sacubitril and Hyperkalemia

While it is well known that angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARBs) increase the risk of acute renal failure, the role of neprilysin inhibition (NEPi) is unclear and some physicians are reluctant to prescribe sacubitril/valsartan because of safety concerns. This meta-analysis aimed to examine the risk for renal events, progression of chronic kidney disease (CKD) or progression to dialysis on combined NEPi and ACEi/ARBs compared with ACEi or ARBs.. We performed a systematic meta-analysis including 17 randomized controlled trials (study drug sacubitril/valsartan or omapatrilat), involving a total of 23 569 patients, after searching PubMed, Cochrane, ClinicalTrials.org and Embase for eligible studies. From the included trials, all renal endpoints, including long- and short-term outcomes and hyperkalemia, were extracted. Pooled odds ratios (ORs) were calculated using the DerSimonian and Laird method. The study was registered at PROSPERO.. Overall, treatment with sacubitril/valsartan or omapatrilat showed a slightly lower risk of any renal event [OR 0.82 (0.7-0.97)] compared with treatment with an ACEi or ARB alone. Also, there was a decreased risk of severe acute renal events [OR 0.8 (0.69-0.93)] and a decrease in estimated glomerular filtration rate decline [mean difference -0.58 mL/min (-0.83 to -0.33 mL/min)]. There was no difference in chronic renal events [OR 0.92 (0.8-1.05)] or hyperkalemia [OR 1.02 (0.84-1.23)].. NEPi + ACEi/ARBs are safe in terms of renal adverse events. Longer trials focusing on CKD are needed to evaluate the effect of NEPi on decreasing progression of CKD.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Humans; Hyperkalemia; Neprilysin; Randomized Controlled Trials as Topic; Renal Dialysis; Renal Insufficiency, Chronic; Valsartan

Hypertension is a leading cause of cardiovascular disease and chronic kidney disease, resulting in premature death and disability. The Renin-Angiotensin-Aldosterone System (RAAS) blockers, including Angiotensin-Converting Enzyme (ACE) inhibitors or Angiotensin Receptor Blockers (ARBs), are used as first-line antihypertensive therapy to treat hypertensive patients with comorbidities, including diabetes, ischemic heart disease, heart failure, and chronic kidney disease. The use of RAS blockers is associated with the risks, such as hyperkalemia, angioedema, etc. The drugs potentiating them interact pharmacodynamically, resulting in adverse consequences. This review article focuses on the clinically important drug interactions of RAAS blockers.. The electronic databases, such as Medline/PubMed Central/PubMed, Google Scholar, ScienceDirect, Cochrane Library, Directory of Open Access Journals (DOAJ), Embase, and reference lists were searched to identify relevant articles.. The risk of hyperkalemia may be enhanced potentially in patients receiving a RAS blocker and potassium-sparing diuretics, potassium supplements, trimethoprim, adrenergic betablockers, antifungal agents, calcineurin inhibitors, pentamidine, heparins or an NSAID, concomitantly. The patients taking ACE inhibitors and mTOR inhibitors, DPP4 inhibitors, alteplase, or sacubitril/valsartan concurrently may be at increased risk of developing angioedema.. Clinicians, pharmacists, and other healthcare practitioners should be accountable for medication safety. To avoid adverse implications, prescribers and pharmacists must be aware of the drugs that interact with RAAS blockers.

Topics: Angioedema; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Drug Interactions; Humans; Hyperkalemia; Hypertension; Potassium; Renal Insufficiency, Chronic; Renin-Angiotensin System

In PARADIGM-HF, sacubitril/valsartan showed a significant reduction in mortality and hospitalization for patients with heart failure with reduced ejection fraction. Despite proven efficacy, sacubitril/valsartan has moderate uptake in clinical practice. This study explores the safety profile of sacubitril/valsartan by comparing adverse events in RCT and real-world use.. We studied hypotension, renal dysfunction, hyperkalemia, and angioedema associated with sacubitril/valsartan in RCTs and pharmacovigilance databases. A random-effects meta-analysis was performed with six RCTs investigating sacubitril/valsartan vs. control/comparators in heart failure patients. WHO's VigiBase, FAERS, and EMA's EudraVigilance were mined to obtain spontaneously reported real-world adverse events. Disproportionality analysis was performed with the FDA's OpenVigil 2.0.. Six RCTs enrolled 15,538 patients with heart failure with reduced and preserved ejection fractions. There was no statistical difference for the composite of hypotension, renal dysfunction, hyperkalemia, and angioedema between sacubitril/valsartan and its comparators viz. ACEi or ARBs (OR 1.23, CI 0.98-1.56; p = 0.08). A total of 103,038 adverse events were registered in the spontaneous reporting systems. Hypotension was the most reported adverse event. Proportions of composite adverse events were 20% in VigiBase, 17% in FAERS, and 39% with EudraVigilance. Disproportionality analysis showed a lower risk of adverse events with sacubitril/valsartan than other guideline-directed heart failure medications used in clinical practice.. With increased uptake of sacubitril/valsartan, risks of hypotension, renal dysfunction, hyperkalemia, and angioedema appear low and acceptable in RCTs and global clinical practice.

Topics: Aminobutyrates; Angioedema; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Biphenyl Compounds; Drug Combinations; Heart Failure; Humans; Hyperkalemia; Hypotension; Kidney Diseases; Pharmacovigilance; Randomized Controlled Trials as Topic; Stroke Volume; Tetrazoles; Treatment Outcome; Valsartan

Angiotensin receptor blocker and a neprilysin inhibitor (ARNI) has emerged as an innovative therapy for patients of heart failure with reduced ejection fraction (HFrEF). The purpose of this study was to assess the safety and tolerability of Sacubitril/Valsartan in patient with HFrEF in Pakistani population.. This proof-of-concept, open label non-randomized clinical trial was conducted at a tertiary care cardiac center of Karachi, Pakistan. Patients with HFrEF were prescribed with Sacubitril/Valsartan and followed for 12 weeks for the assessment of safety and tolerability. Safety measures included incidence of hypotension, renal dysfunction, hyperkalemia, and angioedema.. Among the 120 HFrEF patients, majority were male (79.2%) with means age of 52.73 ± 12.23 years. At the end of 12 weeks, four (3.3%) patients died and eight (6.7%) dropped out of the study. In the remaining 108 patients, 80.6% (87) of the patients were tolerant to the prescribed dose. Functional class improved gradually with 75.0% (81) in class I and 24.1% (26) in class II, and only one (0.9%) patient in class III at the end of 12 weeks. Hyperkalemia remains the main safety concern with incidence rate of 21.3% (23) followed by hypotension in 19.4% (21), and renal dysfunction in 3.7% (4) of the patients.. Sacubitril/Valsartan therapy in HFrEF patients is safe and moderately tolerated among the Pakistani population. It can be used as first line of treatment for these patients.. NCT05387967. Registered 24 May 2022-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT05387967.

Topics: Adult; Aminobutyrates; Angiotensin Receptor Antagonists; Biphenyl Compounds; Female; Heart Failure; Humans; Hyperkalemia; Hypotension; Kidney Diseases; Male; Middle Aged; Stroke Volume; Tetrazoles; Treatment Outcome; Valsartan; Ventricular Dysfunction, Left

We assessed a subset of the 5040 patients in VICTORIA receiving sacubitril/valsartan, either at randomization (n = 731) or post-randomization drop-in use (n = 425), to evaluate the relationship between the efficacy and safety of combination therapy with vericiguat.. The efficacy of vericiguat on the primary composite endpoint, heart failure (HF) hospitalization, and all-cause mortality was assessed. Safety outcomes included symptomatic hypotension, syncope, worsening renal function, and hyperkalaemia. At randomization, 731 patients received sacubitril/valsartan; they were more frequently from Western Europe or North America, had lower ejection fraction and systolic blood pressure, and more use of triple background HF therapy (65.9% vs. 58.6%), biventricular pacemakers (17.9% vs. 14.1%), or implantable cardioverter defibrillators (42.3% vs. 25.3%). For patients on versus not on sacubitril/valsartan at randomization, adjusted hazard ratios (95% confidence intervals) for vericiguat's treatment effect on the primary composite outcome, cardiovascular death, and HF hospitalization were 0.92 (0.71-1.19) versus 0.89 (0.80-0.98), 0.71 (0.45-1.12) versus 0.95 (0.82-1.11), and 0.98 (0.74-1.29) versus 0.87 (0.78-0.98), respectively. No significant interaction existed between sacubitril/valsartan and vericiguat's treatment effect (p-values for interaction: 0.81, 0.23 and 0.47, respectively). Post-randomization, more drop-in sacubitril/valsartan use occurred in those assigned to placebo (n = 238) versus vericiguat (n = 187) (p = 0.007). Symptomatic hypotension (21.0% vs. 23.1%; p = 0.41), renal dysfunction (29.9% vs. 31.9%; p = 0.50), and hyperkalaemia (10.3% vs. 7.9%; p = 0.20) in patients receiving sacubitril/valsartan (n = 992) for ≥3 months were not different by treatment arm.. Concomitant use of sacubitril/valsartan for at least 3 months did not alter the efficacy of vericiguat and was similarly safe and tolerated in both study arms. Sacubitril/valsartan was initiated more frequently after randomization in patients assigned to placebo versus vericiguat.. ClinicalTrials.gov NCT02861534.

Topics: Aminobutyrates; Biphenyl Compounds; Drug Combinations; Heart Failure; Heterocyclic Compounds, 2-Ring; Humans; Hyperkalemia; Hypotension; Pyrimidines; Stroke Volume; Treatment Outcome; Valsartan; Ventricular Dysfunction, Left

As a first-line therapy, sacubitril/valsartan (S/V) plays a significant role in the treatment of heart failure. However, its effect on renal function is still uncertain. We searched PubMed, EMBASE, the Cochrane Library, and Clinical Trials for randomized controlled trials to evaluate the effect of S/V on renal function in patients. The results are reported as the mean difference, relative ratio, and 95% confidence intervals. A total of 13 randomized controlled trials were included (19,367 patients). Among them, 11 studies focused on patients with heart failure, 1 on patients with acute myocardial infarction, and 1 on patients with chronic kidney disease. We found that fewer worsening renal function events, elevated creatine level events, and severe hyperkalemia events (blood potassium >6.0 mmol/L) occurred in the S/V group than those in the renin-angiotensin-aldosterone system inhibitor (RASi) group. The estimated glomerular filtration rate decreased in both the S/V group and the RASi group, but the change was more obvious in the RASi group. There was no significant difference in hyperkalemia events (blood potassium >5.5 mmol/L) between the 2 groups. Subgroup analysis showed that with the extension of follow-up time (>6 months), worsening renal function events occurred less frequently in the S/V group than in the RASi group. Existing evidence has shown that S/V is superior to RASi in general renal safety. Perhaps with the prolongation of treatment time, the advantages of S/V are more obvious.

Topics: Angiotensin Receptor Antagonists; Biphenyl Compounds; Drug Combinations; Enzyme Inhibitors; Heart Failure; Humans; Hyperkalemia; Kidney; Potassium; Randomized Controlled Trials as Topic; Stroke Volume; Tetrazoles; Valsartan

Hyperkalaemia frequently leads to interruption and discontinuation of neurohormonal antagonists, which may worsen heart failure prognosis. Some studies suggested that sodium-glucose cotransporter 2 inhibitors reduce hyperkalaemia, an effect that may have important clinical implications. This analysis evaluates the effect of empagliflozin on the occurrence of hyper- and hypokalaemia in HF.. EMPEROR-Pooled (i.e. EMPEROR-Reduced and EMPEROR-Preserved combined) included 9583 patients with available serum potassium levels at baseline (98.6% of the total EMPEROR-Pooled population, n = 9718). Hyperkalaemia was identified by investigators' reports of adverse events, and by a laboratory serum potassium value above 5.5 mmol/L and 6.0 mmol/L. The main outcome was a composite of investigator-reported hyperkalaemia or initiation of potassium binders. Patients with high potassium at baseline were more frequently diagnosed with diabetes and ischaemic HF aetiology and had lower left ventricular ejection fraction and estimated glomerular filtration rate but were more frequently treated with sacubitril/valsartan or mineralocorticoid receptor antagonists. Empagliflozin (compared with placebo) reduced the composite of investigator-reported hyperkalaemia or initiation of potassium binders [6.5% vs. 7.7%, hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.71-0.95, P = 0.01]. Empagliflozin reduced hyperkalaemia rates regardless of the definition used (serum potassium >5.5 mmol/l: 8.6% vs. 9.9%, HR 0.85, 95% CI 0.74-0.97, P = 0.017; serum potassium >6.0 mmol/l: 1.9% vs. 2.9%, HR 0.62, 95% CI 0.48-0.81, P < 0.001). The incidence of hypokalaemia (investigator-reported or serum potassium <3.0 mmol/l) was not significantly increased with empagliflozin.. Empagliflozin reduced the incidence of hyperkalaemia without significant increase in hypokalaemia.

Topics: Aminobutyrates; Benzhydryl Compounds; Biphenyl Compounds; Glucosides; Heart Failure; Humans; Hyperkalemia; Hypokalemia; Potassium; Stroke Volume; Ventricular Function, Left