Showing papers by "Bertram Pitt published in 2016"

Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction

Abstract: Aims While mineralocorticoid receptor antagonists (MRAs) have been shown to benefit patients with reduced left ventricular ejection fraction (LVEF), spironolactone did not reduce the primary endpoint of cardiovascular death, heart failure hospitalization, or aborted cardiac arrest in patients with heart failure with preserved ejection fraction (HFpEF) in the TOPCAT trial, which enrolled patients with LVEF of 45% or greater. We utilized data from TOPCAT to assess the relationship between LVEF as well as outcomes and efficacy of spironolactone. Methods and results We assessed differences in baseline characteristics and outcomes across LVEF categories in 3444 patients with HFpEF, and determined whether LVEF modified the treatment effect of spironolactone. Ejection fraction ranged from 44 to 85%. Patients with higher ejection fraction were older, more likely to be female, less likely to have a history of myocardial infarction, and more likely to have a history of hypertension and diabetes. The incidence of the primary endpoint and cardiovascular death was highest in patients at the lower end of the ejection fraction spectrum. Ejection fraction modified the spironolactone treatment effect, particularly in the patients enrolled in the Americas, for the primary outcome ( P = 0.046) and for heart failure hospitalization ( P = 0.039), with stronger estimated benefits of spironolactone at the lower end of the ejection fraction spectrum with respect to the primary endpoint (LVEF <50%: HR 0.72, 95% CI 0.50, 1.05; LVEF ≥60%: HR 0.97, 95% CI 0.76, 1.23) and heart failure hospitalization (LVEF <50%: HR 0.76, 95% CI 0.46, 1.27; LVEF ≥60%: HR 0.98, 95% CI 0.74, 1.30). Conclusion In patients with HFpEF enrolled in TOPCAT, patient characteristics and outcomes varied substantially by LVEF. The potential efficacy of spironolactone was greatest at the lower end of the LVEF spectrum. ClinicalTrials.gov number NCT00094302.

A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease

Abstract: Aims To evaluate oral doses of the non-steroidal mineralocorticoid receptor antagonist finerenone given for 90 days in patients with worsening heart failure and reduced ejection fraction and chronic kidney disease and/or diabetes mellitus. Methods and results Miner Alocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF) was a randomized, double-blind, phase 2b multicentre study (ClinicalTrials.gov: [NCT01807221][1]). Of 1286 screened patients, 1066 were randomized. Patients received oral, once-daily finerenone (2.5, 5, 7.5, 10, or 15 mg, uptitrated to 5, 10, 15, 20, or 20 mg, respectively, on Day 30) or eplerenone (25 mg every other day, increased to 25 mg once daily on Day 30, and to 50 mg once daily on Day 60) for 90 days. The primary endpoint was the percentage of individuals with a decrease of >30% in plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline to Day 90. A key exploratory endpoint was a composite clinical endpoint of death from any cause, cardiovascular hospitalizations, or emergency presentation for worsening HF until Day 90. Mean age ranged from 69.2 to 72.5 years in different treatment groups (standard deviation 9.7–10.6 years). Decreases in NT-proBNP of >30% from baseline occurred in 37.2% of patients in the eplerenone group and 30.9, 32.5, 37.3, 38.8, and 34.2% in the 2.5→5, 5→10, 7.5→15, 10→20, and 15→20 mg finerenone groups, respectively ( P = 0.42–0.88). Except for the 2.5→5 mg finerenone group, the composite clinical endpoint occurred numerically less frequently in finerenone-treated patients compared with eplerenone; this difference reached nominal statistical significance in the 10→20 mg group (hazard ratio 0.56, 95% confidence interval, CI, 0.35; 0.90; nominal P = 0.02), despite the fact that this phase 2 study was not designed to detect statistical significant differences. A potassium level increase to ≥5.6 mmol/L at any time point occurred in 4.3% of patients, with a balanced distribution among all treatment groups. Conclusion Finerenone was well tolerated and induced a 30% or greater decrease in NT-proBNP levels in a similar proportion of patients to eplerenone. The finding of reduced clinical events in the finerenone 10→20 mg group should be further explored in a large outcomes trial. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01807221&atom=%2Fehj%2F37%2F27%2F2105.atom

Prognostic Relevance of Left Atrial Dysfunction in Heart Failure With Preserved Ejection Fraction

Abstract: Background—Left atrial (LA) size is an established marker of risk for adverse outcomes in heart failure with preserved ejection fraction (HFpEF). However, the independent prognostic importance of L...

Steroidal and Novel Non-steroidal Mineralocorticoid Receptor Antagonists in Heart Failure and Cardiorenal Diseases: Comparison at Bench and Bedside

Abstract: Characterization of mice with cell-specific deletion or overexpression of the mineralocorticoid receptor (MR) shed a new light on its role in health and disease. Pathophysiological MR activation contributes to a plethora of deleterious molecular mechanisms in the development of cardiorenal diseases like chronic kidney disease (CKD) and heart failure (HF). Accordingly, the available steroidal MR antagonists (MRAs) spironolactone (first generation MRA) and eplerenone (second generation MRA) have been shown to be effective in reducing cardiovascular (CV) mortality and morbidity in patients with chronic HF and a reduced left ventricular ejection fraction (HFrEF). However, they remain underutilized, in large part owing to the risk inducing severe adverse events including hyperkalemia and worsening of kidney function, particularly when given on top of inhibitors of the renin angiotensin system (RAS) to patients with concomitant kidney dysfunction. Novel, potent, and selective non-steroidal MRAs (third generation) were identified in drug discovery campaigns and a few entered clinical development recently. One of these is finerenone with different physicochemical, pharmacokinetics, and pharmacological properties in comparison with the steroidal MRAs. Available data from five clinical phase II trials with finerenone in more than 2,000 patients with HF and additional CKD and/or diabetes as well as in patients with diabetic kidney disease demonstrated that neither hyperkalemia nor reductions in kidney function were limiting factors to its use. Moreover, finerenone demonstrated a nominally improved outcome compared to eplerenone in a phase IIb trial with 1,066 patients with HFrEF and concomitant type 2 diabetes mellitus (T2DM) and/or CKD.

Impact of Spironolactone on Longitudinal Changes in Health-Related Quality of Life in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial

Abstract: Background—Heart failure (HF) with preserved ejection fraction patients have equally impaired health-related quality of life (HRQL) compared with those with HF with reduced ejection fraction, but limited studies have evaluated the impact of therapies on changes in HRQL. Methods and Results—Patients ≥50 years of age, with symptomatic HF and left ventricular ejection fraction ≥45%, were enrolled in Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) and randomized to spironolactone or placebo. Patients completed the Kansas City Cardiomyopathy Questionnaire (KCCQ), which was the primary HRQL instrument, and EQ5D visual analog scale at baseline, 4 months, 12 months, and annually thereafter. McMaster Overall Treatment Evaluation was assessed at 4 and 12 months to assess global change scores. Change scores (+SD) were calculated to determine between-group differences, and multivariable repeated-measures models were created to identify other factors associated with change...

Renal function estimation and Cockroft-Gault formulas for predicting cardiovascular mortality in population-based, cardiovascular risk, heart failure and post-myocardial infarction cohorts: The Heart 'OMics' in AGEing (HOMAGE) and the high-risk myocardial infarction database initiatives.

Abstract: Renal impairment is a major risk factor for mortality in various populations. Three formulas are frequently used to assess both glomerular filtration rate (eGFR) or creatinine clearance (CrCl) and mortality prediction: body surface area adjusted-Cockcroft–Gault (CG-BSA), Modification of Diet in Renal Disease Study (MDRD4), and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. The CKD-EPI is the most accurate eGFR estimator as compared to a “gold-standard”; however, which of the latter is the best formula to assess prognosis remains to be clarified. This study aimed to compare the prognostic value of these formulas in predicting the risk of cardiovascular mortality (CVM) in population-based, cardiovascular risk, heart failure (HF) and post-myocardial infarction (MI) cohorts. Two previously published cohorts of pooled patient data derived from the partners involved in the HOMAGE-consortium and from four clinical trials – CAPRICORN, EPHESUS, OPTIMAAL and VALIANT – the high risk MI initiative, were used. A total of 54,111 patients were included in the present analysis: 2644 from population-based cohorts; 20,895 from cardiovascular risk cohorts; 1801 from heart failure cohorts; and 28,771 from post-myocardial infarction cohorts. Participants were patients enrolled in the respective cohorts and trials. The primary outcome was CVM. All formulas were strongly and independently associated with CVM. Lower eGFR/CrCl was associated with increasing CVM rates for values below 60 mL/min/m2. Categorical renal function stages diverged in a more pronounced manner with the CG-BSA formula in all populations (higher χ2 values), with lower stages showing stronger associations. The discriminative improvement driven by the CG-BSA formula was superior to that of MDRD4 and CKD-EPI, but remained low overall (increase in C-index ranging from 0.5 to 2%) while not statistically significant in population-based cohorts. The integrated discrimination improvement and net reclassification improvement were higher (P < 0.05) for the CG-BSA formula compared to MDRD4 and CKD-EPI in CV risk, HF and post-MI cohorts, but not in population-based cohorts. The CKD-EPI formula was superior overall to MDRD4. The CG-BSA formula was slightly more accurate in predicting CVM in CV risk, HF, and post-MI cohorts (but not in population-based cohorts). However, the CG-BSA discriminative improvement was globally low compared to MDRD4 and especially CKD-EPI, the latter offering the best compromise between renal function estimation and CVM prediction.

Heart Failure Clinical Trials in East and Southeast Asia: Understanding the Importance and Defining the Next Steps

Abstract: Heart failure (HF) is a major and increasing global public health problem. In Asia, aging populations and recent increases in cardiovascular risk factors have contributed to a particularly high burden of HF, with outcomes that are poorer than those in the rest of the world. Representation of Asians in landmark HF trials has been variable. In addition, HF patients from Asia demonstrate clinical differences from patients in other geographic regions. Thus, the generalizability of some clinical trial results to the Asian population remains uncertain. In this article, we review differences in HF phenotype, HF management, and outcomes in patients from East and Southeast Asia. We describe lessons learned in Asia from recent HF registries and clinical trial databases and outline strategies to improve the potential for success in future trials. This review is based on discussions among scientists, clinical trialists, industry representatives, and regulatory representatives at the CardioVascular Clinical Trialist Asia Forum in Singapore on July 4, 2014.

Effect of Patiromer on Urinary Ion Excretion in Healthy Adults.

Abstract: Background and objectives Patiromer is a nonabsorbed potassium-binding polymer that uses calcium as the counterexchange ion. The calcium released with potassium binding has the potential to be absorbed or bind phosphate. Because binding is not specific for potassium, patiromer can bind other cations. Here, we evaluate the effect of patiromer on urine ion excretion in healthy adults, which reflects gastrointestinal ion absorption. Design, setting, participants, & measurements We analyzed the effect of patiromer on urine potassium, sodium, magnesium, calcium, and phosphate in two studies. Healthy adults on controlled diets in a clinical research unit were given patiromer up to 50.4 g/d divided three times a day for 8 days (dose-finding study) or 25.2 g/d in a crossover design as daily or divided (two or three times a day) doses for 18 days (dosing regimen study). On the basis of 24-hour collections, urinary ion excretion during the baseline period (days 5–11) was compared with that during the treatment period (days 13–19; dose-finding study), and the last 4 days of each period were compared across regimens (dosing regimen study). Results In the dose-finding study, patiromer induced a dose-dependent decrease in urine potassium, urine magnesium, and urine sodium ( P P P =0.01). Urine phosphate also decreased less with daily compared with two or three times a day dosing ( P Conclusions In healthy adults, patiromer reduces urine potassium, urine sodium, urine magnesium, and urine phosphate, while modestly increasing urine calcium. Compared with divided dosing, administration of patiromer once daily provides equivalent reductions in urine potassium, urine sodium, and urine magnesium, with less effect on urine calcium and urine phosphate.

QRS Duration Is a Predictor of Adverse Outcomes in Heart Failure With Preserved Ejection Fraction.

Abstract: Objectives This study examined the relationship between baseline QRS duration and clinical outcomes in subjects enrolled in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial. Background Heart failure with preserved ejection fraction (HFPEF) is a heterogeneous clinical syndrome. Whether QRS duration identifies HFPEF subjects at an increased risk of adverse outcomes has not been well studied. Methods QRS duration was analyzed as a dichotomous variable (≥120 ms or Results The QRS duration of ≥120 ms was independently associated with an increased risk of the primary outcome (p = 0.009) and HFH (p = 0.003) in the entire study cohort and in the subset enrolled in the Americas. There was a linear relation of QRS duration with risk of the primary outcome and HFH. No interaction was observed between treatment with spironolactone and QRS duration. The risk of adverse outcomes was increased independently of the type of conduction abnormality underlying prolonged QRS duration. Conclusions This post hoc analysis demonstrated that prolonged QRS duration identifies HFPEF subjects at a higher risk of adverse clinical outcomes and that spironolactone had a similar effect on outcomes independent of QRS duration. (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function [TOPCAT]; NCT00094302)

Recent advances in pharmacological treatments of hyperkalemia: focus on patiromer.

Abstract: Introduction: Hyperkalemia is a common electrolyte disorder, especially among patients with chronic kidney disease (CKD), diabetes mellitus, or heart failure, and is associated with a significantly increased risk for all-cause mortality. Hyperkalemia remains a vexing and challenging problem for clinicians, particularly in the management of patients with chronic kidney disease and congestive heart failure. Several observational and retrospective studies have reported a large gap between recommendations in guidelines and real-world practice in the implementation of RAASi therapies. RAASi treatment regimens are frequently down-titrated or discontinued following hyperkalemia events, with consequent worse outcomes than patients who remain on maximum doses.Areas covered: This review covers the preclinical and clinical studies that led to the approval of patiromer for the treatment of hyperkalemia. A literature search on patiromer was carried out using the PubMed database up to December 2015.Expert opini...

Cardiovascular Outcomes According to Systolic Blood Pressure in Patients With and Without Diabetes: An ACCOMPLISH Substudy

Abstract: To evaluate the effects of achieved systolic blood pressure (SBP) during treatment on cardiovascular (CV) outcomes, the authors measured event rates of a composite primary endpoint (CV death or nonfatal myocardial infarction or stroke) at on-treatment SBPs of ≥140 mm Hg and the 10 mm Hg intervals of <140 mm Hg, <130 mm Hg, and <120 mm Hg in 6459 patients with diabetes (mean age, 67) and 4246 patients without diabetes (mean age, 69) from the Avoiding Cardiovascular Events in Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial. In the diabetic cohort, the primary endpoint was 49% lower (P<.001) at <140 mm Hg than at ≥140 mm Hg, and the separate components of this endpoint were also significantly reduced. Further SBP reductions did not improve outcomes, and at <120 mm Hg they were no longer different (except for stroke) from ≥140 mm Hg. In contrast, in the nondiabetic cohort, the primary endpoint event rate fell steadily (although not significantly) through the decreasing SBP categories until it was reduced by 45% (P=.0413) at <120 mm Hg. Total stroke rates for both the diabetic (-56%, P=.0120) and nondiabetic (-68%, P=.0067) cohorts were lowest at <120 mm Hg, and adverse renal events (serum creatinine increase ≥50%) were significantly lowest in the range of 130 mm Hg to 139 mm Hg for both cohorts. Diabetic patients (<140 mm Hg or <130 mm Hg) and nondiabetic patients (<120 mm Hg) may require different SBP targets for optimal CV protection, although stroke and renal considerations should also influence the selection of blood pressure targets.

Challenges to Data Monitoring Committees When Regulatory Authorities Intervene.

Abstract: During ATMOSPHERE, a trial comparing aliskiren, enalapril, or both for heart failure, two other trials suggested harm from aliskiren in patients with diabetes, and regulators stopped aliskiren in such patients in ATMOSPHERE. The data monitoring committee suggests that regulators should trust the DMC to ensure patient safety in a clinical trial. The trial sponsor (Novartis) and the regulatory agencies have responded in letters to the editor.

The association between serum potassium and mortality in patients with hypertension: ‘a wake-up call’

Abstract: This editorial refers to ‘Short-term mortality risk of serum potassium levels in hypertension: a retrospective analysis of nationwide registry data’, by M. Krogager et al . doi:10.1093/eurheartj/ehw129 There has been considerable focus on the risks of hyperkalaemia, especially in patients with chronic kidney disease (CKD), diabetes mellitus, and/or heart failure.1–3 Although the exact level of serum potassium (K+) that is associated with an increase in mortality remains controversial, increasing evidence suggests that in patients with CKD, diabetes mellitus, and/or heart failure, especially the elderly, a K+ >5.0 mmol/L is associated with an increased risk of death.4 Conversely, while a K+ 5.5 mmol/L. In this issue of the journal, Krogager et al .7 used the Danish National Patient Registry to examine the association between K+ and all-cause mortality over 90 days in >40 000 patients with hypertension taking a dual single antihypertensive drug. Patients with renal insufficiency, those with missing …

The safety of mineralocorticoid receptor antagonists (MRAs) in patients with heart failure

Abstract: Introduction: Mineralocorticoid receptor antagonists (MRAs) have been accorded a class 1 indication for patients with chronic heart failure and a reduced left ventricular ejection fraction (HFREF) in both European and American guidelines. Uptake, however, has been less than optimal largely due to concerns about their safety, in particular the risk of hyperkalemia and renal dysfunction.Areas covered: This review presents the current state of affairs regarding the safety of MRAs in heart failure with reduced ejection fraction.Expert opinion: Careful patient selection and adherence to guideline-recommended inclusion and exclusion criteria, dosing, and serial monitoring of serum potassium and renal function, along with patient education regarding the potassium content of common foods, should minimize these risks and allow increased use of MRAs. Additionally, this may also result in a further reduction in cardiovascular mortality and hospitalizations for heart failure. The development of new non-steroi...

Aspirin does not reduce the clinical benefits of the mineralocorticoid receptor antagonist eplerenone in patients with systolic heart failure and mild symptoms: an analysis of the EMPHASIS-HF study.

Abstract: AimsIt is not known whether concomitant use of aspirin might attenuate the beneficial effects of mineralocorticoid receptor antagonists (MRAs). The purpose of this subgroup analysis was to explore the interaction between baseline aspirin treatment and the effect of eplerenone on the primary efficacy outcomes (composite of hospitalization for heart failure or cardiovascular mortality), its components, and safety markers [estimated glomerular filtration rate (eGFR), systolic blood pressure (SBP), and serum potassium >5.5mmol/L] in the Eplerenone in Mild Patients Hospitalization and SurvIval Study in Heart Failure trial (EMPHASIS-HF). Methods and resultsPatients with chronic heart failure, reduced ejection fraction (HFREF), and mild symptoms were enrolled in EMPHASIS-HF. We evaluated baseline characteristics according to aspirin use. We explored the interaction between aspirin and eplerenone, using Cox proportional hazards models providing adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) and P-values for interaction. Of the 2737 patients randomized, 1605 patients (58.6%) were taking aspirin. The beneficial effects of eplerenone on the primary endpoint were similar in patients not treated (adjusted HR 0.59, 95% CI 0.46-0.75) or treated (adjusted HR 0.71, 95% CI 0.59-0.87) with aspirin at baseline (interaction P-value=0.19). We did not observe any significant modification of the safety markers by aspirin that was clinically meaningful. ConclusionAspirin use in patients with chronic systolic heart failure and mild symptoms did not substantially reduce the overall beneficial effects of the MRA eplerenone contrary to what has been described in some studies with ACE inhibitors.

Prognostic Value of the Thrombolysis in Myocardial Infarction Risk Score in ST-Elevation Myocardial Infarction Patients With Left Ventricular Dysfunction (from the EPHESUS Trial)

Abstract: The Thrombolysis in Myocardial Infarction (TIMI) risk score remains a robust prediction tool for short-term and midterm outcome in the patients with ST-elevation myocardial infarction (STEMI). However, the validity of this risk score in patients with STEMI with reduced left ventricular ejection fraction (LVEF) remains unclear. A total of 2,854 patients with STEMI with early coronary revascularization participating in the randomized EPHESUS (Epleronone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) trial were analyzed. TIMI risk score was calculated at baseline, and its predictive value was evaluated using C-indexes from Cox models. The increase in reclassification of other variables in addition to TIMI score was assessed using the net reclassification index. TIMI risk score had a poor predictive accuracy for all-cause mortality (C-index values at 30 days and 1 year ≤0.67) and recurrent myocardial infarction (MI; C-index values ≤0.60). Among TIMI score items, diabetes/hypertension/angina, heart rate >100 beats/min, and systolic blood pressure

Effect of Patiromer on Urinary Ion Excretion in Healthy

Abstract: Background and objectives Patiromer is a nonabsorbed potassium-binding polymer that uses calcium as the counterexchange ion. The calcium released with potassium binding has the potential to be absorbed or bind phosphate. Because binding isnot specificfor potassium, patiromer canbind other cations. Here, weevaluatethe effect of patiromer on urine ion excretion in healthy adults, which reflects gastrointestinal ion absorption. Design, setting, participants, & measurements We analyzed the effect of patiromer on urine potassium, sodium, magnesium, calcium, and phosphate in two studies. Healthy adults on controlled diets in a clinical research unit were given patiromer up to 50.4 g/d divided three times a day for 8 days (dose-finding study) or 25.2 g/d in a crossover design as daily or divided (two or three times a day) doses for 18 days (dosing regimen study). On the basis of 24-hour collections, urinary ion excretion during the baseline period (days 5–11) was compared with that during the treatment period (days 13–19; dose-finding study), and the last 4 days of each period were compared across regimens (dosing regimen study). Results In the dose-finding study, patiromer induced a dose-dependent decrease in urine potassium, urine magnesium, and urine sodium (P,0.01 for each). Patiromer at 25.2 g/d decreased urine potassium (mean6SD) by 11406316 mg/d, urine magnesium by 4561 mg/d, and urine sodium by 2256145 mg/d. Urine calcium increased in a dose-dependent manner, and urine phosphate decreased in parallel (both P,0.01). Patiromer at 25.2 g/d increased urine calcium by 73623 mg/d and decreased urine phosphate by 64640 mg/d. Urine potassium, urine sodium, and urine magnesium were unaffected by dosing regimen, whereas the increase in urine calcium was significantly lower with daily compared with three times a day dosing (P=0.01). Urine phosphate also decreased less with daily compared with two or three times a day dosing (P,0.05). Conclusions In healthy adults, patiromer reduces urine potassium, urine sodium, urine magnesium, and urine phosphate, while modestly increasing urine calcium. Compared with divided dosing, administration of patiromer once daily provides equivalent reductions in urine potassium, urine sodium, and urine magnesium, with less effect on urine calcium and urine phosphate. Clin J Am Soc Nephrol 11: 1769–1776, 2016. doi: 10.2215/CJN.01170216

Response to: Hyperkalaemia in heart failure: binding the patient to improved treatment?

Abstract: We appreciate the insightful and balanced Editorial1 by Dr Konstam regarding our study.2 However, we wish to take issue with one of his statements and its implications. The Editorial states, “Over 4 weeks, in each trial, patients were allowed to have serum potassium levels as high as 6.2 mmol/L (HARMONIZE) or 6.5 mmol/L (OPAL-HK) without intervention and, apparently, they tolerated these levels without difficulty,” as well as the follow-up statement, “These findings strongly suggest that down-titration of RAASi in response to lower levels of hyperkalaemia may be unnecessarily conservative for most patients as long as potassium levels and kidney function are carefully monitored.”1 We would like to point out that in OPAL-HK,3 during the first 3 weeks of the study, patients were treated using a dosing algorithm that required increasing the patiromer dose or discontinuing the reninangiotensin-aldosterone system inhibitor (RAASi) if serum potassium was observed to be 5.5 to <6.5 mmol/L. Patients were only allowed to maintain a serum potassium in this range during a relatively short period (up to ∼9 days) of dose adjustment of either patiromer or their RAASi.3 While there were no apparent deaths related to a serum potassium ≥5.5 mmol/L during the initial 4-week treatment phase of this relatively small study,2 this does not suggest that these levels of serum potassium or even levels as low as