A population-based cohort defined risk of hyperkalemia after initiating SGLT-2 inhibitors, GLP1 receptor agonists or DPP-4 inhibitors to patients with chronic kidney disease and type 2 diabetes.

Hyperkalemia is a common adverse event in patients with chronic kidney disease (CKD) and type 2 diabetes and limits the use of guideline-recommended therapies such as renin-angiotensin system inhibitors. Here, we evaluated the comparative effects of sodium-glucose cotransporter-2 inhibitors (SGLT-2i), glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i) on the risk of hyperkalemia. We conducted a population-based active-comparator, new-user cohort study using claims data from Medicare and two large United States commercial insurance databases (April 2013-April 2022). People with CKD stages 3-4 and type 2 diabetes who newly initiated SGLT-2i vs. DPP-4i (141671 patients), GLP-1RA vs. DPP-4i (159545 patients) and SGLT-2i vs. GLP-1RA (93033 patients) were included. The primary outcome was hyperkalemia diagnosed in inpatient or outpatient settings. Secondary outcomes included hyperkalemia diagnosed in inpatient or emergency department setting, and serum potassium levels of 5.5 mmol/L or more. Pooled hazard ratios and rate differences were estimated after propensity score matching to adjust for over 140 potential confounders. Initiation of SGLT-2i was associated with a lower risk of hyperkalemia compared with DPP-4i (hazard ratio 0.74; 95% confidence interval 0.68-0.80) and contrasted to GLP-1RA (0.92; 0.86-0.99). Compared with DPP-4i, GLP-1RA were also associated with a lower risk of hyperkalemia (0.80; 0.75-0.86). Corresponding absolute rate differences/1000 person-years were -24.8 (95% confidence interval -31.8 to -17.7), -5.0 (-10.9 to 0.8), and -17.7 (-23.4 to -12.1), respectively. Similar findings were observed for the secondary outcomes, among subgroups, and across single agents within the SGLT-2i and GLP-1RA classes. Thus, SGLT-2i and GLP-1RA are associated with a lower risk of hyperkalemia than DPP-4i in patients with CKD and type 2 diabetes, further supporting the use of these drugs in this population.

Impact of Sodium Zirconium Cyclosilicate Plus Renin-Angiotensin-Aldosterone System Inhibitor Therapy on Short-Term Medical Costs in Hyperkalemia: OPTIMIZE II Real-World Study.

INTRODUCTION: Patients receiving cardiorenal-protective renin-angiotensin-aldosterone system inhibitors (RAASis) are at increased risk of developing hyperkalemia, which is associated with increased medical costs. The aim of this study was to evaluate the impact of adding sodium zirconium cyclosilicate (SZC) therapy on 3-month medical costs in patients who experienced hyperkalemia while receiving RAASi therapy. METHODS: The retrospective OPTIMIZE II study used medical and pharmacy claims data from IQVIA PharMetrics® Plus. Patients aged ≥ 18 years who received SZC (≥ 60 day supply over 3 months' follow-up) and continued RAASi between July 2019 and December 2021 (Continue RAASi + SZC cohort) were 1:1 exact and propensity score matched with patients who discontinued RAASi after hyperkalemia diagnosis and did not receive SZC (Discontinue RAASi + no SZC cohort). The primary outcome was hyperkalemia-related medical costs to payers over 3 months; all-cause medical and pharmacy costs were also analyzed. RESULTS: In the Continue RAASi + SZC (n = 467) versus Discontinue RAASi + no SZC (n = 467) cohort, there were significant reductions in mean per-patient hyperkalemia-related medical costs (reduction of $2216.07; p = 0.01) and all-cause medical costs (reduction of $6102.43; p < 0.001); mean hyperkalemia-related inpatient medical costs and all-cause inpatient and emergency department medical costs were significantly reduced. The reduction in all-cause medical cost in the Continue RAASi + SZC cohort offset an increase in the mean per-patient all-cause pharmacy cost (increase of $3117.71; p < 0.001). CONCLUSION: RAASi therapy has well-established cardiorenal benefits. In OPTIMIZE II, management of RAASi-induced hyperkalemia with SZC was associated with lower hyperkalemia-related and all-cause medical costs than RAASi discontinuation without SZC, demonstrating medical cost savings with maintaining RAASi therapy with SZC.

Comparative Safety and Effectiveness of Aldosterone Antagonists Versus Beta-Blockers as Fourth Agents in Patients With Apparent Resistant Hypertension.

BACKGROUND: Limited evidence exists regarding long-term effectiveness and safety of aldosterone antagonists (AAs) versus beta blockers (BBs) as fourth-line antihypertensive agents in patients with resistant hypertension (RH). We evaluated the comparative effectiveness and safety of aldosterone AA versus BB. METHODS: We conducted a real-world retrospective cohort study using IBM MarketScan commercial claims and Medicare Supplemental claims (2007-2019). Patients with RH entered the cohort (ie, index date) when they newly initiated either AA or BB. The effectiveness outcome was major adverse cardiovascular events. Safety outcomes were hyperkalemia, gynecomastia, and kidney function deterioration. Potential confounding was addressed by adjustment for baseline characteristics via stabilized inverse probability of treatment weighting (SIPTW) based on propensity scores. Cox proportional hazards regression with SIPTWs were used to estimate adjusted hazard ratio (aHR) and 95% CI comparing risk for outcomes between AA and BB groups. RESULTS: We identified 80 598 patients with RH (mean age: 61 years, 51% males), of which 6626 initiated AA and 73 972 initiated BB as the fourth antihypertensive agent. Among patients with RH, initiation of AA as a fourth-line antihypertensive agent did not significantly reduce major adverse cardiovascular event risk relative to BB initiation (aHR, 0.77 [95% CI, 0.50-1.19]) but did substantially increase the risk of hyperkalemia (aHR, 3.86 [95% CI, 2.78-5.34]), gynecomastia (aHR, 9.51 [95% CI, 5.69-15.89]), and kidney function deterioration (aHR, 1.63 [95% CI, 1.34-1.99]). CONCLUSIONS: Long-term clinical trials powered to assess major adverse cardiovascular events are necessary to understand the risk-benefit trade-off of AA as fourth-line therapy for RH.

Rates of Spironolactone Initiation and Subsequent Hyperkalemia Hospitalizations in Patients with Heart Failure with Preserved Ejection Fraction Following the TOPCAT trial: A Cohort Study of Medicare Beneficiaries.

BACKGROUND: The impact of the TOPCAT trial publication on spironolactone initiation and subsequent hospitalizations for hyperkalemia among patients with heart failure with preserved ejection fraction (HFpEF) has not been evaluated empirically. METHODS AND RESULTS: We designed a cohort study using US Medicare fee-for-service data. Annual cohorts of patients with HFpEF from 2013 to 2018 were identified based on a validated claims-based phenotyping model. We determined spironolactone initiation in each annual cohort overall and within subgroups with hyperkalemia risk factors of baseline renin-angiotensin system inhibitors use, chronic kidney disease, and diabetes. We reported incidence rates of hospitalization for hyperkalemia within 6 months of treatment initiation. A total of 621,171 patients with HFpEF (mean age 80 ± 8 years, 62.9% female) were included. We identified 40,241 initiations of spironolactone with initiation rate/100 person-years of 16.8 (95% confidence interval [CI] 16.4-17.1) in 2013 and increasing to 19.9 (95% CI 19.4-20.5) in 2018. Among initiators, we identified a total of 164 hyperkalemia hospitalization with stable incidence rates per 1000 person-years between 2013 (12.0, 95% CI 8.8-16.1) and 2018 (10.6, 95% CI 6.2-17.0). These results were consistent for all subgroups. CONCLUSIONS: After the dissemination of TOPCAT findings, we noted a steady increase in the initiation of spironolactone, but not in hyperkalemia hospitalizations.

A Chronology for the Identification and Disclosure of Adverse Effects of Succinylcholine.

BACKGROUND: New therapies are created to address specific problems and enjoy popularity as they enter widespread clinical use. Broader use can reveal unknown adverse effects and impact the life cycle significantly. Succinylcholine, a depolarizing neuromuscular blocker, was the product of decades of research surrounding the ancient compound, curare. It was introduced into practice in the 1950s by Burroughs Wellcome and Company (BW Co) and was welcomed due to its rapidly acting muscle relaxation effects. Global clinical use revealed adverse effects, both minor and major, in particular, hyperkalemia and malignant hyperthermia. We investigated when practitioners and the manufacturer became aware of these adverse effects, how information about these side effects was disseminated, and whether the manufacturer met the regulatory requirements of the time, specifically regarding the timely reporting of adverse effects. SOURCES: Primary literature search using online and archived documents was conducted at the Wood Library-Museum of Anesthesiology, Schaumburg, IL. We consulted documents submitted by BW Co to federal authorities, through the Freedom of Information Act (FOIA), Food and Drug Administration (FDA) reports, promotional advertisements, package inserts, published articles, and textbooks. RESULTS: Initial clinical testing in humans in 1952 found no adverse effects on cardiovascular or respiratory systems. Fasciculations and myalgia were early side effects described in case reports in 1952. Large-scale clinical trials in 1953 found abnormally long recovery times among some patients; the discovery of abnormal pseudocholinesterase enzyme activity was not fully demonstrated until the early 1960s. Bradycardia was first reported in 1957 in children, and in 1959 in adults. In 1960, animal studies reported a transient increase in plasma potassium; further experiments in 1969 clearly demonstrated succinylcholine-induced hyperkalemia in burn patients. Malignant hyperthermia was first described in 1966. Similar cases of elevated temperatures and muscle rigidity were described globally but the underlying mechanism was not elucidated until the 1990s. Standard anesthesia textbooks did not report major side effects of succinylcholine until 1960 and included newly documented side effects with each edition. BW Co's packaging contained warnings as early as the 1950s but were later updated in 1962 and beyond to reflect the newly discovered hyperkalemia and malignant hyperthermia. CONCLUSION: Particularly given the regulatory environment of the time, BW Co appropriately reported the adverse effects of succinylcholine after market entry; it updated promotional and packaging material in a timely manner to reflect newly discovered adverse effects. The toxicity, though alarming and put clinicians on alert, did not seem to heavily impact succinylcholine's use, given its various desirable properties. It is still a choice muscle relaxant used today, although there are efforts to develop superior agents to replace succinylcholine.

Effects of pharmacist participation in chronic kidney disease (CKD) network and CKD manual distribution on drug-related kidney injury.

PURPOSE: Renin-angiotensin system (RAS) inhibitors carry a risk of normotensive ischemic acute kidney injury in dehydration and concurrent nonsteroidal anti-inflammatory drug (NSAID) use. Although the estimated number of patients with chronic kidney disease (CKD) is 20 000, Fujieda, Japan, has only three nephrologists. On 25 March 2016, we reorganized the CKD network to include pharmacists and distributed a CKD manual. We assessed effects of pharmacist participation in the CKD network and CKD manual distribution on patient hospitalizations because of drug-related kidney injury. METHODS: Changes in the prevalence of RAS inhibitor-related estimated glomerular filtration rate (eGFR) declines of greater than or equal to 30% and hyperkalemia of greater than or equal to 6.0 mEq/L in 129 hospitalized CKD patients, drug prescriptions of 14 150 hospitalized patients, and annual medical checkup data in 36 042 citizens were investigated before and after pharmacist participation. RESULTS: After pharmacist participation, patient hospitalizations due to RAS inhibitor-related eGFR declines decreased (71.4% to 38.1%, P = .03) and hyperkalemia declined (38.1% to 9.5%, P = .03). Pharmacist participation influenced the decrease in RAS inhibitor-related eGFR declines (P = .03). NSAID prescriptions decreased (13.4% to 11.8%, P = .003) and acetaminophen prescriptions increased (6.6% to 8.0%, P = .002) among 14 150 hospitalized patients, whereas RAS inhibitor prescriptions decreased (43.2% to 39.4%, P = .002) among 6930 hospitalized patients with eGFR less than 60 mL/min/1.73 m2 . A significant number of citizens shifted from CKD stage G3a-3b to G1-2. CONCLUSIONS: Pharmacist participation in the CKD network and CKD manual distribution decreased both hospitalizations due to RAS inhibitor-related kidney injury and citizens with CKD stage G3a-3b.

The value of maintaining normokalaemia and enabling RAASi therapy in chronic kidney disease.

BACKGROUND: People with chronic kidney disease (CKD) are at an increased risk of developing hyperkalaemia due to their declining kidney function. In addition, these patients are often required to reduce or discontinue guideline-recommended renin-angiotensin-aldosterone system inhibitor (RAASi) therapy due to increased risk of hyperkalaemia. This original research developed a model to quantify the health and economic benefits of maintaining normokalaemia and enabling optimal RAASi therapy in patients with CKD. METHODS: A patient-level simulation model was designed to fully characterise the natural history of CKD over a lifetime horizon, and predict the associations between serum potassium levels, RAASi use and long-term outcomes based on published literature. The clinical and economic benefits of maintaining sustained potassium levels and therefore avoiding RAASi discontinuation in CKD patients were demonstrated using illustrative, sensitivity and scenario analyses. RESULTS: Internal and external validation exercises confirmed the predictive capability of the model. Sustained potassium management and ongoing RAASi therapy were associated with longer life expectancy (+ 2.36 years), delayed onset of end stage renal disease (+ 5.4 years), quality-adjusted life-year gains (+ 1.02 QALYs), cost savings (£3135) and associated net monetary benefit (£23,446 at £20,000 per QALY gained) compared to an absence of RAASi to prevent hyperkalaemia. CONCLUSION: This model represents a novel approach to predicting the long-term benefits of maintaining normokalaemia and enabling optimal RAASi therapy in patients with CKD, irrespective of the strategy used to achieve this target, which may support decision making in healthcare.

Development of a health economic model to evaluate the potential benefits of optimal serum potassium management in patients with heart failure.

AIMS: Patients with heart failure are at increased risk of hyperkalemia, particularly when treated with renin-angiotensin-aldosterone system inhibitor (RAASi) agents. This study developed a model to quantify the potential health and economic value associated with sustained potassium management and optimal RAASi therapy in heart failure patients. MATERIALS AND METHODS: A patient-level, fixed-time increment stochastic simulation model was designed to characterize the progression of heart failure through New York Heart Association functional classes, and predict associations between serum potassium levels, RAASi use, and consequent long-term outcomes. Following internal and external validation exercises, model analyses sought to quantify the health and economic benefits of optimizing both serum potassium levels and RAASi therapy in heart failure patients. Analyses were conducted using a UK payer perspective, independent of costs and utilities related to pharmacological potassium management. RESULTS: Validation against multiple datasets demonstrated the predictive capability of the model. Compared to those who discontinued RAASi to manage serum potassium, patients with normokalemia and ongoing RAASi therapy benefited from longer life expectancy (+1.38 years), per-patient quality-adjusted life year gains (+0.53 QALYs), cost savings (£110), and associated net monetary benefit (£10,679 at £20,000 per QALY gained) over a lifetime horizon. The predicted value of sustained potassium management and ongoing RAASi treatment was largely driven by reduced mortality and hospitalization risks associated with optimal RAASi therapy. LIMITATIONS: Several modeling assumptions were made to account for a current paucity of published literature; however, ongoing refinement and validation of the model will ensure its continued accuracy as the clinical landscape of hyperkalemia evolves. CONCLUSIONS: Predictions generated by this novel modeling approach highlight the value of sustained potassium management to avoid hyperkalemia, enable RAASi therapy, and improve long-term health economic outcomes in patients with heart failure.

Incidence of and Risk Factors for Severe Adverse Events in Elderly Patients Taking Angiotensin-Converting Enzyme Inhibitors or Angiotensin II Receptor Blockers after an Acute Myocardial Infarction.

STUDY OBJECTIVE: To assess the incidence of and risk factors associated with severe adverse events in elderly patients who used angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) after an acute myocardial infarction (AMI). DESIGN: Retrospective cohort study. DATA SOURCES: Centers for Medicare & Medicaid Services Chronic Conditions Data Warehouse (Medicare service claims database), American Community Survey of the U.S. Census Bureau, and Multum Lexicon Drug database. PATIENTS: A total of 101,588 eligible Medicare fee-for-service beneficiaries 66 years or older, who were hospitalized for AMI between January 1, 2008, and December 31, 2009, and used ACEIs or ARBs within 30 days after discharge. MEASUREMENTS AND MAIN RESULTS: Primary outcomes were hospitalizations for acute renal failure (ARF) and hyperkalemia. The secondary outcome was discontinuation or suspension of ACEI/ARB therapy after a visit to a health care provider. The primary risk factors of interest were age, sex, race/ethnicity, and chronic kidney disease (CKD). Cumulative incidence curves and multivariable Fine-Gray proportional hazards models with 95% confidence intervals (CIs) were used with death as a competing risk in both intention-to-treat (ITT) and as-treated (AT) analyses. In the study cohort, 2.8% experienced ARF, 0.5% experienced hyperkalemia, and 63.7% discontinued ACEI/ARB therapy within 1 year after hospital discharge. Approximately half of the incidence of ARF and hyperkalemia occurred within 6 months after hospital discharge, but the cumulative incidence increased after 6 months. Patients older than 85 years had a higher rate of ARF (ITT hazard ratio [HR] 1.15, 95% CI 1.04-1.28) and hyperkalemia (ITT HR 1.33, 95% CI 1.05-1.68) compared with those aged 65-74 years. Patients with baseline CKD had higher rates of ARF (ITT HR 1.61, 95% CI 1.42-1.82), hyperkalemia (ITT HR 1.41, 95% CI 1.11-1.77), and ACEI/ARB therapy discontinuation or suspension (ITT HR 1.05, 95% CI 1.02-1.09). CONCLUSION: We found a low incidence of ARF and hyperkalemia in elderly patients treated with ACEIs or ARBs after AMI hospitalization. However, a high rate of treatment discontinuation might prevent a higher rate of occurrence of these events. Long-term careful monitoring of severe adverse events and timely discontinuation of ACEIs or ARBs among elderly patients with advancing age and CKD after an AMI is warranted in clinical practice.

Characterization of Mineralocorticoid Receptor Antagonist Therapy Initiation in High-Risk Patients With Heart Failure.

BACKGROUND: Heart failure guidelines recommend routine monitoring of serum potassium, and renal function in patients treated with a mineralocorticoid receptor antagonist (MRA). How these recommendations are implemented in high-risk patients or according to setting of drug initiation is poorly characterized. METHODS AND RESULTS: We conducted a retrospective cohort study of Medicare beneficiaries linked to laboratory data in 10 states with prevalent heart failure as of July 1, 2011, and incident MRA use between May 1 and September 30, 2011. Outcomes included laboratory testing before MRA initiation and in the early (days 1-10) and extended (days 11-90) post-initiation periods, based on setting of drug initiation and the presence of renal insufficiency. Additional outcomes included abnormal laboratory results and adverse events proximate to MRA initiation. Of 10 443 Medicare beneficiaries with heart failure started on an MRA, 19.7% were initiated during a hospitalization. Appropriate follow-up laboratory testing across all time periods occurred in 25.2% of patients with inpatient initiation compared with 2.8% of patients begun as an outpatient. Patients with chronic kidney disease had higher rates of both hyperkalemia and acute kidney failure in the early (1.3% and 2.7%, respectively) and extended (5.6% and 9.8%, respectively) post-initiation periods compared with those without chronic kidney disease. CONCLUSIONS: Patients initiated on MRA therapy as an outpatient had extremely poor rates of guideline indicated follow-up laboratory monitoring after drug initiation. In particular, patients with chronic kidney disease are at high risk for adverse events after MRA initiation. Quality improvement initiatives focused on systems to improve appropriate laboratory monitoring are needed.

Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition.

Heart failure affects ≈5.7 million people in the United States alone. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, ß-blockers, and aldosterone antagonists have improved mortality in patients with heart failure and reduced ejection fraction, but mortality remains high. In July 2015, the US Food and Drug Administration approved the first of a new class of drugs for the treatment of heart failure: Valsartan/sacubitril (formerly known as LCZ696 and currently marketed by Novartis as Entresto) combines the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril in a 1:1 ratio in a sodium supramolecular complex. Sacubitril is converted by esterases to LBQ657, which inhibits neprilysin, the enzyme responsible for the degradation of the natriuretic peptides and many other vasoactive peptides. Thus, this combined angiotensin receptor antagonist and neprilysin inhibitor addresses 2 of the pathophysiological mechanisms of heart failure: activation of the renin-angiotensin-aldosterone system and decreased sensitivity to natriuretic peptides. In the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, valsartan/sacubitril significantly reduced mortality and hospitalization for heart failure, as well as blood pressure, compared with enalapril in patients with heart failure, reduced ejection fraction, and an elevated circulating level of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide. Ongoing clinical trials are evaluating the role of valsartan/sacubitril in the treatment of heart failure with preserved ejection fraction and hypertension. We review here the mechanisms of action of valsartan/sacubitril, the pharmacological properties of the drug, and its efficacy and safety in the treatment of heart failure and hypertension.

Effectiveness and Safety of Aldosterone Antagonist Therapy Use Among Older Patients With Reduced Ejection Fraction After Acute Myocardial Infarction.

BACKGROUND: While aldosterone antagonists have proven benefit among post-myocardial infarction (MI) patients with low ejection fraction (EF), how this treatment is used among older MI patients in routine practice is not well described. METHODS AND RESULTS: Using ACTION Registry-GWTG linked to Medicare data, we examined 12 080 MI patients ≥65 years with EF ≤40% who were indicated for aldosterone antagonist therapy per current guidelines and without documented contraindications. Of these, 11% (n=1310) were prescribed aldosterone antagonists at discharge. Notably, 10% of patients prescribed an aldosterone antagonist were eligible for, but not concurrently treated with, an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker. Spironolactone was the predominantly prescribed aldosterone antagonist. At 2-year follow-up, aldosterone antagonist use was not associated with lower mortality (unadjusted 39% versus 38%; HR 0.99, 95% CI 0.88-1.33 using inverse probability-weighted propensity adjustment) except in symptomatic HF patients (HR 0.84, 95% CI 0.72-0.99, Pinteraction=0.009). Risks of hyperkalemia were low at 30 days, but significantly higher among patients prescribed aldosterone antagonists (unadjusted 2.3% versus 1.5%; adjusted HR 2.04, 95% CI 1.16-3.60), as was 2-year risk of acute renal failure (unadjusted 6.7% versus 4.8%; adjusted HR 1.39, 95% CI 1.01-1.92) compared with patients not prescribed aldosterone antagonists. CONCLUSIONS: Aldosterone antagonist use among eligible older MI patients in routine clinical practice was not associated with lower mortality except in patients with HF symptoms, but was associated with increased risks of hyperkalemia and acute renal failure. These results underscore the importance of close post-discharge monitoring of this patient population.

Cotrimoxazol en infecciones óseas: toxicidad e impacto clínico y económico / Cotrimoxazole in bone-related infections: toxicity and clinical and economic impact

Background: Cotrimoxazole is a therapeutic option for bone-related infections but is associated to hyperkalemia and renal failure. Tolerance to this drug may reduce length of stay (LOS) and hospital charges. Aims: To evaluate renal, potassium toxicity, clinical outcome, and use of hospital resources in patients treated with cotrimoxazole for bone-related infections. Methods: Retrospective analysis of adult patients with bone-related infections confirmed by culture and treated with this drug. Serum potassium and creatinine levels were analyzed during follow-up and risk factors for hyperkalemia were searched. Length of stay (LOS) and hospital charges were compared. Clinical outcome was evaluated as a secondary endpoint. Results: From 2011 to 2014, 23 patients were identified (mean age 64.7 years). Diabetes mellitus, peripheral vascular disease, and previous amputations prevalence were high (82.6%, 47.8%, and 43.5%, respectively). Median serum potassium concentration increased significantly at first control (4.35 mEq/L to 4.9 mEq/L; p < 0.001), and also creatinine serum concentration (0.9 to 1.1 mg/dL; p < 0.05). Seven patients developed hyperkalemia. Cotrimoxazole was discontinued in 10 patients (43.5%), and in 6, discharge was postponed. Drugs active against the renin-angiotensin system (DAARAS) were associated with kyperkalemia (OR 10.8 IC95 1.37-85; p < 0.05). LOS was higher among patients with cotrimoxazole toxicity (median LOS 56 versus 30 days, p < 0.05). Patients with no cotrimoxazole interruption had less drug-related hospital charges (median values of 563 versus 2820 USD, respectively; p < 0.01). Conclusions: Cotrimoxazole use must be monitored in order to detect hyperkalemia or renal toxicity and suspend its prescription. Patients that use DAARAS have a higher risk of kyperkalemia. LOS and drug-related hospital charges are reduced when patients can tolerate cotrimoxazole.

Antecedentes: Cotrimoxazol es una alternativa en infecciones óseas pero se ha asociado al desarrollo de falla renal e hiperkalemia. Objetivo: Evaluar toxicidad renal, hiperkalemia, estadía y gastos hospitalarios y evolución clínica en un grupo de pacientes con infecciones óseas tratados con este compuesto. Pacientes y Métodos: Estudio retrospectivo-descriptivo de pacientes adultos con infecciones óseas confirmadas con cultivos y tratados con este compuesto. Seguimiento de creatinina y kalemia y búsqueda de factores de riesgo para hiperkalemia, comparación de gastos y estadía hospitalaria y análisis de eficacia clínica. Resultados: Desde el año 2011 al 2014 se identificaron 23 pacientes (promedio de edad 64,7 años). La prevalencia de diabetes mellitus tipo 2 (82,6%), enfermedad vascular periférica (47,8%) y amputaciones previas (43,5%) fue elevada. La mediana de la kalemia basal aumentó significativamente al primer control (4,35 a 4,9 mEq/L) al igual que la creatinina plasmática (0,9 a 1,1 mg/dL). Siete pacientes desarrollaron hiperkalemia (30,4%). Se suspendió cotrimoxazol en 10 casos (43,5%) y en 6 casos se postergó el alta. El uso de fármacos activos contra el sistema renina-angiotensina (FASRA) se asoció a hiperkalemia (OR 10,8 IC95 1,37-85; p < 0,05). La estadía hospitalaria fue mayor en el grupo con toxicidad a cotrimoxazol (mediana de 56 versus 30 días; p < 0,05) y los pacientes sin suspensión de terapia tuvieron menos gastos por fármacos (medianas de 563 vs 2.820 USD, p < 0,01). Conclusiones: El uso de cotrimoxazol debe ser monitorizado para detectar hiperkalemia o toxicidad renal y suspender su prescripción. Los pacientes que usan FASRA tienen mayor riesgo de hiperkalemia. La estadía y gastos hospitalarios por fármacos son menores en pacientes que toleran el cotrimoxazol.

Risk of hyperkalemia and combined use of spironolactone and long-term ACE inhibitor/angiotensin receptor blocker therapy in heart failure using real-life data: a population- and insurance-based cohort.

PURPOSE: Clinical trials and few observational studies report increased hyperkalemia risks in heart failure patients receiving aldosterone blockers in addition to standard therapy. The aim of this study is to assess the hyperkalemia risk and combined use of spironolactone and long-term ACE (angiotensin-converting enzyme) inhibitor/angiotensin receptor blocker (ARB) therapy for heart failure in a real-life setting of a heterogeneous population. METHODS: Using claims data of the statutory health insurance fund AOK, covering 30% of the German population, we performed a nested case-control study in a cohort of heart failure patients receiving continuous ACE/ARB therapy (n = 1,491,894). Hyperkalemia risk associated with concurrent use of spironolactone and ACE/ARB was calculated by conditional logistic regression in 1062 cases and 10,620 risk-set-sampling-matched controls. RESULTS: Risk of hyperkalemia in heart failure patients was significantly associated with spironolactone use (odds ratio (OR) (95% confidence interval (CI)) = 13.59 (11.63-15.88) in all and 11.05 (8.67-14.08) in those with information on New York Heart Association (NYHA) stage of disease). In the NYHA subpopulation, higher risk estimates were observed in short-term as compared with long-term users (OR (95%CI) = 13.00 (9.82-17.21) and 9.12 (6.78-12.26), respectively). Moreover, the association was stronger in older (≥70 years of age) as compared with younger patients (<70 years of age) (OR (95%CI) = 12.32 (9.35-16.23) and 8.73 (5.05-15.08), respectively), although interaction was not significant (pinteraction = 0.07). CONCLUSIONS: Hyperkalemia risk associated with combined use of spironolactone and ACE/ARB is much stronger in real-life practice than observed in clinical trials. Careful potassium level monitoring in concomitant users of spironolactone and ACE/ARB is necessary.

[Cotrimoxazole in bone-related infections: toxicity and clinical and economic impact]. / Cotrimoxazol en infecciones óseas: toxicidad e impacto clínico y económico.

BACKGROUND: Cotrimoxazole is a therapeutic option for bone-related infections but is associated to hyperkalemia and renal failure. Tolerance to this drug may reduce length of stay (LOS) and hospital charges. AIMS: To evaluate renal, potassium toxicity, clinical outcome, and use of hospital resources in patients treated with cotrimoxazole for bone-related infections. METHODS: Retrospective analysis of adult patients with bone-related infections confirmed by culture and treated with this drug. Serum potassium and creatinine levels were analyzed during follow-up and risk factors for hyperkalemia were searched. Length of stay (LOS) and hospital charges were compared. Clinical outcome was evaluated as a secondary endpoint. RESULTS: From 2011 to 2014, 23 patients were identified (mean age 64.7 years). Diabetes mellitus, peripheral vascular disease, and previous amputations prevalence were high (82.6%, 47.8%, and 43.5%, respectively). Median serum potassium concentration increased significantly at first control (4.35 mEq/L to 4.9 mEq/L; p < 0.001), and also creatinine serum concentration (0.9 to 1.1 mg/dL; p < 0.05). Seven patients developed hyperkalemia. Cotrimoxazole was discontinued in 10 patients (43.5%), and in 6, discharge was postponed. Drugs active against the renin-angiotensin system (DAARAS) were associated with kyperkalemia (OR 10.8 IC95 1.37-85; p < 0.05). LOS was higher among patients with cotrimoxazole toxicity (median LOS 56 versus 30 days, p < 0.05). Patients with no cotrimoxazole interruption had less drug-related hospital charges (median values of 563 versus 2820 USD, respectively; p < 0.01). CONCLUSIONS: Cotrimoxazole use must be monitored in order to detect hyperkalemia or renal toxicity and suspend its prescription. Patients that use DAARAS have a higher risk of kyperkalemia. LOS and drug-related hospital charges are reduced when patients can tolerate cotrimoxazole.

Associations between aldosterone antagonist therapy and risks of mortality and readmission among patients with heart failure and reduced ejection fraction.

CONTEXT: Aldosterone antagonist therapy for heart failure and reduced ejection fraction has been highly efficacious in randomized trials. However, questions remain regarding the effectiveness and safety of the therapy in clinical practice. OBJECTIVE: To examine the clinical effectiveness of newly initiated aldosterone antagonist therapy among older patients hospitalized with heart failure and reduced ejection fraction. DESIGN, SETTING, AND PARTICIPANTS: Using clinical registry data linked to Medicare claims from 2005 through 2010, we examined outcomes of eligible patients hospitalized with heart failure and reduced ejection fraction. We used Cox proportional hazards models and inverse-weighted estimates of the probability of treatment to adjust for treatment selection bias. MAIN OUTCOME MEASURES: All-cause mortality, cardiovascular readmission, and heart failure readmission at 3 years, and hyperkalemia readmission at 30 days and 1 year. RESULTS: Among 5887 patients who met the inclusion criteria, the mean age was 77.6 years; of those 1070 (18.2%) started aldosterone antagonist therapy at discharge. Cumulative incidence rates among treated and untreated patients were 49.9% vs 51.2% (P = .62) for mortality; 63.8% vs 63.9% (P = .65) for cardiovascular readmission; and 38.7% vs 44.9% (P < .001) for heart failure readmission at 3 years; and 2.9% vs 1.2% (P < .001) for hyperkalemia readmission within 30 days and 8.9% vs 6.3% (P = .002) within 1 year. After inverse weighting for the probability of treatment, there were no significant differences in mortality (hazard ratio [HR], 1.04; 95% CI, 0.96-1.14; P = .32) and cardiovascular readmission (HR, 1.00; 95% CI, 0.91-1.09; P = .94). Heart failure readmission was lower among treated patients at 3 years (HR, 0.87; 95% CI, 0.77-0.98; P = .02). Readmission associated with hyperkalemia was higher with aldosterone antagonist therapy at 30 days (HR, 2.54; 95% CI, 1.51-4.29; P < .001) and 1 year (HR, 1.50; 95% CI, 1.23-1.84; P < .001). CONCLUSIONS: Initiation of aldosterone antagonist therapy at hospital discharge was not independently associated with improved mortality or cardiovascular readmission but was associated with improved heart failure readmission among eligible older patients with heart failure and reduced ejection fraction. There was a significant increase in the risk of readmission with hyperkalemia, predominantly within 30 days after discharge.

Laboratory monitoring of patients treated with antihypertensive drugs and newly exposed to non steroidal anti-inflammatory drugs: a cohort study.

BACKGROUND: Drug-Drug Interactions between Non Steroidal Anti-Inflammatory Drugs (NSAIDs) and Angiotensin Converting Enzyme Inhibitors (ACEIs), Angiotensin Receptor Blocker (ARBs) or diuretics can lead to renal failure and hyperkalemia. Thus, monitoring of serum creatinine and potassium is recommended when a first dispensing of NSAID occur in patients treated with these drugs. METHODS: We conducted a pharmacoepidemiological retrospective cohort study using data from the French Health Insurance Reimbursement Database to evaluate the proportion of serum creatinine and potassium laboratory monitoring in patients treated with ACEI, ARB or diuretic and receiving a first dispensing of NSAID. We described the first dispensing of NSAID among 3,500 patients of a 4-year cohort (6,633 patients treated with antihypertensive drugs) and analyzed serum creatinine and potassium laboratory monitoring within the 3 weeks after the first NSAID dispensing. RESULTS: General Practitioners were the most frequent prescribers of NSAIDs (85.5%, 95% CI: 84.3-86.6). The more commonly prescribed NSAIDs were ibuprofen (20%), ketoprofen (15%), diclofenac (15%) and piroxicam (12%). Serum creatinine and potassium monitoring was 10.7% (95% CI: 9.5-11.8) in patients treated by ACEIs, ARBs or diuretics. Overall, monitoring was more frequently performed to women aged over 60, treated with digoxin or glucose lowering drugs, but not to patients treated with ACEIs, ARBs or diuretics. Monitoring was more frequent when NSAIDs' prescribers were cardiologists or anesthesiologists. CONCLUSION: Monitoring of serum creatinine and potassium of patients treated with ACEIs, ARBs or diuretics and receiving a first NSAID dispensing is insufficiently performed and needs to be reinforced through specific interventions.

Serum potassium influencing interacting drugs: risk-modifying strategies also needed at discontinuation.

BACKGROUND: Although the discontinuation of a medication may have important clinical consequences, there is generally much less attention given to medication surveillance when a drug is stopped than when it is started. OBJECTIVE: To investigate the consequences on serum potassium levels of discontinuing a drug that increases the serum potassium level (PID↑) and a drug that decreases the serum potassium level (PLD↓) in patients taking both. METHODS: Patients who were hospitalized in the University Medical Centre Utrecht in 2004-2009 and were using both a PID↑ and a PLD↓ were included when one of these drugs was discontinued during hospitalization. Serum potassium levels measured before (potassium(1)) and after (potassium(2)) discontinuation were compared in patients who stopped the PLD↓ and in patients who stopped the PID↑. RESULTS: In the group of patients who stopped the PLD↓ (ie, continued the PID↑), mean serum potassium levels increased 0.19 mEq/L (range -0.9 to 1.8 mEq/L). After discontinuation of the PLD↓, serum potassium levels increased in 91 (59%) patients. Five patients (3.2%) developed hyperkalemia (potassium(2) >5.5 mEq/L). In the group of patients who stopped the PID↑ (ie, continued the PLD↓), mean serum potassium levels decreased 0.40 mEq/L (range -2.6 to 0.7 mEq/L). Serum potassium levels decreased in 61 (70%) patients after discontinuation of the PID↑. Fifteen patients (17%) developed hypokalemia (potassium(2) <3.5 mEq/L). Results were not influenced by length of stay, age, sex, renal function, and type of medication discontinued. CONCLUSIONS: The effects of serum potassium-influencing drugs need to be monitored not only after starting but also after stopping the medication. The same may hold true for the effects of other drugs. Clinical risk management should therefore focus on the risks not only when new medication is prescribed, but also when medication is stopped.