia: A Disproportionality Analysis in USFDA Adverse Event Reporting System Database

Signal detection is one of the most advanced and promising techniques in the world of pharmacovigilance. Remdesivir is approved for emergency use by the US Food and Drug Administration (FDA) for patients with coronavirus disease 2019 (COVID-19). Its benefit- risk ratio is still being explored because data in the field are rather scant. On the other hand hyperkalemia is a potentially life-threatening electrolyte disorder. Severe hyperkalemia can occur suddenly and can cause life-threatening heart rhythm changes (arrhythmia) that cause a heart attack. Even mild hyperkalemia can cause heart related problems over time if not treated. To evaluate the potential association of Remdesivir with risk of Hyperkalemia by analyzing the spontaneous reports through disproportionality analysis. Data were obtained from the public release of data in FAERS. Case/non-case method was adopted for the analysis of association between Remdesivir use and Hyperkalemia. The data-mining algorithm used for the analysis were Reporting Odds Ratio(ROR) and Proportional Reporting Ratio (PRR). A value of ROR-1.96SE>, PRR≥2 were considered as positive signal. A total of 7 DE’s associated with Remdesivir use and hyperkalemia were reported. The mean age of the patients of Remdesivir associated events was found to be 75 years [95% CI]. The reports by gender were distributed with a male to female ratio of 3:1, though gender was not revealed in 3 reports. The data mining algorithms exhibited positive signal for hyperkalemia (PRR: 2.349, ROR: 2.354) upon analysis as those were well above the pre-set threshold. Three case reports were identified which strengthened these findings and highlighted the importance of laboratory parameters for the early detection of hyperkalemia The current study found a potential risk of hyperkalemia with the use of Remdesivir and there is an urgent need to thoroughly investigate the same and take the necessary action to avoid or minimize the risk.

Influence of SGLT2i and RAASi and Their Combination on Risk of Hyperkalemia in DKD: A Network Meta-Analysis.

This network meta-analysis investigated the effect of various combined regimens of sodium-glucose cotransporter-2 inhibitors (SGLT2is) and renin-angiotensin-aldosterone system inhibitors (RAASis) on the occurrence of hyperkalemia in diabetic kidney disease. The risk of hyperkalemia was compared using the random-effects model of network meta-analysis, with results expressed as odds ratios (ORs) with 95% confidence intervals (CIs). The comparative effects of all medications and their combinations with placebo were ranked using the surface under the cumulative ranking probabilities. In total, 27 eligible studies involving 43,589 participants with diabetic kidney disease were included. Major findings showed that the use of mineralocorticoid receptor antagonists (MRAs) on top of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) prominently increased hyperkalemia incidence when compared with placebo (OR, 6.08; 95% CI, 2.30 to 16.08), ACEI (OR, 3.07; 95% CI, 1.14 to 8.31), ARB (OR, 2.57; 95% CI, 1.10 to 6.02), SGLT2i (OR, 9.22; 95% CI, 2.99 to 28.46), renin inhibitors+ACEI/ARB (OR, 2.23; 95% CI, 1.14 to 4.36), or SGLT2i+ACEI/ARB (OR, 4.10; 95% CI, 2.32 to 7.26). Subgroup analysis among different generations of MRA found that spironolactone had the strongest effect in combination with ACEI/ARB, even higher than the combined use of ACEI and ARB (OR, 2.89; 95% CI, 1.26 to 6.63). In addition, SGLT2i had a significantly lower incidence of hyperkalemia compared with ACEI (OR, 0.33; 95% CI, 0.12 to 0.91), ARB (OR, 0.28; 95% CI, 0.13 to 0.61), dual RAASi (ACEI combined with ARB; OR, 0.17; 95% CI, 0.06 to 0.47), or MRA or renin inhibitors combined with ACEI/ARB (OR, 0.11; 95% CI, 0.04 to 0.33; OR, 0.24; 95% CI, 0.08 to 0.76, respectively). Moreover, adding SGLT2i to the combination of MRA and ACEI/ARB, as well as the combinations of different RAASis, markedly reduced the occurrence of hyperkalemia. Among the therapeutic drugs with the potential risk of increasing serum potassium in patients with diabetic kidney disease, MRA added an extra risk of hyperkalemia while SGLT2i had the opposite effect and could even reverse the elevation of serum potassium caused by the combined regimen, including MRAs.

The efficacy and safety of sacubitril/valsartan in chronic kidney disease: a systematic review and meta-analysis.

Sacubitril/valsartan, a new pharmacological class of angiotensin receptor neprilysin inhibitor, is beneficial to heart failure through blocking the degradation of natriuretic peptides and inhibiting renin-angiotensin-aldosterone system (RAAS) activation which also relate to the pathophysiologic mechanisms of chronic kidney disease (CKD). However, its effects on CKD remain unclear. To assess the efficacy and safety of sacubitril/valsartan for patients with CKD, we performed this meta-analysis. The Embase, PubMed and the Cochrane Library were searched for randomized controlled trials (RCTs) that compared sacubitril/valsartan with ACEI/ARBs in patients with CKD whose estimated glomerular filtration rate (eGFR) was below 60mL/min/1.73m2. We adopted the Cochrane Collaboration tool for assessing the risk of bias. The effect size was estimated using the odds ratio (OR) with 95% confidence interval (CI). Six trials with a total of 6217 patients with CKD were included. In terms of cardiovascular events, sacubitril/valsartan attenuated the risk of cardiovascular death or heart failure hospitalization (OR: 0.68, 95% CI 0.61-0.76, P < 0.00001, I2 = 43%). With respect to renal function, sacubitril/valsartan prevented the incidence of serum creatinine (Scr) elevation among patients with CKD (OR: 0.79, 95% CI 0.67-0.95, P = 0.01, I2 = 0%). Subgroup analysis about eGFR demonstrated that with long follow-up, sacubitril/valsartan significantly decreased the number of patients with more than 50% reduction in eGFR compared with ACEI/ARBs (OR: 0.52, 95% CI 0.32-0.84, P = 0.008, I2 = 9%). In patients with CKD, the incidence of end-stage renal disease (ESRD) was reduced with sacubitril/valsartan treatment, despite no statistically significant difference between the two groups (OR: 0.59, 95% CI 0.29-1.20, P = 0.14, I2 = 0%). As for the safety, we found that sacubitril/valsartan was associated with the occurrence of hypotension (OR: 1.71, 95% CI 1.15-2.56, P = 0.008, I2 = 51%). However, there was no trend towards increasing the risk of hyperkalemia in patients who received sacubitril/valsartan (OR: 1.09, 95% CI 0.75-1.60, P = 0.64, I2 = 64%). This meta-analysis indicated that sacubitril/valsartan improved renal function and conferred effective cardiovascular benefits in patients with CKD, without serious safety issues being observed. Thus, sacubitril/valsartan may be a promising option for patients with CKD. Certainly, further large-scale randomized controlled trials are needed to confirm these conclusions. [ https://inplasy.com/inplasy-2022-4-0045/ ], identifier [INPLASY202240045].

Safety and efficacy of new potassium binders on hyperkalemia management in patients with heart failure: a systematic review and meta-analysis of randomized controlled trials.

Hyperkalemia leads to suboptimal use of evidence-based therapies in patients with heart failure (HF). Therefore, we aimed to assess whether new potassium binders are effective and safe to promote medical optimization in patients with HF. MEDLINE, Cochrane, and Embase were searched for randomized controlled trials (RCTs) that reported outcomes after initiation of Patiromer or Sodium Zirconium Cyclosilicate (SZC) versus placebo in patients with HF at high risk of hyperkalemia development. Risk ratios (RR) with 95% confidence intervals (CI) were pooled with a random effects model. Quality assessment and risk of bias were performed according to Cochrane recommendations. A total of 1432 patients from 6 RCTs were included, of whom 737 (51.5%) patients received potassium binders. In patients with HF, potassium binders increased the use of renin-angiotensin-aldosterone inhibitors (RR 1.14; 95% CI 1.02-1.28; p = 0.021; I2 = 44%) and reduced the risk of hyperkalemia (RR 0.66; 95% CI 0.52-0.84; p < 0.001; I2 = 46%). The risk of hypokalemia was significantly increased in patients treated with potassium binders (RR 5.61; 95% CI 1.49-21.08; p = 0.011; I2 = 0%). There was no difference between groups in all-cause mortality rates (RR 1.13; 95% CI 0.59-2.16; p = 0.721; I2 = 0%) or in adverse events leading to drug discontinuation (RR 1.08; 95% CI 0.60-1.93; p = 0.801; I2 = 0%). The use of new potassium binders Patiromer or SZC in patients with HF at risk for hyperkalemia increased the rates of medical therapy optimization with renin-angiotensin-aldosterone inhibitors and reduced the incidence of hyperkalemia, at the cost of an increased prevalence of hypokalemia.

Meta-analysis on the effectiveness of SGLT2 inhibitors in heart failure

Abstract Funding Acknowledgements Type of funding sources: None. Aims We aimed to carry out a meta-analysis on the effectiveness of sodium-glucose co transporter 2 (SGLT2) inhibitors in heart failure patients (HF) with preserved and reduced ejection fraction. Methods and results From their inception till September 2022, MEDLINE, Scopus, Cochrane CENTRAL, and ClinicalTrials.gov were searched for placebo-controlled randomized controlled trials of SGLT2 inhibitors. Randomized controlled studies were chosen if they included HF patients and reported at least one of the predetermined outcomes. A random effects model was used to pool hazard ratios (HRs) or risk ratios together with the appropriate 95% confidence intervals. There were fourteen trials in total, with 42409 HF patients participating (N = 21678 in the SGLT2 inhibitor arms and N = 20731 in the placebo arms). In the overall HF cohort, SGLT2 inhibitors significantly reduced the composite of first HF hospitalization or cardiovascular death [HR: 0.75 (0.71–0.79); P &amp;lt;0.001; I2 = 0%]. Also resulted in a significant reduction in total hospitalizations for heart failure [HR: 0.70 (0.66–0.75); P &amp;lt; 0.001; I2 = 0%] and reduced the occurrence of cardiovascular death [HR: 0.86 (0.81–0.92); P &amp;lt; 0.001; I2 = 43%]. Sub-group analysis was conducted to based on HF status at baseline, ejection fraction, diabetes status at baseline, and gender. SGLT2 inhibitors significantly reduced the composite heart failure hospitalization and cardiovascular death for all the subgroups except for patients with HFpEF at baseline [HR: 0.87 (0.74–1.03); P = 0.11; I2 = 60%] and no diabetes status at baseline [HR: 0.92 (0.73–1.16); P = 0.50; I2 = 78%]. SGLT2 inhibitors seemed to have no risk of hypovolaemia, hyperkalaemia, or hypotension when compared to the placebo. Conclusions In patients with HF, SGLT2 inhibitors substantially increase cardiovascular outcomes, including all-cause and cardiovascular mortality. In this meta-analysis, SGLT2 inhibitors did not show reduction in composite heart failure in patients with heart failure with preserved ejection fraction (HFpEF) at baseline.

Dose- and time-dependent renoprotection of Angelica sinensis in patients with chronic kidney disease: A longitudinal cohort study.

Background: Based on their anti-oxidative and anti-fibrotic properties, Angelica sinensis (Oliv.) Diels roots [Apiaceae; Radix Angelicae sinensis] (Danggui [abbreviated as S in the context]), Astragalus membranaceus (Fisch.) Bunge [Fabaceae; Astragalus membranaceus] (Huangqi [A]), Rheum palmatum L. [Polygonaceae; Rheum palmatum] (Dahuang [R]), and Salvia miltiorrhiza Bunge [Lamiaceae; Salvia miltiorrhiza Bunge radix et rhizoma] (Danshen [D]) are potential renoprotective Chinese herbal medicines (CHMs). Renoprotection using ARD alone for the treatment of chronic kidney disease (CKD) has been documented in pre-clinical, clinical, and meta-analysis research; however, only pre-clinical data are available for the use of S alone. Moreover, with an increasing number of CKD patients taking prescribed CHMs, hyperkalemia risk remains unclear. Methods: This study retrospectively analyzed national health insurance claims data in 2001-2017. Propensity score matching was used to analyze renal and survival outcomes and the dose-response effects of S without ARD use in 18,348 new S users, 9,174 new ARD users, and 36,696 non-users. Cox proportional hazard regression was used to investigate adjusted hazard ratios (aHRs) for end-stage renal disease (ESRD) in the presence of competing mortality and death. The additive effect of the S herb in single form to compounds was also analyzed. Additionally, to analyze hyperkalemia risk, an exact match on each covariate was used to include 42,265 new CHM users and non-users, while Poisson regression was used to estimate adjusted incidence rate ratios (aIRRs) of hyperkalemia of prescribed CHMs. Results: S users and ARD users were associated with aHRs of 0.77 (95% confidence interval; 0.69-0.86) and 1.04 (0.91-1.19), respectively, for ESRD and 0.55 (0.53-0.57) and 0.71 (0.67-0.75), respectively, for death. The renal and survival benefits of S use were consistent in several sensitivity analyses. The dose- and time-dependent renoprotection and dose-dependent survival benefits were observed for S use. The top two additive renoprotective collocations of the S herb in compounds were Xue-Fu-Zhu-Yu-Tang and Shen-Tong-Zhu-Yu-Tang, followed by Shu-Jing-Huo-Xue-Tang and Shen-Tong-Zhu-Yu-Tang. Moreover, CHM users were associated with aIRRs of 0.34 (0.31-0.37) for hyperkalemia. Conclusion: This study suggests dose- and time-dependent renoprotection and dose-dependent survival benefits of the S herb in compounds and no increased hyperkalemia risk of the prescribed CHMs in CKD patients.