Risk Of Hyperkalemia In Patients Research Articles

Sulfamethoxazole-Trimethoprim-Induced Hyperkalemia in Hospitalized Patients Using Potassium-Sparing Drugs: An Observational Study.

The objective of this analysis is to investigate the risk of hyperkalemia in hospitalized patients using sulfamethoxazole-trimethoprim (Co-trimoxazole) and a potassium-sparing drug (potassium-sparing diuretic or renin-angiotensin system [RAS]-inhibitor). Researchers conducted a nested case control study within a cohort of hospitalized patients using a potassium-sparing diuretic and/or a RAS-inhibitor from the PHARMO Database Network. Researchers estimated the odds ratios (ORs) and 95% confidence intervals (CI) for the risk of hyperkalemia in patients receiving both Co-trimoxazole and a potassium-sparing drug compared with patients only receiving a potassium-sparing drug. Among a cohort of 25,849 patients, researchers identified 2054 cases of hyperkalemia during hospitalization in patients also using a potassium-sparing drug. Using Co-trimoxazole in addition to a potassium-sparing drug was associated with an increased risk of hyperkalemia in hospitalized patients (ORadj = 1.65, 95% CI 1.26-2.16) compared with using only a potassium-sparing drug. There was a trend of a more pronounced association between hyperkalemia and the co-use of Co-trimoxazole and potassium-sparing drugs in patients with an estimated GFR of 15-29 mL/min (ORadj = 3.15, 95% CI 1.29-7.70). The number needed to harm for hyperkalemia induced by adding Co-trimoxazole to patients receiving a potassium-sparing drug is 19.5. Using the combination of Co-trimoxazole with a potassium-sparing drug in hospitalized patients increases the risk of hyperkalemia compared with using only a potassium-sparing drug. Physicians and other prescribers should be aware of hyperkalemia and routinely monitor serum potassium levels in hospitalized patients using this combination of drugs.

Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone Improves Diastolic Dysfunction in Preclinical Nondiabetic Chronic Kidney Disease.

The mineralocorticoid receptor plays a significant role in the development of chronic kidney disease (CKD) and associated cardiovascular complications. Classic steroidal mineralocorticoid receptor antagonists are a therapeutic option, but their use in the clinic is limited due to the associated risk of hyperkalemia in patients with CKD. Finerenone is a nonsteroidal mineralocorticoid receptor antagonist that has been recently investigated in 2 large phase III clinical trials (FIDELIO-DKD [Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease] and FIGARO-DKD [Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease]), showing reductions in kidney and cardiovascular outcomes. We tested whether finerenone improves renal and cardiac function in a preclinical nondiabetic CKD model. Twelve weeks after 5/6 nephrectomy, the rats showed classic signs of CKD characterized by a reduced glomerular filtration rate and increased kidney weight, associated with left ventricular (LV) diastolic dysfunction and decreased LV perfusion. These changes were associated with increased cardiac fibrosis and reduced endothelial nitric oxide synthase activating phosphorylation (ser 1177). Treatment with finerenone prevented LV diastolic dysfunction and increased LV tissue perfusion associated with a reduction in cardiac fibrosis and increased endothelial nitric oxide synthase phosphorylation. Curative treatment with finerenone improves nondiabetic CKD-related LV diastolic function associated with a reduction in cardiac fibrosis and increased cardiac phosphorylated endothelial nitric oxide synthase independently from changes in kidney function. Short-term finerenone treatment decreased LV end-diastolic pressure volume relationship and increased phosphorylated endothelial nitric oxide synthase and nitric oxide synthase activity. We showed that the nonsteroidal mineralocorticoid receptor antagonist finerenone reduces renal hypertrophy and albuminuria, attenuates cardiac diastolic dysfunction and cardiac fibrosis, and improves cardiac perfusion in a preclinical nondiabetic CKD model.

Risk of hyperkalaemia in patients with type 2 diabetes mellitus prescribed with SGLT2 versus DPP-4 inhibitors.

To investigate the risk of hyperkalaemia in new users of sodium-glucose cotransporter 2 (SGLT2) inhibitors vs. dipeptidyl peptidase-4 (DPP-4) inhibitors among patients with type 2 diabetes mellitus (T2DM). Patients with T2DM who commenced treatment with an SGLT2 or a DPP-4 inhibitor between 2015 and 2019 were collected. A multivariable Cox proportional hazards analysis was applied to compare the risk of central laboratory-determined severe hyperkalaemia, hyperkalaemia, hypokalaemia (serum potassium ≥6.0, ≥5.5, and <3.5mmol/L, respectively), and initiation of a potassium binder in patients newly prescribed an SGLT2 or a DPP-4 inhibitor. A total of 28599 patients (mean age 60±11 years, 60.9% male) were included after 1:2 propensity score matching, of whom 10586 were new users of SGLT2 inhibitors and 18013 of DPP-4 inhibitors. During a 2-year follow-up, severe hyperkalaemia developed in 122 SGLT2 inhibitor users and 325 DPP-4 inhibitor users. Use of SGLT2 inhibitors was associated with a 29% reduction in incident severe hyperkalaemia [hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.58-0.88] compared with DPP-4 inhibitors. Risk of hyperkalaemia (HR 0.81, 95% CI 0.71-0.92) and prescription of a potassium binder (HR 0.74, 95% CI 0.67-0.82) were likewise decreased with SGLT2 inhibitors compared with DPP-4 inhibitors. Occurrence of incident hypokalaemia was nonetheless similar between those prescribed an SGLT2 inhibitor and those prescribed a DPP-4 inhibitor (HR 0.90, 95% CI 0.81-1.01). Our study provides real-world evidence that compared with DPP-4 inhibitors, SGLT2 inhibitors were associated with lower risk of hyperkalaemia and did not increase the incidence of hypokalaemia in patients with T2DM.

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.

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].

Effects of sodium glucose cotransporter 2 inhibitors on the risk of hyperkalemia in patients on mineralocorticoid receptor antagonist: a systematic review and meta-analysis

Abstract Funding Acknowledgements Type of funding sources: None. Background Occurrence of hyperkalemia has been a great limitation in the full implementation of a guideline-directed medical therapy especially in patients with heart failure. Recent developments have exhibited the positive role of SGLT2 inhibitors, not only on the cardiovascular outcomes but also conferred renal protection. Purpose We explored the effects of SGLT2i and MRA combination on the risk of developing hyperkalemia. Methods Randomized controlled trials on SGLT2i versus placebo in patients already on MRA regardless of heart failure status reporting outcomes of potassium homeostasis were searched using Pubmed, CENTRAL, and ScienceDirect. Outcome of interest was the effects on the risk of hyperkalemia. Pooled hazard ratios with 95% confidence intervals were used as effect estimates using fixed-effects model. Results Five studies were included with a total of 11,123 patients. There was a significant reduction on the risk of hyperkalemia in the MRA with SGLT2i group (HR 0.61, 95% CI 0.50-0.75, p&amp;lt;0.00001) compared to MRA without SGLT2i group. Conclusion SGLT2i provides significant risk reduction on the development of hyperkalemia in patients already on a mineralocorticoid receptor antagonist.

Comparison of risk of hyperkalemia between SGLT2 inhibitors and DPP4-inhibitors in patients with type 2 diabetes

Abstract Funding Acknowledgements Type of funding sources: None. Background Hyperkalemia is a common complication and increases the risk of cardiac arrhythmias and mortality in patients with type 2 diabetes (T2DM), especially in those with diabetic nephropathy. We investigated the risk of hyperkalemia in patients initiated on SGLT2 inhibitors versus DPP-4 inhibitors among patients with T2DM. Methods This study included patients with T2DM who initiated on SGLT2 inhibitors or DPP-4 inhibitors between January 01, 2015 and December 31, 2019 from a territory-wide clinical registry in Hong Kong (Clinical Data Analysis and Reporting System [CDARS]). A multivariable cox proportional hazards analysis, adjusting for key confounders, was used to compare the risk of central laboratory-determined hyperkalemia (serum potassium ≥6.0mmol/L) and hypokalemia (serum potassium &amp;lt;3.5mmol/L), respectively, between SGLT2 inhibitors and DPP-4 inhibitors. Results 10193 new users of SGLT2 inhibitors were matched to 17305 new users of DPP-4 inhibitors. During the 2-year follow-up, there were 104 hyperkalemia events (incident rate [IR] = 5.17 per 1000 person-years) among SGLT2 inhibitors and 306 events (IR = 9.09 per 1000 person-years) among DPP-4 inhibitors, of which SGLT2 inhibitors were associated with a lower risk of incident hyperkalemia (Adjusted HR: 0.66 [95%CI 0.53-0.83], p&amp;lt;0.001), compared to DPP-4 inhibitors. The incident hypokalemia was similar between SGLT2 inhibitors and DPP-4 inhibitors (Adjusted HR: 0.91 [95%CI 0.81-1.03], P=0.13). Conclusion SGLT2 inhibitors reduced incident hyperkalemia, but without increasing incident hypokalemia compared to DPP-4 inhibitors.

Trimethoprim-sulfamethoxazole and the risk of a hospital encounter with hyperkalemia: a matched population-based cohort study.

Trimethoprim-sulfamethoxazole (TMP-SMX) can cause hyperkalemia by reducing renal potassium excretion. We assessed the risk of hyperkalemia after initiating TMP-SMX versus amoxicillin and determined if this risk is modified by a patient's baseline kidney function [estimated glomerular filtration rate (eGFR)]. We conducted a population-based cohort study in Ontario, Canada involving adults ≥66years of age newly treated with TMP-SMX (n=58999) matched 1:1 with those newly treated with amoxicillin (2008-2020). The primary outcome was a hospital encounter with hyperkalemia defined by a laboratory serum potassium value ≥5.5mmol/L within 14days of antibiotic treatment. Secondary outcomes included a hospital encounter with acute kidney injury (AKI) and all-cause hospitalization. Risk ratios (RRs) were obtained using a modified Poisson regression. A hospital encounter with hyperkalemia occurred in 269/58999 (0.46%) patients treated with TMP-SMX versus 80/58999 (0.14%) in those treated with amoxicillin {RR 3.36 [95% confidence interval (CI) 2.62-4.31]}. The absolute risk of hyperkalemia in patients treated with TMP-SMX versus amoxicillin increased progressively with decreasing eGFR (risk difference of 0.12% for an eGFR ≥60ml/min/1.73m2, 0.42% for eGFR 45-59, 0.85% for eGFR 30-44 and 1.45% for eGFR <30; additive interaction P<.001). TMP-SMX versus amoxicillin was associated with a higher risk of a hospital encounter with AKI [RR 3.15 (95% CI 2.82-3.51)] and all-cause hospitalization [RR 1.43 (95% CI 1.34-1.53)]. The 14-day risk of a hospital encounter with hyperkalemia was higher in patients newly treated with TMP-SMX versus amoxicillin and the risk was highest in patients with a low eGFR.

Effects of sodium glucose cotransporter 2 inhibitors on the risk of hyperkalemia in patients on mineralocorticoid receptor antagonist: a systematic review and meta-analysis

Abstract Background Occurrence of hyperkalemia has been a great limitation in the full implementation of a guideline-directed medical therapy especially in patients with heart failure. Recent developments have exhibited the positive role of SGLT2 inhibitors, not only on the cardiovascular outcomes but also conferred renal protection. Purpose We explored the effects of SGLT2i and MRA combination on the risk of developing hyperkalemia. Methods Randomized controlled trials on SGLT2i versus placebo in patients already on MRA regardless of heart failure status reporting outcomes of potassium homeostasis were searched using Pubmed, CENTRAL, and ScienceDirect. Outcome of interest was the effects on the risk of hyperkalemia. Pooled hazard ratios with 95% confidence intervals were used as effect estimates using fixed-effects model. Results Four studies were included with a total of 8,996 patients. There was a significant reduction on the risk of hyperkalemia in the MRA with SGLT2i group (HR 0.53, 95% CI 0.39–0.73, p&amp;lt;0.0001) compared to MRA without SGLT2i group. Conclusion SGLT2i provides significant risk reduction on the development of hyperkalemia in patients already on a mineralocorticoid receptor antagonist. Funding Acknowledgement Type of funding sources: None.

Management of hypertension in advanced kidney disease.

The aim of this study was to present recent developments in pharmacotherapy of hypertension in patients with advanced chronic kidney disease (CKD). In the AMBER trial, compared with placebo, the potassium-binder patiromer mitigated the risk of hyperkalaemia and enabled more patients with uncontrolled resistant hypertension and stage 3b/4 CKD to tolerate and continue spironolactone treatment; add-on therapy with spironolactone provoked a clinically meaningful reduction of 11-12 mmHg in unattended automated office SBP over 12 weeks of follow-up. In the BLOCK-CKD trial, the investigational nonsteroidal mineralocorticoid-receptor-antagonist (MRA) KBP-5074 lowered office SBP by 7-10 mmHg relative to placebo at 84 days with a minimal risk of hyperkalaemia in patients with advanced CKD and uncontrolled hypertension. The CLICK trial showed that the thiazide-like diuretic chlorthalidone provoked a placebo-subtracted reduction of 10.5 mmHg in 24-h ambulatory SBP at 12 weeks in patients with stage 4 CKD and poorly controlled hypertension. Enablement of more persistent spironolactone use with newer potassium-binding agents, the clinical development of novel nonsteroidal MRAs with a more favourable benefit-risk profile and the recently proven blood pressure lowering action of chlorthalidone are three therapeutic opportunities for more effective management of hypertension in high-risk patients with advanced CKD.

Lactated Ringer's solution and risk of hyperkalemia in patients with reduced kidney function

BackgroundEmerging evidence supports the superiority of balanced crystalloids such as Lactated Ringer's (LR) compared to normal saline but concerns for the development of hyperkalemia have limited its use. Although LR inherently contains potassium, there exists a paucity of evidence to suggest that LR could potentiate hyperkalemia. To address this, we evaluated the effect of LR on serum potassium in patients with reduced kidney function who are at risk of developing hyperkalemia. MethodsWe conducted a single-center, retrospective cohort-based observational clinical study that included 293 clinical encounters who were hospitalized with an estimated glomerular filtration rate (eGFR) of < 30 ml/min/1.73m2, at the time of hospital admission. Subjects must have received a minimum of 500 ml of LR continuously during the admission. Only those with a minimum of one lab report within 24 hours prior to-, and post-LR administration that reported serum measurements of potassium, glucose, and bicarbonate levels were included. Other potential risk factors for developing hyperkalemia including medication, tube feeds, potassium supplements, and red blood cell transfusion during or within 24 hours after LR administration were recorded. ResultsSerum potassium prior to LR use was highly correlated and predictive of the serum potassium after LR use [P < 0.0001; Odds Ratio 6.77 (3.73 – 12.28)]. Sixteen encounters (5%) developed de-novo hyperkalemia following LR use. No significant positive correlation between the amount of LR administered and the development of hyperkalemia was found. ConclusionsLR use was not independently associated with the development of hyperkalemia in patients with reduced kidney function.

Hyperkalemia as a cause of undertreatment with mineralcorticoid receptor antagonists for patients with newly onset of heart failure with reduced ejection fraction

Abstract Background Despite beneficial effects on mortality and morbidity the use of mineralocorticoid receptor antagonists (MRA) in patients with reduced ejection fraction (&amp;lt;40%) (HFrEF) remains poor. Hyperkalemia is assumed as an important cause, but the reported incidence is low and varies hugely. Thus, available data of magnitude of hyperkalemia in real life settings are insufficient to explain why under-utilization of MRA occurred. Aim To determine the incidence and magnitude of documented hyperkalemia and potential risk of hyperkalemia in patients with HFrEF in a real-world HF population. Methods Patients aged 18–85 years at the time of the baseline, hospitalized for newly onset of HFrEF between 2016–01–01 and 2019–12–31, were identified retrospectively and consecutively from hospital discharge records, by use of international classification of disease (ICD)-10 codes I50.0-I50.9 as principal diagnosis. Potential higher risk of hyperkalemia was based on an overall assessment of current potassium level, presence of diabetes mellitus and eGFR &amp;lt;30 ml/min at patient level. Results In total, 3456 patients with HF were identified, 642 (18.6%) were eligible, hospitalized for newly onset of HFrEF (66.8±12.7 years, 68.4% men and EF 29.4% ±6.8%). After six months 336 (52.3%) did not have MRA of which 279 (83%) never received MRAs and 57 (17%) had MRAs discontinued. Among patients on MRA treatment, 306 (14.4%) needed dose reduction. Occurrence of hypertension, ischemic heart disease, diabetes mellitus and renal dysfunction at baseline did not differ between groups with or without MRA. The incidence and magnitude of documented and potentially higher risk of hyperkalemia were assessed both at baseline and as highest potassium within six months after established diagnosis. Among patients without MRA after six months, at baseline only 3 (0.9%) patients had documented S/P-K ≥6 mmol/L, 7 (2.1%) patients had S/P-K 5.5–5.9 mmol/L and 26 (7.7%) patients had S/P-K 4.8–5.4 mmol/L. Moreover, 12.4% had potentially high risk of hyperkalemia at baseline. During the six-month follow up after initiation of HF therapy, 15 (4.5%) patients had documented hyperkalemia with S/P-K ≥6 mmol/L, 23 (6.8%) patients had S/P-K 5.4–5.9 mmol/L, and 123 (36.6%) patients had S/P-K 4.8–5.4 mmol/L during at least one occasion. Besides, 13.4% had potentially high risk of hyperkalemia. Hyperkalemia occurred frequently (40.4% vs 36.4%) in patients with discontinuation and dose reduction of MRA. Figure 1 presents the distribution of patients with risk of or documented hyperkalemia in the group without MRA. Conclusions Hyperkalemia was the most common cause for both discontinuation and dose reduction of MRA. Hyperkalemia was also increased significantly from baseline and during subsequent up-titration, with 4.6-fold increased risk for borderline hyperkalemia (S/P-K 4.8–5.4). This might explain why physicians refrain from prescribing MRAs to patients with HFrEF. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Vifor Pharma

Moderate potassium lowering effect of exogenous atrial natriuretic peptide in patients with acute heart failure

Background Recent data suggest that the angiotensin receptor neprilysin inhibitor modulates plasma levels of natriuretic peptides and attenuates the risk of hyperkalemia in patients with heart failure (HF). However, the impact of natriuretic peptides on serum electrolyte abnormalities, especially abnormalities in sodium and potassium levels in patients with HF remains unclear.Methods We performed a post-hoc analysis of a multicenter prospective cohort study in 162 patients with acute HF (74.2 ± 13.3 years, 64.2% male, left ventricular ejection fraction 44 ± 15%) treated with intravenous carperitide, an exogenous atrial natriuretic peptide.Results The dose of carperitide was correlated with urine volume (σ = 0.205, p = 0.009), suggesting a significant diuretic effect. During the initial 48 h, serum sodium level remained unchanged both in 53 patients with carperitide alone (from 140 ± 4 to 140 ± 3 mEq/L, p = 0.653) and 109 patients treated with a combination of carperitide and furosemide (141 ± 4 to 141 ± 4 mEq/L, p = 0.644). On the contrary, serum potassium level was decreased both in patients with carperitide alone (from 4.32 ± 0.70 to 4.08 ± 0.47 mEq/L, p = 0.004) and patients treated with a combination of carperitide and furosemide (4.17 ± 0.55 to 3.98 ± 0.47, p < 0.001), with a significant association between urine volume and change in potassium level in patients treated with carperitide alone (σ = -0.313, p = 0.023). The incidence of hypokalemia at 24 h was higher in patients treated with 20 mg furosemide or more (12.5% vs. 2.8%, p = 0.039).Conclusions Serum potassium level decreased after HF treatment with exogenous atrial natriuretic peptide, with a significant correlation to urine volume. The risk of hypokalemia was low, unless treated with additional furosemide.

Effect of high-dose sulfamethoxazole/trimethoprim and glucocorticoid use on hyperkalemic event: A retrospective observational study

IntroductionSulfamethoxazole/trimethoprim causes hyperkalemia; however, the effect of sulfamethoxazole/trimethoprim dose and co-administered glucocorticoids on hyperkalemia has not been clarified. MethodsThis single-center, retrospective, observational cohort, chart review study involving patients (>20 years) who were treated with sulfamethoxazole/trimethoprim was conducted at Tokyo Women's Medical University, Medical Center East from June 2015 to May 2019. Multivariate Cox proportional hazard model was used to identify risk factors for hyperkalemia (serum potassium level > 5.5 mEq/L). Additionally, Kaplan–Meier curve analyzed the cumulative incidence of hyperkalemia focusing on sulfamethoxazole/trimethoprim dose and concomitant use of glucocorticoids with mineralocorticoid activity. ResultsAmong 333 patients, 44 (13%) patients developed hyperkalemia associated with sulfamethoxazole/trimethoprim use for over 49 (interquartile range; 17–233) days. We found associations between the time to hyperkalemia development and sulfamethoxazole/trimethoprim dose (hazard ratio 1.238, 95% confidence interval 1.147–1.338, p < 0.001) and glucocorticoid use (hazard ratio 0.678, 95% confidence interval 0.524–0.877, p = 0.003). Interestingly, the Kaplan–Meier curves revealed that the concomitant use of glucocorticoids did not attenuate the risk of hyperkalemia in patients receiving high-dose sulfamethoxazole/trimethoprim (p = 0.747), whereas concomitant use of glucocorticoids significantly reduced the risk of hyperkalemia in patients receiving non-high dose sulfamethoxazole/trimethoprim (p < 0.001). ConclusionsHigh-dose sulfamethoxazole/trimethoprim is a significant predictor of hyperkalemia. The effect of glucocorticoids on hyperkalemia varies depending on the sulfamethoxazole/trimethoprim dose.

Comparative risk of new‐onset hyperkalemia for antihypertensive drugs in patients with diabetic nephropathy: A Bayesian network meta‐analysis

Several randomised controlled trials (RCTs) have evaluated the risk of hyperkalemia of antihypertensive drugs on diabetic nephropathy, yet the results are conflicting. We searched MEDLINE, Embase, The Cochrane Library, and Web of Science for RCTs investigating the risk of antihypertensive drugs on hyperkalemia in diabetic nephropathy from inception to May 31, 2020. Direct comparative meta-analysis showed that the proportion of patients with hyperkalemia was significantly higher in the ARB, aldosterone antagonist, renin inhibitor group than in the placebo group. Moreover, the risk of hyperkalemia in the ARB group was higher than that in the CCB group. Network meta-analysis showed the risk of hyperkalemia in the ARB, aldosterone antagonist, and renin inhibitor group was higher than in the placebo group, but there was no statistical difference between the CCB, ACEI, β blocker, endothelin inhibitor, and diuretic groups than in the placebo group. The possibility of antihypertensive drugs in risk of hyperkalemia being the worst treatment was aldosterone antagonist (98.8%), followed by ARB (73.8%), renin inhibitor (63.8%), diuretic (53.1%), ACEI (46.9%), β blocker (36.8%), endothelin inhibitor (35.2%), placebo (27.1%), and finally CCB (14.3.1%). Therefore, aldosterone antagonist seems worse than other antihypertensive drugs in the risk of hyperkalemia in patients with diabetic nephropathy.

A Model to Predict Risk of Hyperkalemia in Patients with Chronic Kidney Disease Using a Large Administrative Claims Database.

BackgroundChronic kidney disease (CKD) is responsible for substantial clinical and economic burden. Drugs that inhibit the renin-angiotensin-aldosterone system inhibitors (RAASi) slow CKD progression in many common clinical scenarios. Guideline-directed medical therapy requires maximal recommended doses of RAASi, which clinicians are often reluctant to prescribe because of the associated risk of hyperkalemia (HK).ObjectiveThis study aims to develop and validate a model to identify individuals with CKD at elevated risk for developing HK over a 12-month period on the basis of lab, medical, and pharmacy claims.MethodsUsing claims from a large US healthcare payer, we developed a model to predict the probability of individuals identified with CKD but not HK in 2016 (baseline year [BY]) who developed HK in 2017 (prediction year [PY]). The study population was comprised of members continuously enrolled with medical and pharmacy benefits and CKD (BY). Members were excluded from the analysis if they had HK (by lab results or diagnosis code) or dialysis (BY). Prediction model performance measures included area under the receiver operating characteristic curve (AUROC), calibration, and gain and lift charts.ResultsOf 435,512 members identified with CKD but not HK (BY), 6235 (1.43%) showed incident HK (PY). Compared with individuals without incident HK (PY), these members had a higher comorbidity burden, use of RAASi, and healthcare utilization. The AUROC and calibration analyses showed good predictive accuracy (area under the curve [AUC]=0.843 and calibration). The top 2 HK-prediction deciles identified 75.94% of members who went on to develop HK (PY).ConclusionGuideline-recommended doses of RAASi therapy can be limited by the risk of HK. Novel potassium binders may permit more patients at risk to benefit from these maximal RAASi doses. This predictive model successfully identified the risk of developing HK up to 1 year in advance.

Dapagliflozin reduces the risk of hyperkalaemia in patients with heart failure and reduced ejection fraction: a secondary analysis DAPA-HF

Abstract Background Hyperkalaemia often limits the use of mineralocorticoid receptor antagonists (MRAs) in patients with heart failure and reduced ejection fraction (HFrEF), denying these patients a life-saving therapy. Purpose To determine whether treatment with the sodium-glucose cotransporter 2 (SGLT-2) inhibitor dapagliflozin reduces the risk of hyperkalaemia associated with MRA use in patients with HFrEF. Methods The risk of developing mild hyperkalaemia (potassium &amp;gt;5.5 mmol/L) and moderate/severe hyperkalaemia (&amp;gt;6.0 mmol/L) was examined in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF) according to background MRA use, and randomized treatment assignment, by use of Cox regression analyses. Results Overall, 3370 (70.1%) patients in DAPA-HF were treated with an MRA. Mild hyperkalaemia and moderate/severe hyperkalaemia occurred in 182 (11.1%) and 23 (1.4%) patients treated with dapagliflozin as compared to 204 (12.6%) and 40 (2.4%) of patients given placebo (Table and Figure). This yielded a hazard ratio (HR) of 0.86 (0.70–1.05) for mild hyperkalaemia and 0.50 (0.29, 0.85) for moderate/severe hyperkalaemia, comparing dapagliflozin to placebo. Conclusions Patients with HFrEF and taking a MRA who were randomized to dapagliflozin had half the incidence of moderate/severe hyperkalaemia, compared with those randomized to placebo. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): DAPA-HF study was funded by AstraZeneca

Dapagliflozin Reduces the Risk of Hyperkalaemia in Patients with Heart Failure and Reduced Ejection Fraction: A Secondary Analysis from DAPA-HF

Dapagliflozin Reduces the Risk of Hyperkalaemia in Patients with Heart Failure and Reduced Ejection Fraction: A Secondary Analysis from DAPA-HF

Mineralocorticoid Receptor Antagonists for Hypertension Management in Advanced Chronic Kidney Disease

Spironolactone, a steroidal mineralocorticoid receptor antagonist, is recommended as add-on therapy for treatment-resistant/uncontrolled hypertension. However, caution is advised in patients with advanced chronic kidney disease (CKD) due to an increased risk for hyperkalemia. KBP-5074 is a nonsteroidal mineralocorticoid receptor antagonist under investigation for the treatment of treatment-resistant and uncontrolled hypertension in patients with moderate-to-severe CKD. BLOCK-CKD is a phase 2, international, multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of KBP-5074, on top of current therapy, in patients with stage 3B/4 CKD (estimated glomerular filtration rate ≥15 and ≤44 mL/[min·1.73 m2]) and resistant hypertension (trough cuff seated systolic blood pressure ≥140 mm Hg, despite treatment with maximally tolerated doses of 2 or more antihypertensive medicines with complementary mechanisms). Patients (n=240) will be randomized 1:1:1 to once-daily treatment with KBP-5074 0.25 mg, KBP-5074 0.5 mg, or placebo, stratified by estimated glomerular filtration rate (≥30 versus <30 mL/[min·1.73 m2]) and systolic blood pressure (≥160 versus <160 mm Hg). Approximately 30% of enrolled patients should have an estimated glomerular filtration rate of 15 to 29 mL/(min·1.73 m2). The primary efficacy analysis is the change in trough cuff seated systolic blood pressure from baseline to day 84 for the KBP-5074 doses compared with placebo. Changes in urinary albumin-creatinine ratio will be assessed along with changes in serum potassium/incidence of hyperkalemia and changes in estimated glomerular filtration rate and serum creatinine. BLOCK-CKD will determine whether the addition of KBP-5074 will effectively lower blood pressure without an increased risk of hyperkalemia in patients who are not candidates for steroidal mineralocorticoid receptor antagonists due to advanced CKD. Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT03574363.

P0671THE ASSOCIATION BETWEEN HYPERKALAEMIA RISK AND CARDIOVASCULAR AND RENAL COMORBIDITIES IN A LARGE REAL-WORLD COHORT OF CKD PATIENTS

Abstract Background and Aims Approximately 275.9 million people globally and 5.6 million people in the UK are living with chronic kidney disease (CKD). The risk of hyperkalaemia (HK) is elevated in CKD due to renal impairment and may increase further upon treatment with renin-angiotensin-aldosterone system inhibitors, which are commonly used in many cardiovascular and renal conditions. This study aimed to assess the relationship between comorbidity burden and HK risk in a large cohort of UK CKD patients. Method Primary and secondary care data from the UK Clinical Practice Research Datalink (CPRD) and linked Hospital Episode Statistics (HES) were used to identify patients aged ≥18 years who had a diagnosis of stage 3+ CKD (identified as either a READ code for non-dialysis CKD stage 3+ or an estimated glomerular filtration rate (eGFR) &amp;lt;60 mL/min/1.73m2 without a prior READ code for dialysis) during the study period (2008–June 2018) or the five-year look-back period (2003–2007). Patient’s index date was 1st January 2008 or the first date of CKD diagnosis, whichever occurred later. Diagnoses based on the presence of READ codes were used to define the accumulation of further cardiovascular or renal comorbidities of interest (resistant hypertension, heart failure, diabetes or dialysis-dependent CKD). The incidence of HK was defined as serum potassium (K+) thresholds of ≥5.0, ≥5.5 and ≥6.0 mmol/L. Results In total, 297,702 eligible patients had a CKD diagnosis during the study or look back periods and their mean follow-up was 5.6 (SD 3.2) years from index date. At baseline, mean age was 74.7 (11.3) years, mean body mass index was 28.3 (5.9) kg/m2, and 58.6% of patients were female. CKD was the first diagnosis in 169,532 patients (56.9% of all CKD diagnoses), second diagnosis in 92,651 patients (31.1%), third in 32,606 patients (11.0%) and fourth or fifth in 2,913 patients (1.0%); however, only 11,129 CKD patients (3.74%) developed four or more comorbidities of interest. In total, 1.5% of the cohort (4,544 patients) progressed to dialysis and 29.6% (88,245 patients) died during the study period. In general, the incidence of HK increased with the number of comorbidities of interest (Figure 1). At a K+ threshold of ≥5.0 mmol/L, crude incidence rate of HK was 286.5 (95% CI: 285.2–287.8) per 1,000 patient-years in patients with CKD only; this increased 2.8-fold to 806.8 (741.5–876.4) in patients with five comorbidities of interest. A similar trend was observed at K+ thresholds of ≥5.5 mmol/L and ≥6.0 mmol/L. A 5.9 fold increase was observed in crude incidence rate of HK (from 59.7 [59.1–60.3] with CKD only, to 350.3 [307.7–397.1] with all five comorbidities) at a threshold of ≥5.5 mmol/L and a 10.6-fold increase (from 9.1 [8.9–9.4] to 96.2 [74.6–122.2]) at the ≥6.0 mmol/L threshold. Conclusion This assessment of a large real-world patient cohort showed that the risk of HK in patients with CKD increases with the number of cardiovascular or renal comorbidities. Emphasis should be put on effective prevention and treatment of HK in CKD, especially in patients with high comorbidity burden.